'On the Living and the Dead' dives into Israeli artist Hava Raucher’s fearless views on society.

Emilia Perez tells a colorful story of cartels, gender, and redemption.

On October 28, the Israeli parliament voted to ban activity from the United Nations Relief and Works Agency for Palestinian Refugees in the Near East (UNRWA) in Israel. Two bills were passed by the Knesset, Israel’s house of representatives, one that barred all UNRWA efforts, and another that prevents interactions between Israeli authorities and UNRWA […]

Remarks by Masatsugu Asakawa, President, Asian Development Bank, at the 21st Annual Meeting of the Independent Accountability Mechanisms of Multilateral Banks and International Financial Institutions, 1 October 2024, ADB headquarters, Manila, Philippines

Prime Minister Shehbaz Sharif on Tuesday said that debt cannot become the “acceptable new normal” in climate financing, as he addressed the challenges faced by developing countries within the global climate finance framework.

His statement came during a Climate Finance Round Table Conference organised by Pakistan on the sidelines of the two-day World Leaders Climate Action Summit, also known as COP29, currently being held in Azerbaijan’s capital of Baku.

“We stand at a crucial threshold where global climate finance framework must be redefined to effectively meet the needs of vulnerable nations,” PM Shehbaz said.

He explained that financing in the form of loans increases the debt of developing nations and pushes them towards “mounting debt traps” which he referred to as “death traps”.

He added, “Debt cannot become the acceptable new normal in climate financing which is why we must resume focus on non-debt financing solutions enabling countries to fund climate initiatives.”

“Despite years of promises and commitments, the gaps are growing, leading to aggregate barriers in achieving objectives of the UN Framework Convention on Climate Change (UNFCCC).”

PM Shehbaz called climate financing an “urgent need of the hour”, stating that developing countries need to deliver Nationally Determined Contributions (NDCs) and “need an estimated $6.8 trillion by 2030 to implement less than half of their current NDCs.”

The prime minister further urged donor countries to “fulfil their commitment” which is 4.7 per cent of their gross national product (GNP) and capitalise on existing climate funds.

“One such commitment is a $100bn annual climate pledge established a decade ago at COP15 [which] is now reported by OECD to have reached only $160bn,” he said.

PM Shehbaz said that Pakistan can relate to the “agony and pain of other vulnerable countries”, highlighting how the country faced two devastating floods.

“In 2022, one-third of Pakistan was under water and the country had to repurpose all development and climate funds for financing basic relief and humanitarian efforts,” he said.

Pakistan is ranked among the top 10 most climate-vulnerable countries, according to the Global Climate Risk Index 2021. It has faced increasingly frequent and severe weather events, such as unprecedented floods, intense monsoon rains, devastating heat waves, rapid glacial melting and glacial lake outburst floods.

Pakistan witnessed devastating floods during the 2022 monsoon season, induced by climate change, resulting in the loss of at least 1,700 lives.

With 33 million people affected and swathes of agricultural land washed away, the damage incurred losses worth $30 billion, according to government estimates.

In June 2024, a heat wave brought record-high temperatures, severely impacting public health and agriculture.

While emphasising transparency and coordination in financial commitments made to developing countries, he stated that Pakistan alongside other developing countries, calls for stronger more equitable climate finance mechanisms under the UNFCCC.

He reiterated the pertinent need for reform of international financial architecture saying that “now is the time to build up on the momentum for international financial reforms” so that no nation is left behind in the global response to climate change.

PM to highlight ‘balanced and ambitious’ climate action

According to the Foreign Office, several high-level events and roundtable discussions hosted by Pakistan will also take place at the Pakistan Pavilion during COP29.

It added that at COP29, Pakistan will call for “balanced and ambitious progress on all issues such as loss and damage, adaptation, mitigation and means of implementation”.

“It will seek predictable financing to address developing countries’ climate goals. Pakistan will also underscore the historical responsibility and the principle of Equity and Common but Differentiated Responsibility and call on developed nations to undertake deeper emission cuts.”

PM Shehbaz was warmly received by Azerbaijan President Ilham Aliyev and UN Secretary-General António Guterres upon his arrival at the summit venue today, state-run Radio Pakistan reported.

The first day of the Climate Action Summit will feature statements from various heads of states, beginning from 3pm Pakistan time.

Speakers include the United Kingdom’s PM Keir Starmer, Saudi Arabia’s Crown Prince Mohammed bin Salman, Turkiye President Recep Tayyip Erdoğan and Ukraine President Volodymyr Zelenskyy.

Among those scheduled to address the high-level meeting tomorrow, besides PM Shehbaz, are Bangladesh leader Muhammad Yunus and Russia’s PM Mikhail Mishustin.

PM Shehbaz is listed as the 37th speaker out of 47 leaders during the session scheduled from 10am to 6pm (Pakistan time).

The prime minister will also participate in a high-level event ‘Glaciers 2025: Actions for Glaciers’ organised by Tajikistan President Emomali Rahmon on the protection of glaciers.

PM Shehbaz will also hold separate meetings with the prime ministers of Denmark and the Czech Republic, who are also attending COP-29, Radio Pakistan stated.

PM meets world leaders

On the sidelines of COP29, PM Shehbaz interacted with UAE President Sheikh Mohammed bin Zayed Al Nahyan and discussed cooperation on climate change and matters of mutual interest, Radio Pakistan reported.

The premier also met with PM Starmer, where the two discussed enhancing Pakistan-UK cooperation.

He also met with Turkish President Recep Tayyip Erdogan and his wife Emine Erdogan, where they discussed environmental pollution as well as matters of mutual interest between the two friendly nations, the report added.

In his interactions with Nepal’s President Ramchandra Paudel and Bangladesh’s Yunus, PM Shehbaz discussed growing temperatures, the threat of rising sea levels, and forest conservation in South Asia.

Kazakhstan President Kassym-Jomart Tokayev and PM Shehbaz explored strengthening bilateral relations as well as expanding regional connectivity.

In his meetings with Uzbekistan President Shavkat Mirziyoyev and Tajikistan’s Rahmon, the leaders spoke about the conservation of glaciers and water resources in Central Asian countries and Pakistan.

They also exchanged views on expanding communication links among Pakistan, Tajikistan and Uzbekistan, Radio Pakistan highlighted.

World leaders meet for climate talks, but big names missing

Dozens of world leaders convene in Azerbaijan for COP29 but many big names are skipping the UN climate talks where the impact of Donald Trump’s election victory is keenly felt.

UK’s Starmer will unveil an “ambitious” update to the UK’s climate goals later today, and said he wanted his country “to show leadership on the climate challenge.”

Joe Biden, Xi Jinping, Narendra Modi and Emmanuel Macron are among G20 leaders missing the event, where uncertainty over future US unity on climate action hung over the opening day.

“It’s not an ideal situation,” acknowledged Steven Guilbeault, Canada’s environment minister. “But in 30 years of COP, it’s not the first time that we’ve faced obstacles,” he told AFP.

“Certainly, everything is still possible.”

Washington’s top climate envoy John Podesta is seeking to reassure countries in Baku that Trump’s re-election will not end US efforts on global warming, even if the issue will be “on the back burner”.

But despite calls for global cooperation, the opening day got off to a rocky start, with feuds over the official agenda delaying by hours the start of formal proceedings in the stadium venue near the Caspian Sea.

“This will be a tough COP,” said Fernanda Carvalho, global climate and energy policy lead at WWF.

“Countries are divided. There is a lack of trust,” she told AFP, and divisions over climate finance “will be reflected in every room of those negotiations.”

Our gardening columnist James Wong isn’t convinced, and does the maths to get some answers

Fishers in Albania caught a blue shark with an 18-centimetre fragment of swordfish bill embedded in its skull, in the first known case of a shark surviving such an injury

Experiments where vampire bats were made to run on a treadmill have revealed how they extract energy from protein in their latest blood meal

Experiments where vampire bats were made to run on a treadmill have revealed how they extract energy from protein in their latest blood meal

New archaeological evidence shows that ancient humans ate each other surprisingly often - sometimes for compassionate reasons. The finds give us an opportunity to reassess our views on the practice

Title: What Happens to Metabolism in Fasting?
Category: Health and Living
Created: 8/26/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM

We propose a paper that provides education on commonly used long-acting injectable antipsychotics (LAIs) to improve primary care based mental health interventions in patients with severe mental illnesses (SMIs) such as schizophrenia, schizoaffective disorder, and bipolar disorders. With the expanding interface of primary care and psychiatry across all healthcare settings, it has become increasingly important for primary care clinicians to have a broader understanding of common psychiatric treatments, including LAIs. Long-acting injectable antipsychotics have been shown to be helpful in significantly improving treatment adherence, preventing disease progression, improving treatment response, decreasing readmission rates, and reducing social impairment. We discuss evidence-based indications and guidelines for use of long-acting injectable antipsychotics. We provide an overview of the treatment of SMI with LAIs, mainly focusing on the most commonly used long-acting injectable antipsychotics, advantages and disadvantages of each, along with outlining important clinical pearls for ease of practical application. Equipped with increased familiarity and understanding of these essential therapies, primary care clinicians can better facilitate early engagement with psychiatric care, promote more widespread use, and thus significantly improve the wellbeing and quality of life of patients with severe mental illness.

Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.

The noncoding RNA BC200 is elevated in human cancers and is implicated in translation regulation as well as cell survival and proliferation. Upon BC200 overexpression, we observed correlated expression of a second, smaller RNA species. This RNA is expressed endogenously and exhibits cell-type-dependent variability relative to BC200. Aptamer-tagged expression constructs confirmed that the RNA is a truncated form of BC200, and sequencing revealed a modal length of 120 nt; thus, we refer to the RNA fragment as BC120. We present a methodology for accurate and specific detection of BC120 and establish that BC120 is expressed in several normal human tissues and is also elevated in ovarian cancer. BC120 exhibits remarkable stability relative to BC200 and is resistant to knockdown strategies that target the 3' unique sequence of BC200. Combined knockdown of BC200 and BC120 exhibits greater phenotypic impacts than knockdown of BC200 alone, and overexpression of BC120 negatively impacts translation of a GFP reporter, providing insight into a potential translational regulatory role for this RNA. The presence of a novel, truncated, and stable form of BC200 adds complexity to the investigation of this noncoding RNA that must be considered in future studies of BC200 and other related Alu RNAs.

The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases, including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.

Background

Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting.

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long noncoding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has four annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the small interfering RNAs or small hairpin RNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, four annotated and two newly identified transcripts were confirmed. These six transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism.

Exogenous substances, including drugs and chemicals, can transfer into human seminal fluid and influence male fertility and reproduction. In addition, substances relevant in the context of sports drug testing programs, can be transferred into the urine of a female athlete (after unprotected sexual intercourse) and trigger a so-called adverse analytical finding. Here, the question arises as to whether it is possible to distinguish analytically between intentional doping offenses and unintentional contamination of urine by seminal fluid. To this end, 480 seminal fluids from nonathletes were analyzed to identify concentration ranges and metabolite profiles of therapeutic drugs that are also classified as doping agents. Therefore, a screening procedure was developed using liquid chromatography connected to a triple quadrupole mass spectrometer, and suspect samples (i.e., samples indicating the presence of relevant compounds) were further subjected to liquid chromatography-high-resolution accurate mass (tandem) mass spectrometry. The screening method yielded 90 findings (including aromatase inhibitors, selective estrogen receptor modulators, diuretics, stimulants, glucocorticoids, beta-blockers, antidepressants, and the nonapproved proliferator-activated receptor delta agonist GW1516) in a total of 81 samples, with 91% of these suspected cases being verified by the confirmation method. In addition to the intact drug, phase-I and -II metabolites were also occasionally observed in the seminal fluid. This study demonstrated that various drugs including those categorized as doping agents partition into seminal fluid. Monitoring substances and metabolites may contribute to a better understanding of the distribution and metabolism of exogenous substances in seminal fluid that may be responsible for the impairment of male fertility.

ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a membrane-bound transporter responsible for the efflux of various xenobiotics and endobiotics, including protoporphyrin IX (PPIX), an intermediate in the heme biosynthesis pathway. Certain genetic mutations and chemicals impair the conversion of PPIX to heme and/or increase PPIX production, leading to PPIX accumulation and toxicity. In mice, deficiency of ABCG2 protects against PPIX-mediated phototoxicity and hepatotoxicity by modulating PPIX distribution. In addition, in vitro studies revealed that ABCG2 inhibition increases the efficacy of PPIX-based photodynamic therapy by retaining PPIX inside target cells. In this review, we discuss the roles of ABCG2 in modulating the tissue distribution of PPIX, PPIX-mediated toxicity, and PPIX-based photodynamic therapy.

The regulation of drug-metabolizing enzymes and transporters by cytokines has been extensively studied in vitro and in clinic. Cytokine-mediated suppression of cytochrome P450 (CYP) or drug transporters may increase or decrease the systemic clearance of drug substrates that are primarily cleared via these pathways; neutralization of cytokines by therapeutic proteins may thereby alter systemic exposures of such drug substrates. The Food and Drug Administration recommends evaluating such clinical drug interactions during clinical development and has provided labeling recommendations for therapeutic proteins. To determine the clinical relevance of these drug interactions to dose adjustments, trends in steady-state exposures of CYP-sensitive substrates coadministered with cytokine modulators as reported in the University of Washington Drug Interaction Database were extracted and examined for each of the CYPs. Coadministration of cytochrome P450 family 3 subfamily A (CYP3A) (midazolam/simvastatin), cytochrome P450 subfamily 2C19 (omeprazole), or cytochrome P450 subfamily 1A2 (caffeine/tizanidine) substrates with anti-interleukin-6 and with anti-interleukin-23 therapeutics led to changes in systemic exposures of CYP substrates ranging from ~ –58% to ~35%; no significant trends were observed for cytochrome P450 subfamily 2D6 (dextromethorphan) and cytochrome P450 subfamily 2C9 (warfarin) substrates. Although none of these changes in systemic exposures have been reported as clinically meaningful, dose adjustment of midazolam for optimal sedation in acute care settings has been reported. Simulated concentration-time profiles of midazolam under conditions of elevated cytokine levels when coadministered with tocilizumab, suggest a ~six- to sevenfold increase in midazolam clearance, suggesting potential implications of cytokine–CYP drug interactions on dose adjustments of sensitive CYP3A substrates in acute care settings. Additionally, this article also provides a brief overview of nonclinical and clinical assessments of cytokine–CYP drug interactions in drug discovery and development.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

Drug–drug interaction (DDI) assessment of therapeutic peptides is an evolving area. The industry generally follows DDI guidelines for small molecules, but the translation of data generated with commonly used in vitro systems to in vivo is sparse. In the current study, we investigated the ability of advanced human hepatocyte in vitro systems, namely HepatoPac, spheroids, and Liver-on-a-chip, to assess potential changes in regulation of CYP1A2, CYP2B6, CYP3A4, SLCO1B1, and ABCC2 in the presence of selected therapeutic peptides, proteins, and small molecules. The peptide NN1177, a glucagon and GLP-1 receptor co-agonist, did not suppress mRNA expression or activity of CYP1A2, CYP2B6, and CYP3A4 in HepatoPac, spheroids, or Liver-on-a-chip; these findings were in contrast to the data obtained in sandwich cultured hepatocytes. No effect of NN1177 on SLCO1B1 and ABCC2 mRNA was observed in any of the complex systems. The induction magnitude differed across the systems (e.g., rifampicin induction of CYP3A4 mRNA ranged from 2.8-fold in spheroids to 81.2-fold in Liver-on-a-chip). Small molecules, obeticholic acid and abemaciclib, showed varying responses in HepatoPac, spheroids, and Liver-on-a-chip, indicating a need for EC₅₀ determinations to fully assess translatability data. HepatoPac, the most extensively investigated in this study (3 donors), showed high potential to investigate DDIs associated with CYP regulation by therapeutic peptides. Spheroids and Liver-on-a-chip were only assessed in one hepatocyte donor and further evaluations are required to confirm their potential. This study establishes an excellent foundation toward the establishment of more clinically-relevant in vitro tools for evaluation of potential DDIs with therapeutic peptides.

Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, , and ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ~100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system.

ABSTRACTToxicological emergencies present a significant health challenge in Nepal. Despite the high burden, the country has inadequate formal toxicology training, medical toxicology expertise, and adequate poison control infrastructure. In recognition of this need, the Nepal Poison Information Center (PIC) was established as a collaborative effort involving local and international partners. Through a comprehensive partnership framework, the Nepal PIC provides 24 hours a day, 7 days a week expert guidance to health care workers, conducts educational webinars, and engages in research. Initial data from the pilot phase indicate successful consultation delivery. Challenges include bureaucratic hurdles and the need for sustainable funding. Despite these challenges, the Nepal PIC demonstrates early feasibility and potential for expansion into a comprehensive toxicology center, contributing to the advancement of clinical toxicology in Nepal. Long-term sustainability relies on governmental support and continued advocacy efforts.

ABSTRACTMore than half of births among Indigenous women in Guatemala are still being attended at home by providers with no formal training. We describe the incorporation of comadronas (traditional midwives) into casas maternas (birthing centers) in the rural highlands of western Guatemala. Although there was initial resistance to the casa, comadronas and clients have become increasingly enthusiastic about them. The casas provide the opportunity for comadronas to continue the cultural traditions of prayers, massages, and other practices that honor the vital spiritual dimension of childbirth close to home in a home-like environment with extended family support while at the same time providing a safer childbirth experience in which complications can be detected by trained personnel at the casa, managed locally, or promptly referred to a higher-level facility. Given the growing acceptance of this innovation in an environment in which geographical, financial, and cultural barriers to deliveries at higher-level facilities lead most women to deliver at home, casas maternas represent a feasible option for reducing the high level of maternal mortality in Guatemala.This article provides an update on the growing utilization of casas and provides new insights into the role of comadronas as birthing team members and enthusiastic promotors of casas maternas as a preferable alternative to home births. Through the end of 2023, these casas maternas had cared for 4,322 women giving birth. No maternal deaths occurred at a casa, but 4 died after referral.The Ministry of Health of Guatemala has recently adopted this approach and has begun to implement it in other rural areas where home births still predominate. This approach deserves consideration as a viable and feasible option for reducing maternal mortality throughout the world where home births are still common, while at the same time providing women with respectful and culturally appropriate care.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro–in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

BACKGROUND AND PURPOSE:

Low-field 64 mT portable brain MRI has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of portable MRI (pMRI) in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI.

BACKGROUND AND PURPOSE:

Prediction of aneurysm instability is crucial to guide treatment decisions and to select appropriate patients with unruptured intracranial aneurysms (IAs) for preventive treatment. High-resolution 4D MR flow imaging and 3D quantification of aneurysm morphology could offer insights and new imaging markers for aneurysm instability. In this cross-sectional study, we aim to identify 4D MR flow imaging markers for aneurysm instability by relating hemodynamics in the aneurysm sac to 3D morphologic proxy parameters for aneurysm instability.

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1⁺ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs. Appropriate testing may be predictive of outcome and inform the utility of targeted therapy in these genetically diverse and historically treatment-refractory malignancies.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.

The Nintendo Switch was the best-selling console in Japan with 241,803 units sold for October 2024, according to VGChartz estimates. The Nintendo Switch has now sold an estimated 34.30 million units lifetime in Japan.

The PlayStation 5 sold an estimated 49,056 units to bring its lifetime sales to 6.12 million units. The Xbox Series X|S sold 5,862 units to bring their lifetime sales to 0.64 million units. The PlayStation 4 sold an estimated 162 units to bring its lifetime sales to 9.68 million units.

PS5 sales compared to the same month for the PS4 in 2017 are down by nearly 53,000 units, while the Xbox Series X|S compared to the same month for the Xbox One are up by over 5,000 units. PS4 sold 101,851 units for the month of October 2017 and Xbox One sales were at 563 units.

Nintendo Switch sales compared to the same month a year ago are down by 41,368 units (-14.6%). PlayStation 5 sales are down by 17,208 (-26.0%) and Xbox Series X|S sales are down by 2,294 units (-28.1%). The PlayStation 4 is down by 5,362 units (-97.1%) year-over-year.

Looking at sales month-on-month, Nintendo Switch sales are down up nearly 67,000 units, the PlayStation 5 sales are down by over 4,000 units, and Xbox Series X|S sales are up by over 2,000 units.

2024 year-to-date, the Nintendo Switch has sold an estimated 2.47 million units, the PlayStation 5 has sold 1.16 million units, and the Xbox Series X|S has sold 0.09 million units.

Monthly Sales:

Japan hardware estimates for October 2024 (Followed by lifetime sales):

1. Switch - 241,803 (34,300,699)
2. PlayStation 5 - 49,056 (6,121,649)
3. Xbox Series X|S - 5,862 (636,764)
4. PlayStation 4 - 162 (9,679,626)

Weekly Sales:

Japan October 12, 2024 hardware estimates:

1. Switch - 55,097
2. PlayStation 5 - 11,810
   
3. Xbox Series X|S - 429
4. PlayStation 4 - 31

Japan October 19, 2024 hardware estimates:

1. Switch - 58,866
2. PlayStation 5 - 11,324
3. Xbox Series X|S - 1,612
4. PlayStation 4 - 36

Japan October 26, 2024 hardware estimates:

1. Switch - 67,736
2. PlayStation 5 - 11,951
3. Xbox Series X|S - 1,207
4. PlayStation 4 - 40

Japan November 2, 2024 hardware estimates:

1. Switch - 60,104
2. PlayStation 5 - 13,971
3. Xbox Series X|S - 2,614
4. PlayStation 4 - 55

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463008/switch-comfortably-best-seller-japan-hardware-estimates-for-october-2024/

Disaster was averted at a Kentucky hospital when an ostensibly deceased organ donor began “thrashing” around in the operating theater, a preservationist tells NPR.

“He was moving around,” Natasha Miller recalled of the patient, whom NPR identified as Anthony Thomas “TJ” Hoover II. “He was crying visibly.”

The two surgeons assigned to the transplant naturally refused to go through with the procedure, which was reportedly scheduled to take place at Baptist Health Richmond Hospital in October 2021. But when her colleague called Kentucky Organ Donor Affiliates, which coordinated the harvest, Miller said the supervisor told them they “were going to do the case” and needed to “find another doctor.”

Read more at The Daily Beast.

If we want to terraform the Red Planet to make it better able to host microbial life, tiny rods of iron and aluminium may be the answer

A 6000-kilogram spacecraft will embark on a six-year journey to Jupiter to explore whether its icy moon Europa has the conditions to support life

Google DeepMind has been using its AI watermarking method on Gemini chatbot responses for months – and now it’s making the tool available to any AI developer

Video Friday is your weekly selection of awesome robotics videos, collected by your friends at IEEE Spectrum robotics. We also post a weekly calendar of upcoming robotics events for the next few months. Please send us your events for inclusion.

ICRA@40: 23–26 September 2024, ROTTERDAM, NETHERLANDS

IROS 2024: 14–18 October 2024, ABU DHABI, UAE

ICSR 2024: 23–26 October 2024, ODENSE, DENMARK

Cybathlon 2024: 25–27 October 2024, ZURICH

Enjoy today’s videos!

Imbuing robots with “human-level performance” in anything is an enormous challenge, but it’s worth it when you see a robot with the skill to interact with a human on a (nearly) human level. Google DeepMind has managed to achieve amateur human-level competence at table tennis, which is much harder than it looks, even for humans. Pannag Sanketi, a tech-lead manager in the robotics team at DeepMind, shared some interesting insights about performing the research. But first, video!

Some behind the scenes detail from Pannag:

• The robot had not seen any participants before. So we knew we had a cool agent, but we had no idea how it was going to fare in a full match with real humans. To witness it outmaneuver even some of the most advanced players was such a delightful moment for team!
• All the participants had a lot of fun playing against the robot, irrespective of who won the match. And all of them wanted to play more. Some of them said it will be great to have the robot as a playing partner. From the videos, you can even see how much fun the user study hosts sitting there (who are not authors on the paper) are having watching the games!
• Barney, who is a professional coach, was an advisor on the project, and our chief evaluator of robot’s skills the way he evaluates his students. He also got surprised by how the robot is always able to learn from the last few weeks’ sessions.
• We invested a lot in remote and automated 24x7 operations. So not the setup in this video, but there are other cells that we can run 24x7 with a ball thrower.
• We even tried robot-vs-robot, i.e. 2 robots playing against each other! :) The line between collaboration and competition becomes very interesting when they try to learn by playing with each other.

[ DeepMind ]

Thanks, Heni!

Yoink.

[ MIT ]

Considering how their stability and recovery is often tested, teaching robot dogs to be shy of humans is an excellent idea.

[ Deep Robotics ]

Yes, quadruped robots need tow truck hooks.

[ Paper ]

Earthworm-inspired robots require novel actuators, and Ayato Kanada at Kyushu University has come up with a neat one.

[ Paper ]

Thanks, Ayato!

Meet the AstroAnt! This miniaturized swarm robot can ride atop a lunar rover and collect data related to its health, including surface temperatures and damage from micrometeoroid impacts. In the summer of 2024, with support from our collaborator Castrol, the Media Lab’s Space Exploration Initiative tested AstroAnt in the Canary Islands, where the volcanic landscape resembles the lunar surface.

[ MIT ]

Kengoro has a new forearm that mimics the human radioulnar joint giving it an even more natural badminton swing.

[ JSK Lab ]

Thanks, Kento!

Gromit’s concern that Wallace is becoming too dependent on his inventions proves justified, when Wallace invents a “smart” gnome that seems to develop a mind of its own. When it emerges that a vengeful figure from the past might be masterminding things, it falls to Gromit to battle sinister forces and save his master… or Wallace may never be able to invent again!

[ Wallace and Gromit ]

ASTORINO is a modern 6-axis robot based on 3D printing technology. Programmable in AS-language, it facilitates the preparation of classes with ready-made teaching materials, is easy both to use and to repair, and gives the opportunity to learn and make mistakes without fear of breaking it.

[ Kawasaki ]

Engineers at NASA’s Jet Propulsion Laboratory are testing a prototype of IceNode, a robot designed to access one of the most difficult-to-reach places on Earth. The team envisions a fleet of these autonomous robots deploying into unmapped underwater cavities beneath Antarctic ice shelves. There, they’d measure how fast the ice is melting — data that’s crucial to helping scientists accurately project how much global sea levels will rise.

[ IceNode ]

Los Alamos National Laboratory, in a consortium with four other National Laboratories, is leading the charge in finding the best practices to find orphaned wells. These abandoned wells can leak methane gas into the atmosphere and possibly leak liquid into the ground water.

[ LANL ]

Looks like Fourier has been working on something new, although this is still at the point of “looks like” rather than something real.

[ Fourier ]

Bio-Inspired Robot Hands: Altus Dexterity is a collaboration between researchers and professionals from Carnegie Mellon University, UPMC, the University of Illinois and the University of Houston.

[ Altus Dexterity ]

PiPER is a lightweight robotic arm with six integrated joint motors for smooth, precise control. Weighing just 4.2kg, it easily handles a 1.5kg payload and is made from durable yet lightweight materials for versatile use across various environments. Available for just $2,499 USD.

[ AgileX ]

At 104 years old, Lilabel has seen over a century of automotive transformation, from sharing a single car with her family in the 1920s to experiencing her first ride in a robotaxi.

[ Zoox ]

Traditionally, blind juggling robots use plates that are slightly concave to help them with ball control, but it’s also possible to make a blind juggler the hard way. Which, honestly, is much more impressive.

[ Jugglebot ]

Video Friday is your weekly selection of awesome robotics videos, collected by your friends at IEEE Spectrum robotics. We also post a weekly calendar of upcoming robotics events for the next few months. Please send us your events for inclusion.

ICRA@40: 23–26 September 2024, ROTTERDAM, NETHERLANDS

IROS 2024: 14–18 October 2024, ABU DHABI, UAE

ICSR 2024: 23–26 October 2024, ODENSE, DENMARK

Cybathlon 2024: 25–27 October 2024, ZURICH

Enjoy today’s videos!

Researchers at the Max Planck Institute for Intelligent Systems and ETH Zurich have developed a robotic leg with artificial muscles. Inspired by living creatures, it jumps across different terrains in an agile and energy-efficient manner.

[ Nature ] via [ MPI ]

Thanks, Toshi!

ETH Zurich researchers have now developed a fast robotic printing process for earth-based materials that does not require cement. In what is known as “impact printing,” a robot shoots material from above, gradually building a wall. On impact, the parts bond together, and very minimal additives are required.

[ ETH Zurich ]

How could you not be excited to see this happen for real?

[ arXiv paper ]

Can we all agree that sanding, grinding, deburring, and polishing tasks are really best done by robots, for the most part?

[ Cohesive Robotics ]

Thanks, David!

Using doors is a longstanding challenge in robotics and is of significant practical interest in giving robots greater access to human-centric spaces. The task is challenging due to the need for online adaptation to varying door properties and precise control in manipulating the door panel and navigating through the confined doorway. To address this, we propose a learning-based controller for a legged manipulator to open and traverse through doors.

[ arXiv paper ]

Isaac is the first robot assistant that’s built for the home. And we’re shipping it in fall of 2025.

Fall of 2025 is a long enough time from now that I’m not even going to speculate about it.

[ Weave Robotics ]

By patterning liquid metal paste onto a soft sheet of silicone or acrylic foam tape, we developed stretchable versions of conventional rigid circuits (like Arduinos). Our soft circuits can be stretched to over 300% strain (over 4x their length) and are integrated into active soft robots.

[ Science Robotics ] via [ Yale ]

NASA’s Curiosity rover is exploring a scientifically exciting area on Mars, but communicating with the mission team on Earth has recently been a challenge due to both the current season and the surrounding terrain. In this Mars Report, Curiosity engineer Reidar Larsen takes you inside the uplink room where the team talks to the rover.

[ NASA ]

I love this and want to burn it with fire.

[ Carpentopod ]

Very often, people ask us what Reachy 2 is capable of, which is why we’re showing you the manipulation possibilities (through teleoperation) of our technology. The robot shown in this video is the Beta version of Reachy 2, our new robot coming very soon!

[ Pollen Robotics ]

The Scalable Autonomous Robots (ScalAR) Lab is an interdisciplinary lab focused on fundamental research problems in robotics that lie at the intersection of robotics, nonlinear dynamical systems theory, and uncertainty.

[ ScalAR Lab ]

Astorino is a 6-axis educational robot created for practical and affordable teaching of robotics in schools and beyond. It has been created with 3D printing, so it allows for experimentation and the possible addition of parts. With its design and programming, it replicates the actions of #KawasakiRobotics industrial robots, giving students the necessary skills for future work.

[ Astorino ]

I guess fish-fillet-shaping robots need to exist because otherwise customers will freak out if all their fish fillets are not identical, or something?

[ Flexiv ]

Watch the second episode of the ExoMars Rosalind Franklin rover mission—Europe’s ambitious exploration journey to search for past and present signs of life on Mars. The rover will dig, collect, and investigate the chemical composition of material collected by a drill. Rosalind Franklin will be the first rover to reach a depth of up to two meters below the surface, acquiring samples that have been protected from surface radiation and extreme temperatures.

[ ESA ]

The Tablelands in Gros Morne National Park, a UNESCO World Heritage Site, is one of the most unique landscapes in the world — and its orange peridotite rocks could hold the secret to finding life on Mars.

Other Windows Insider updates include new CPU instructions for Prism x86 emulator.