Pamela Coke-Hamilton, Director, Division on International Trade and Commodities, UN Conference on Trade & Development (UNCTAD)

The post Impact of COVID-19 on Tourism in Small Island Developing States appeared first on Inter Press Service.

The finance ministry has slashed €367 million from public expenditure as part of a revision of the 2020 state budget amid the coronavirus crisis. The government savings were passed by the Council of Ministers. Giorgos Panteli, permanent secretary of the finance ministry, told the Cyprus News Agency that the savings...

The post Coronavirus: Government slashes spending by €367 million appeared first on Cyprus Mail.

Eight-time Grand Slam winner Ivan Lendl said whoever ends up winning the most majors among the ‘Big Three’ of Roger Federer, Rafa Nadal and Novak Djokovic should be considered the greatest male tennis player of the Open era. The ‘GOAT’ (greatest of all time) debate in men’s tennis has divided...

The post Grand Slam tally should decide ‘GOAT’ debate, says Lendl appeared first on Cyprus Mail.

Sona Mohapatra recently called out controversial filmmaker Ram Gopal Varma after he made a sexist remark

1

The stuntwoman died while filming a scene for an actress

The Environment Ministry is fining Mercedes-Benz W77.6 billion for illegally tampering with emissions tests, the biggest fine ever for a carmaker here (US$1=W1,225). The ministry on Wednesday said Mercedes-Benz, Nissan and Porsche tampered with the emissions of around 40,000 diesel cars sold in Kore...

KARACHI: Afghan Taliban chief Mullah Akhtar Mansour’s five properties, estimated to be worth over Rs32 million and purchased by him in Karachi by using fake identities, have been taken over by the anti-terrorism court for auction, sources told Dawn on Thursday.

The FIA had booked Mullah Mansour, aliases Mohammad Wali and Gul Mohammad, Akhtar Mohammad and Amaar in a case lodged under Section 11H (pertaining to fundraising and money laundering) of the Anti-Terrorism Act, 1997, read with sections 420 (cheating and dishonestly inducing delivery of property), 468 (forgery for purpose of cheating) and 471 (using as genuine a forged document) of the Pakistan Penal Code.

Mullah Mansour, who was killed in a drone strike along the Pakistan-Iran border on May 21, 2016, had purchased five properties, including plots and houses, in Karachi.

This revelation came in a report submitted by the Federal Investigation Agency to the ATC-II in July last year regarding an investigation into a case related to alleged fundraising by the slain Afghan Taliban leader and his accomplices through the purchase of properties on the back of forged identities.

Mullah Akhtar Mansour bought Rs32m properties in Karachi using fake identities

Since January, the court had been directing the investigation officer (IO) to complete the process of attachment of Mullah Mansour’s properties and proclamation of his two alleged absconding accomplices — Akhtar Mohammad and Amaar — under sections 87 and 88 of the Criminal Procedure Code.

On April 24, the court had ordered the Nazir (a court official) to take over the properties of Mullah Mansour after the IO submitted a compliance report regarding completion of the attachment process of the properties by the Federal Investigation Agency.

The court had ordered the Nazir to auction those properties and get advertisements published in newspapers.

When the matter came up before the ATC-II judge recently, the court’s Nazir filed a report regarding seizure of property owned by Mullah Akhtar Mansour on behalf of the court.

The judge asked the Nazir to file a report about publication of the auction advertisement in newspapers on the next date of hearing.

The judge granted a request by Rehmatullah Domki, the investigation officer, to hear the case next month. She scheduled a hearing from June 11.

During a previous hearing, the IO had informed the court that the FIA had unearthed five properties purchased by the Taliban leader before his death. An estimated value of the properties is Rs32 million.

The court had already called for reports from the commissioners of Peshawar and Quetta regarding the process of proclamation of Mullah Mansour’s alleged absconding accomplices and attachment of their properties.

Published in Dawn, May 8th, 2020

"Nigeria is a secular state and freedom of speech is one of the fundamental characteristics of a modern democratic state. Criticizing a religion is not a criminal offence."

Since the start of India's COVID-19 lockdown on March 25, 2020, instances of Islamophobia have intensified, threatening the life, rights, and integrity of millions of Muslims.

ADB today announced the release of a $6 million grant from its Pacific Disaster Resilience Program (Phase 2) to help finance the Government of the Marshall Islands’ response to the novel coronavirus disease (COVID-19) pandemic.

ADB today announced the release of a $3 million grant and a $3 million concessional loan from its Pacific Disaster Resilience Program (Phase 2) to help finance the Government of Solomon Islands’ response to the COVID-19...

The project aimed to construct the Fiu River hydropower plant and extend the distribution grid to peri-urban households in the main provincial center of Auki in Solomon Islands. Hydropower generation was to benefit the economy by reducing fossil fuel imports and lowering the cost of power generation. Likewise, it was intended to improve energy security and minimize tariff volatility. The use of renewable energy was also aimed at reducing greenhouse gas emissions. This report validates the completion report's assessment of the project. IED overall assessment: Unsuccessful. 

13 lawyers from our Singapore office have volunteered and been appointed to serve as assessors under temporary COVID-19 legislation. 

ADB’s Transport Sector Flood Recovery Project helped reinstate bridge approach roads, culverts, and stream crossings and rebuilt three elevated bridges, reestablishing a seamless east–west road link on Guadalcanal and within Honiara. All works incorporated climate- and disaster-proof design.

Thanks to investment from Australia and ADB, a new clean water plant in Ebeye, in the north-west corner of the Marshall Islands, is changing lives.

It may not be the biggest in the world, but the Faroe Islands' Betri League will for once be in the spotlight when its season kicks off on Saturday.

Nigerian comedian Maryam Apaokagi has a sure-fire way of getting people to listen to her coronavirus health advice - she delivers it with a hard slap in the face.

The steep plunge in U.S. payrolls caused by the pandemic also slammed the healthcare sector, as many workers in dentists' and doctors' offices lost their jobs. Fred Katayama reports.

The remote Fijian island of Cicia has launched a novel business in organic produce that could prove to be a template for other developing communities around the world. The island declared itself chemical free and fully organic eight years ago and is now producing food that's attracting the interest of foreign buyers. Tara Cleary reports.

The landscape of Banks Island in the far north of Canada is being reshaped by global warming-triggered land slumps, and the situation is set to get much worse

To find subjects to photograph, Kacper Kowalski takes to the air in a paramotor or gyrocopter, barely steering to allow the wind to dictate the direction

This week, catch the last few days of an art show that gives mothers their due, explore a land of orchids and discover how loving maths makes us better people

Eight-time Grand Slam winner Ivan Lendl said whoever ends up winning the most majors among the 'Big Three' of Roger Federer, Rafa Nadal and Novak Djokovic should be considered the greatest male tennis player of the Open era.

The Metropolitan Museum of Art in New York leads Islamic art tours to improve understanding of its contributions to the world heritage. Fred Katayama reports.

Hurricane Irma’s deadly tear through the Caribbean will hobble the region’s multi-billion dollar tourism industry for months, just as hotels, airlines, and cruises were gearing up for the region’s peak winter season.

Rival lawmakers scuffled in Hong Kong's legislature on Friday in a row over electing the chairman of a key committee, a fresh sign of rising political tension as the coronavirus pandemic tapers off in the Chinese-ruled city. Francesca Lynagh reports.

The remains of three slaves found in Mexico contain the earliest signs of the hepatitis B virus and yaws bacteria in the Americas, suggesting transatlantic slavery introduced these diseases

The steep plunge in U.S. payrolls caused by the pandemic also slammed the healthcare sector, as many workers in dentists' and doctors' offices lost their jobs. Fred Katayama reports.

Title: Does Dopamine Explain Why Slackers Slack?
Category: Health News
Created: 5/2/2012 11:00:00 AM
Last Editorial Review: 5/2/2012 12:00:00 AM

Title: New Drug Class Slashes 'Bad' Cholesterol, Review Finds
Category: Health News
Created: 4/27/2015 12:00:00 AM
Last Editorial Review: 4/28/2015 12:00:00 AM

Title: Reading to Babies Translates Into More Literate Preschoolers
Category: Health News
Created: 5/4/2017 12:00:00 AM
Last Editorial Review: 5/5/2017 12:00:00 AM

ABSTRACT

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris. These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans. Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen.

IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans. Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.

ABSTRACT

Bacteria that encounter antibiotics can efficiently change their physiology to develop resistance. This intrinsic antibiotic resistance is mediated by multiple pathways, including a regulatory system(s) that activates specific genes. In some Streptomyces and Mycobacterium spp., the WblC/WhiB7 transcription factor is required for intrinsic resistance to translation-targeting antibiotics. Wide conservation of WblC/WhiB7 within Actinobacteria indicates a critical role of WblC/WhiB7 in developing resistance to such antibiotics. Here, we identified 312 WblC target genes in Streptomyces coelicolor, a model antibiotic-producing bacterium, using a combined analysis of RNA sequencing and chromatin immunoprecipitation sequencing. Interestingly, WblC controls many genes involved in translation, in addition to previously identified antibiotic resistance genes. Moreover, WblC promotes translation rate during antibiotic stress by altering the ribosome-associated protein composition. Our genome-wide analyses highlight a previously unappreciated antibiotic resistance mechanism that modifies ribosome composition and maintains the translation rate in the presence of sub-MIC levels of antibiotics.

IMPORTANCE The emergence of antibiotic-resistant bacteria is one of the top threats in human health. Therefore, we need to understand how bacteria acquire resistance to antibiotics and continue growth even in the presence of antibiotics. Streptomyces coelicolor, an antibiotic-producing soil bacterium, intrinsically develops resistance to translation-targeting antibiotics. Intrinsic resistance is controlled by the WblC/WhiB7 transcription factor that is highly conserved within Actinobacteria, including Mycobacterium tuberculosis. Here, identification of the WblC/WhiB7 regulon revealed that WblC/WhiB7 controls ribosome maintenance genes and promotes translation in the presence of antibiotics by altering the composition of ribosome-associated proteins. Also, the WblC-mediated ribosomal alteration is indeed required for resistance to translation-targeting antibiotics. This suggests that inactivation of the WblC/WhiB7 regulon could be a potential target to treat antibiotic-resistant mycobacteria.

To better the health of all North Carolinians, policymakers must come together to improve access to care, expand broadband, and close the coverage gap.

Current health inequities are rooted in more than simple systems failures and inefficiencies. Historical legacy has corrupted health outcomes, and resolution requires both acknowledgment and intention.

The chloroplast glutamyl-tRNA (tRNA^Glu) is unique in that it has two entirely different functions. In addition to acting in translation, it serves as the substrate of glutamyl-tRNA reductase (GluTR), the enzyme catalyzing the committed step in the tetrapyrrole biosynthetic pathway. How the tRNA^Glu pool is distributed between the two pathways and whether tRNA^Glu allocation limits tetrapyrrole biosynthesis and/or protein biosynthesis remains poorly understood. We generated a series of transplastomic tobacco (Nicotiana tabacum) plants to alter tRNA^Glu expression levels and introduced a point mutation into the plastid trnE gene, which has been reported to uncouple protein biosynthesis from tetrapyrrole biosynthesis in chloroplasts of the protist Euglena gracilis. We show that, rather than comparable uncoupling of the two pathways, the trnE mutation is lethal in tobacco because it inhibits tRNA processing, thus preventing translation of Glu codons. Ectopic expression of the mutated trnE gene uncovered an unexpected inhibition of glutamyl-tRNA reductase by immature tRNA^Glu. We further demonstrate that whereas overexpression of tRNA^Glu does not affect tetrapyrrole biosynthesis, reduction of GluTR activity through inhibition by tRNA^Glu precursors causes tetrapyrrole synthesis to become limiting in early plant development when active photosystem biogenesis provokes a high demand for de novo chlorophyll biosynthesis. Taken together, our findings provide insight into the roles of tRNA^Glu at the intersection of protein biosynthesis and tetrapyrrole biosynthesis.

Legionella pneumophila, the etiological agent of Legionnaires’ disease, employs an arsenal of hundreds of Dot/Icm-translocated effector proteins to facilitate replication within eukaryotic phagocytes. Several effectors, called metaeffectors, function to regulate the activity of other Dot/Icm-translocated effectors during infection. The metaeffector Lpg2505 is essential for L. pneumophila intracellular replication only when its cognate effector, SidI, is present. SidI is a cytotoxic effector that interacts with the host translation factor eEF1A and potently inhibits eukaryotic protein translation by an unknown mechanism. Here, we evaluated the impact of Lpg2505 on SidI-mediated phenotypes and investigated the mechanism of SidI function. We determined that Lpg2505 binds with nanomolar affinity to SidI and suppresses SidI-mediated inhibition of protein translation. SidI binding to eEF1A and Lpg2505 is not mutually exclusive, and the proteins bind distinct regions of SidI. We also discovered that SidI possesses GDP-dependent glycosyl hydrolase activity and that this activity is regulated by Lpg2505. We have therefore renamed Lpg2505 MesI (metaeffector of SidI). This work reveals novel enzymatic activity for SidI and provides insight into how intracellular replication of L. pneumophila is regulated by a metaeffector.

Upon infection, the highly structured 5' untranslated region (5' UTR) of picornavirus is involved in viral protein translation and RNA synthesis. As a critical element in the 5' UTR, the internal ribosome entry site (IRES) binds to various cellular proteins to function in the processes of picornavirus replication. Foot-and-mouth disease virus (FMDV) is an important member in the family Picornaviridae, and its 5' UTR contains a functional IRES element. In this study, the cellular heterogeneous nuclear ribonucleoprotein L (hnRNP L) was identified as an IRES-binding protein for FMDV by biotinylated RNA pulldown assays, mass spectrometry (MS) analysis, and determination of hnRNP L-IRES interaction regions. Further, we found that hnRNP L inhibited the growth of FMDV through binding to the viral IRES and that the inhibitory effect of hnRNP L on FMDV growth was not due to FMDV IRES-mediated translation, but to influence on viral RNA synthesis. Finally, hnRNP L was demonstrated to coimmunoprecipitate with RNA-dependent RNA polymerase (3D^pol) in an FMDV RNA-dependent manner in the infected cells. Thus, our results suggest that hnRNP L, as a critical IRES-binding protein, negatively regulates FMDV replication by inhibiting viral RNA synthesis, possibly by remaining in the replication complex.

IMPORTANCE Picornaviruses, as a large family of human and animal pathogens, cause a bewildering array of disease syndromes. Many host factors are implicated in the pathogenesis of these viruses, and some proteins interact with the viral IRES elements to affect function. Here, we report for the first time that cellular hnRNP L specifically interacts with the IRES of the picornavirus FMDV and negatively regulates FMDV replication through inhibiting viral RNA synthesis. Further, our results showed that hnRNP L coimmunoprecipitates with FMDV 3D^pol in a viral RNA-dependent manner, suggesting that it may remain in the replication complex to function. The data presented here would facilitate further understanding of virus-host interactions and the pathogenesis of picornavirus infections.

This case study aims to identify the cubic capacity and geometry of the geological body of silt–organic sediments in the environment of a former gravel pit situated in a drainless depression of the alluvium of the Čierna voda River. It is located in the well-known geotourism locality of Slnečné Jazera in Senec, in the SW of Slovakia. To identify the body, electrical resistivity tomography was combined with the use of sonar. The research shows that this approach is appropriate for a number of activities that are subjects of engineering-geological investigations. The cubic capacity and geometry of specific aqueous engineering-geological environments must be determined in connection with the need for the management, control, quantification and extraction of selected sedimentary bodies. In addition, the management of sustainable development of reservoirs, sedimentation basins, industrial ponds, settling pits and natural pools for recreation (the subject of the case study) is important to control the limit amounts of sediments in such environments. The results of this study may be applied in analogous engineering-geological conditions. The drainless depression Slnečné Jazera contained a body of silt–organic sediments amounting to 23 000 m³ (41 Olympic-size pools of 25 m x 12.5 m x 1.8 m). The maximum thickness of the bottom sediments was about 6.3 m on the alluvium with an articulated morphology owing to the submerged digging of gravel. The proposed approach improved the control of extraction of the sedimentary body and optimized the engineering-geological conditions in this geotourism locality.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus– or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness.

Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain.

PF06821497 has been identified as an orally available small-molecule enhancer of zeste homolog 2 inhibitor. The objectives of the present study were to characterize pharmacokinetic-pharmacodynamic-disease relationships of PF06821497 in xenograft mouse models with diffuse large B-cell lymphoma (Karpas422). An indirect-response model reasonably fit dose-dependent pharmacodynamic responses [histone H3 on lysine 27 (H3K27) me3 inhibition] with an unbound EC₅₀ of 76 nM, whereas a signal-transduction model sufficiently fit dose-dependent disease responses (tumor growth inhibition) with an unbound tumor stasis concentration (T_sc) of 168 nM. Thus, effective concentration for 70% of maximal effect (EC₇₀) for H3K27me3 inhibition was roughly comparable to T_sc, suggesting that 70% H3K27me3 inhibition could be required for tumor stasis. Consistently, an integrated pharmacokinetic-pharmacodynamic-disease model adequately describing tumor growth inhibition also suggested that ~70% H3K27me3 inhibition was associated with tumor stasis. Based on these results, we would propose that an EC₇₀ estimate for H3K27me3 inhibition corresponding to tumor stasis could be considered a minimum target efficacious concentration of PF06821497 in cancer patients.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33–amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS.

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC₅₀ and in vivo human IC₅₀ values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden.

The requisites for protein translation in T cells are poorly understood and how translation shapes the antitumor efficacy of T cells is unknown. Here we demonstrated that IL15-conditioned T cells were primed by the metabolic energy sensor AMP-activated protein kinase to undergo diminished translation relative to effector T cells. However, we showed that IL15-conditioned T cells exhibited a remarkable capacity to enhance their protein translation in tumors, which effector T cells were unable to duplicate. Studying the modulation of translation for applications in cancer immunotherapy revealed that direct ex vivo pharmacologic inhibition of translation elongation primed robust T-cell antitumor immunity. Our work elucidates that altering protein translation in CD8⁺ T cells can shape their antitumor capability.

Burkholderia sp. strain SG-MS1 and Pseudomonas sp. strain SG-MS2 have previously been found to mineralize (+)-pinoresinol through a common catabolic pathway. Here, we used comparative genomics, proteomics, protein semipurification, and heterologous expression to identify a flavoprotein from the vanillyl alcohol oxidase/p-cresol methyl hydroxylase (VAO/PCMH) enzyme family in SG-MS2 that carries out the initial hydroxylation of (+)-pinoresinol at the benzylic carbon. The cognate gene is translationally coupled with a downstream cytochrome gene, and the cytochrome is required for activity. The flavoprotein has a unique combination of cofactor binding and cytochrome requirements for the VAO/PCMH family. The heterologously expressed enzyme has a K_m of 1.17 μM for (+)-pinoresinol. The enzyme is overexpressed in strain SG-MS2 upon exposure to (+)-pinoresinol, along with 45 other proteins, 22 of which were found to be encoded by genes in an approximately 35.1-kb cluster also containing the flavoprotein and cytochrome genes. Homologs of 18 of these 22 genes, plus the flavoprotein and cytochrome genes, were also found in a 38.7-kb cluster in SG-MS1. The amino acid identities of four of the other proteins within the SG-MS2 cluster suggest they catalyze conversion of hydroxylated pinoresinol to protocatechuate and 2-methoxyhydroquinone. Nine other proteins upregulated in SG-MS2 on exposure to (+)-pinoresinol appear to be homologs of proteins known to comprise the protocatechuate and 2-methoxyhydroquinone catabolic pathways, but only three of the cognate genes lie within the cluster containing the flavoprotein and cytochrome genes.

IMPORTANCE (+)-Pinoresinol is an important plant defense compound, a major food lignan for humans and some other animals, and the model compound used to study degradation of the β-β' linkages in lignin. We report a gene cluster, in one strain each of Pseudomonas and Burkholderia, that is involved in the oxidative catabolism of (+)-pinoresinol. The flavoprotein component of the α-hydroxylase which heads the pathway belongs to the 4-phenol oxidizing (4PO) subgroup of the vanillyl alcohol oxidase/p-cresol methyl hydroxylase (VAO/PCMH) enzyme family but constitutes a novel combination of cofactor and electron acceptor properties for the family. It is translationally coupled with a cytochrome gene whose product is also required for activity. The work casts new light on the biology of (+)-pinoresinol and its transformation to other bioactive molecules. Potential applications of the findings include new options for deconstructing lignin into useful chemicals and the generation of new phytoestrogenic enterolactones from lignans.