Unisa is working incredibly hard to meet the challenges arising from COVID-19 and to ensure that we are able to meet the ever-increasing...

Ambassador Anwarul K. Chowdhury is a former Under-Secretary-General and High Representative of the UN (2002-2007), Permanent Representative of Bangladesh to UN (1996-2001) and Chairman of the UN General Assembly’s Administrative and Budgetary Committee (1997-1998)

The post UN Faces Financial & Liquidity Crisis as Global Pandemic Rages appeared first on Inter Press Service.

Daily Hürriyet’s travel supplement, Seyahat, has listed the top 10 boutique hotels in Turkey. Click through for the story in photos...

If you come to Turkey, you should not leave without experiencing at least some of its uniqueness. See, hear, feel, eat, travel, have fun and love in Turkish style. Click through our list of unique experiences that you can only have in Turkey...

Canyons around the Euphrates River in eastern Malatya province are becoming favorite destinations for nature lovers.  (Source: Anadolu Agency)

Although preserving food can seem time consuming and old-fashioned, freezing and pickling your produce is an easy way to save money and avoid food waste.

In the lead-up to the Truth Matters conference in October, we will be focusing our attention on the sufficiency, authority, and clarity of Scripture. Of our previous blog series, none better embodies that emphasis than Frequently Abused Verses. The following entry from that series originally appeared on April 10, 2017. -ed.

False teaching thrives in environments where it is unlikely to be questioned. Charlatans and heretics prey on uncritical minds, and work tirelessly to protect and preserve that gullibility. Their success depends on dismantling every challenge to their authority and accuracy.

John MacArthur describes why that problem is rampant in the modern church:

In a time like this of tolerance, listen, false teaching will always cry intolerance; it will always say you’re being divisive, you’re being unloving, you’re being ungracious, because it can only survive when it doesn’t get scrutinized. And so it cries against any intolerance. It cries against any examination, any scrutiny.

In recent decades, some of the most notorious charismatic church leaders have been doing just that. They continually warn their critics to back off or face the imminent danger of divine judgment. Claiming God’s stamp of approval, they wield Psalm 105:15 like a loaded gun: “Touch not [the Lord’s] anointed” (KJV).

And lest you think such a description to be hyperbole, the following clip from Benny Hinn is a spectacular example. 

Hinn’s handling of Psalm 105:15, as well as the story of Saul and David, is hopelessly wrong on too many levels to address in one blog post.

For example we could discuss how Hinn utterly fails to understand Judas’s role in God’s sovereign plan for the crucifixion, while woefully underestimating the deity of Christ. We could invalidate Hinn’s warnings against criticism by pointing out the time Paul rebuked Peter—or when Hinn has publicly rebuked Joel Osteen, among others. Then there’s the problem of Hinn basing his threats upon the extra-biblical revelation of another false teacher (Kenneth Copeland).

 What does it mean to “touch”?

But there is one simple, glaring error that explains all the other problems and exposes Hinn as the incompetent and unqualified Bible teacher that he is. When David says, “I will not stretch out my hand against [Saul], for he is the Lord’s anointed” (1 Samuel 24:10), he is explaining why he didn’t kill Saul, not why he didn’t criticize Saul. In fact, David was openly critical of Saul on numerous occasions. Moreover, 1 Samuel 24:10 is part of a larger discourse where David rebukes Saul face-to-face over his murderous scheming: “I have not sinned against you, though you are lying in wait for my life to take it. May the Lord judge between you and me, and may the Lord avenge me on you; but my hand shall not be against you” (1 Samuel 24:11–13). Even if Benny Hinn was “the Lord’s anointed”—he’s not—none of his critics are attempting to “touch” him in the sense described in 1 Samuel 24:10 (or Psalm 105:15; or 1 Chronicles 16:22).

Who are the anointed?

There is another fatal flaw in Hinn’s interpretation. He—and all those who follow this teaching—assume that only certain persons are “anointed.” They claim that pastors and self-appointed prophets and apostles have a unique anointing from God that immunizes them from criticism. But such a concept is foreign to Scripture. In short, the Bible teaches that all believers have an anointing from God.

In his first epistle, the apostle John explained what it means to be anointed as a New Testament believer. After warning his readers about antichrists who were coming to deceive them, John reminded them of their security because of Christ’s anointing:

These things I have written to you concerning those who are trying to deceive you. As for you, the anointing which you received from Him abides in you, and you have no need for anyone to teach you; but as His anointing teaches you about all things, and is true and is not a lie, and just as it has taught you, you abide in Him. (1 John 2:26–27)

The anointing John refers to is the indwelling of the Holy Spirit—a reality for all true Christians. John MacArthur explains the context and meaning of “anointing” as it appears in 1 John:

The false teachers who threatened John’s readers employed the terms for knowledge and anointing to describe their religious experience. They arrogantly saw themselves as possessing an elevated and esoteric form of divine knowledge, and as the recipients of a special, secret, transcendent anointing. That led them to believe they were privy to truth that the uninitiated lacked. John’s response, which was both a rebuttal to the antichrists and a reassurance to the believers, was to assert that, in reality, all true Christians have an anointing from the Holy One.

Because believers have received that anointing, they have the true understanding of God that comes exclusively through Jesus Christ (2 Corinthians 4:6), “in whom are hidden all the treasures of wisdom and knowledge” (Colossians 2:3). They do not need any secret, special, or transcendent understanding or esoteric insight. Anointing (chrisma) literally means “ointment” or “oil” (cf. Hebrews 1:9). In this text it refers figuratively to the Holy Spirit (cf. 2 Corinthians 1:21–22), who has taken up residency in believers at the behest of Jesus Christ, the Holy One (cf. Luke 4:34; Acts 3:14), and reveals through Scripture all they need to know (John 14:26; 16:13; 1 Corinthians 2:9–10). ^[1] John MacArthur, The MacArthur New Testament Commentary: 1–3 John (Chicago, IL: Moody Press, 2007), 102.

The anointing we have as believers reveals the truth and therefore exposes the lies of false teachers. How ironic that the “anointing” Benny Hinn evokes to extort and manipulate churchgoers is actually our warning system to expose the self-serving deception of wolves like him.   

Violence and chaos marred India’s first day of freedom from its stringent virus lockdown as migrant workers clashed with police in western India and brawls erupted outside liquor shops in the national capital.The country on Monday partially eased movement curbs across all but the worst infection-hit areas in an attempt to restart its stalled economy. Liquor shops, closed for 40 days under the strict stay-at-home orders, also reopened allowing state governments to earn some much-needed tax…

The production of reusable masks for all Hongkongers was not for profit, a government official said as she revealed the manufacturer’s identity and defended the lack of a public tender for the project worth hundreds of millions of dollars.Annie Choi Suk-han, permanent secretary of the Innovation and Technology Bureau, said most of the masks were being made by Crystal International Group at a facility in Vietnam.The rest were assembled, disinfected and packed using three local facilities offered…

The video has won the hearts on social media and garnered thousands of hearts within no time.

Despite decreases in hunger due to economic growth, millions in Asia remain malnourished and without direct action the situation could get worse.

Climate-smart and resource-saving farming technologies could be one way to address hunger in Asia.

The transmission channels of perishables like fruits and vegetables from producers to consumers in developing countries need a revamp to provide benefits to all involved.

For quality evaluations of international development projects and programs to lead to better results, they need to be influential.

Hunger and malnutrition were an increasing problem worldwide before the pandemic. Restrictions imposed to curb disease spread have disrupted local and international food supply chains, making the problem even more urgent.

До начала пандемии голод и неправильное питание становились все более серьезной проблемой во всем мире. Ограничения, введенные для обуздания распространения болезни, разрушили местные и международные цепочки поставок продовольствия, что делает проблему еще более актуальной.

In some of his YouTube videos, the user "Beleza em pessoa" criticized Mozambican prophets.

The government has advised people to make homemade masks using capulanas – a traditional Mozambican cloth generally worn by women – and other readily available materials.

NEW DELHI: Real estate developers and property consultants today welcomed the RBI decision to cut statutory liquidity ratio (SLR), saying this would enable banks to lend more to industry, including cash-starved realty sector. However, developers demanded easing of interest rates to boost housing sales. RBI today decided to keep the key policy rate unchanged but slashed statutory liquidity ratio (SLR) by 0.5 per cent to unlock about Rs 40,000 crore into the system. “The RBI’s move to cut SLR by 50 basis points to 22 per cent will give banks more headroom to lend and thereby spur lending in future. However, the much anticipated cut in rates would have been […]

MUNICH, Germany – HARMAN International, a wholly-owned subsidiary of Samsung Electronics Co., Ltd. focused on connected technologies for automotive, consumer and enterprise markets, today announced the opening of its first Experience Store in Europe....

CES 2020, LAS VEGAS – JANUARY 6, 2020 – HARMAN International Industries, a wholly-owned subsidiary of Samsung Electronics Co. Ltd., focused on connected technologies for automotive, consumer and enterprise markets, announces that the Personi-Fi platform...

This week, hide behind the sofa from mind-altering plants, listen and learn from technologies past and find out how the world is underpinned by numbers

A lightweight liquid metal alloy that is less dense than water could be used to make exoskeletons and transformable flexible robots

Dozens of people have died in Indonesia and Mozambique as a result of storms and flooding, possibly driven by climate change

Our ape cousins have asymmetrical brains just like we do, which might require us to rethink ideas on the evolution of brain specialism in our hominin ancestors

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This article describes the development of medical competencies for oral medicine specialty training in the UK and Ireland by a collaborative working group using a modified Delphi technique. The current specialty training curriculum for oral medicine (OM) in the UK was developed by a working group including members of the British Society for Oral Medicine (BSOM) and members of the Specialty Advisory Committee for Additional Dental Specialties (SACADS) and adopted by the UK General Dental Council (GDC) in 2010. When the curriculum was developed, the entry requirements for specialty training in OM included undergraduate degrees in both dentistry and medicine. At the time of adoption, the requirement for a medical degree was removed. Medical competencies were assumed to have been delivered in medical undergraduate and postgraduate training. Accordingly, there was a need to define the medical competencies for OM specialty training to benefit trainees, trainers, and assessors. In 2018, a group comprising specialty trainers, recent former specialty trainees, and current specialty trainees in OM held face-to-face meetings in addition to email discussions and developed an updated curriculum document to better reflect the medical competencies required in specialty training. A collaborative modified Delphi approach was used to evaluate medical foundation competencies and to include only those that were considered relevant to OM specialty training. A list of relevant and achievable medical competencies was determined that has been approved by SACADS and will be incorporated into a revised OM curriculum from the UK GDC. The newly agreed-upon document for medical competencies in OM specialty training will serve as a reference for trainees, trainers, and assessors and reflects a successful use of a modified Delphi approach.

ABSTRACT

The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection.

IMPORTANCE Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets.

Ventilatory settings are critical in mechanically ventilated extremely preterm newborn infants due to the risk of ventilation-induced lung injury (VILI) and the subsequent development of bronchopulmonary dysplasia (BPD) [1]. Positive end-expiratory pressure (PEEP) settings usually rely on blood gases, oxygen requirement, lung auscultation, evaluation of chest radiograph and assessment of the pressure/volume curves provided by ventilators. Studies of optimal PEEP settings in the surfactant-treated preterm infant in need of mechanical ventilation are limited and evidence-based clinical guidelines are sparse [2, 3]. A bedside method identifying the PEEP value that comprises maximal lung volume recruitment and minimising tissue overdistension could improve real-time optimisation of PEEP and potentially minimise the risk of VILI and BPD [4, 5].

There is increasing interest in developing diagnostics that discriminate individual mutagenic mechanisms in a range of applications that include identifying population-specific mutagenesis and resolving distinct mutation signatures in cancer samples. Analyses for these applications assume that mutagenic mechanisms have a distinct relationship with neighboring bases that allows them to be distinguished. Direct support for this assumption is limited to a small number of simple cases, e.g., CpG hypermutability. We have evaluated whether the mechanistic origin of a point mutation can be resolved using only sequence context for a more complicated case. We contrasted single nucleotide variants originating from the multitude of mutagenic processes that normally operate in the mouse germline with those induced by the potent mutagen N-ethyl-N-nitrosourea (ENU). The considerable overlap in the mutation spectra of these two samples make this a challenging problem. Employing a new, robust log-linear modeling method, we demonstrate that neighboring bases contain information regarding point mutation direction that differs between the ENU-induced and spontaneous mutation variant classes. A logistic regression classifier exhibited strong performance at discriminating between the different mutation classes. Concordance between the feature set of the best classifier and information content analyses suggest our results can be generalized to other mutation classification problems. We conclude that machine learning can be used to build a practical classification tool to identify the mutation mechanism for individual genetic variants. Software implementing our approach is freely available under an open-source license.

Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap ’n’ collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins.

Christopher T. Richards and Enrico A. Eberhard

Muscle force-length dynamics are governed by intrinsic contractile properties, motor stimulation and mechanical load. Although intrinsic properties are well-characterised, physiologists lack in vitro instrumentation accounting for combined effects of limb inertia, musculoskeletal architecture and contractile dynamics. We introduce in vitro virtual-reality (in vitro-VR) which enables in vitro muscle tissue to drive a musculoskeletal jumping simulation. In hardware, muscle force from a frog plantaris was transmitted to a software model where joint torques, inertia and ground reaction forces were computed to advance the simulation at 1 kHz. To close the loop, simulated muscle strain was returned to update in vitro length. We manipulated 1) stimulation timing and, 2) the virtual muscle's anatomical origin. This influenced interactions among muscular, inertial, gravitational and contact forces dictating limb kinematics and jump performance. We propose that in vitro-VR can be used to illustrate how neuromuscular control and musculoskeletal anatomy influence muscle dynamics and biomechanical performance.

Qingxiang Guo, Yang Liu, Yanhua Zhai, and Zemao Gu

Disassembling the parasitic spores and acquiring the main subunits is a prerequisite for deep understanding of the basic biology of parasites. Herein we present a fast and efficient method to dissect the myxospores in a few steps, which mainly involved sonication, sucrose density gradient and Percoll density gradient. We tested our method on three myxozoans species and demonstrated this method allows the dismembering of myxospores, isolation of intact and clean nematocysts and shell valves within 2h by low-cost. This new tool will facilitate subsequent analyses and enable a better understanding of the ecological and evolutionary significance of parasitic spores.

Marc E. Deetjen, Diana D. Chin, and David Lentink

Animal flight requires aerodynamic power, which is challenging to determine accurately in vivo. Existing methods rely on approximate calculations based on wake flow field measurements, inverse dynamics approaches, or invasive muscle physiological recordings. In contrast, the external mechanical work required for terrestrial locomotion can be determined more directly by using a force platform as an ergometer. Based on an extension of the recent invention of the aerodynamic force platform, we now present a more direct method to determine the in vivo aerodynamic power by taking the dot product of the aerodynamic force vector on the wing with the representative wing velocity vector based on kinematics and morphology. We demonstrate this new method by studying a slowly flying dove, but it can be applied more generally across flying and swimming animals as well as animals that locomote over water surfaces. Finally, our mathematical framework also works for power analyses based on flow field measurements.

Histone H2B monoubiquitylation (H2Bub1) has central functions in multiple DNA-templated processes, including gene transcription, DNA repair, and replication. H2Bub1 also is required for the trans-histone regulation of H3K4 and H3K79 methylation. Although previous studies have elucidated the basic mechanisms that establish and remove H2Bub1, we have only an incomplete understanding of how H2Bub1 is regulated. We report here that the histone H4 basic patch regulates H2Bub1. Yeast cells with arginine-to-alanine mutations in the H4 basic patch (H42RA) exhibited a significant loss of global H2Bub1. H42RA mutant yeast strains also displayed chemotoxin sensitivities similar to, but less severe than, strains containing a complete loss of H2Bub1. We found that the H4 basic patch regulates H2Bub1 levels independently of interactions with chromatin remodelers and separately from its regulation of H3K79 methylation. To measure H2B ubiquitylation and deubiquitination kinetics in vivo, we used a rapid and reversible optogenetic tool, the light-inducible nuclear exporter, to control the subcellular location of the H2Bub1 E3 ligase, Bre1. The ability of Bre1 to ubiquitylate H2B was unaffected in the H42RA mutant. In contrast, H2Bub1 deubiquitination by SAGA-associated Ubp8, but not by Ubp10, increased in the H42RA mutant. Consistent with a function for the H4 basic patch in regulating SAGA deubiquitinase activity, we also detected increased SAGA-mediated histone acetylation in H4 basic patch mutants. Our findings uncover that the H4 basic patch has a regulatory function in SAGA-mediated histone modifications.

Dalton Buysse, Anna-Katharina Pfitzner, Matt West, Aurelien Roux, and Greg Odorizzi

The ESCRT-III protein complex executes reverse-topology membrane scission. The scission mechanism is unclear but is linked to remodeling of ESCRT-III complexes at the membrane surface. At endosomes, ESCRT-III mediates the budding of intralumenal vesicles (ILVs). In Saccharomyces cerevisiae, ESCRT-III activity at endosomes is regulated through an unknown mechanism by Doa4, an ubiquitin hydrolase that deubiquitylates transmembrane proteins sorted into ILVs. We report that the non-catalytic N-terminus of Doa4 binds Snf7, the predominant ESCRT-III subunit. Through this interaction, Doa4 overexpression alters Snf7 assembly status and inhibits ILV membrane scission. In vitro, the Doa4 N-terminus inhibits association of Snf7 with Vps2, which functions with Vps24 to arrest Snf7 polymerization and remodel Snf7 polymer structure. In vivo, Doa4 overexpression inhibits Snf7 interaction with Vps2 and also with the ATPase Vps4, which is recruited by Vps2 and Vps24 to remodel ESCRT-III complexes by catalyzing subunit turnover. Our data suggest a mechanism by which the deubiquitylation machinery regulates ILV biogenesis by interfering with ESCRT-III remodeling.

Ubiquitin (UB) transfer cascades consisting of E1, E2, and E3 enzymes constitute a complex network that regulates a myriad of biologic processes by modifying protein substrates. Deubiquitinating enzymes (DUBs) reverse UB modifications or trim UB chains of diverse linkages. Additionally, many cellular proteins carry UB-binding domains (UBDs) that translate the signals encoded in UB chains to target proteins for degradation by proteasomes or in autophagosomes, as well as affect nonproteolytic outcomes such as kinase activation, DNA repair, and transcriptional regulation. Dysregulation of the UB transfer pathways and malfunctions of DUBs and UBDs play causative roles in the development of many diseases. A greater understanding of the mechanism of UB chain assembly and the signals encoded in UB chains should aid in our understanding of disease pathogenesis and guide the development of novel therapeutics. The recent flourish of protein-engineering approaches such as unnatural amino acid incorporation, protein semisynthesis by expressed protein ligation, and high throughput selection by phage and yeast cell surface display has generated designer proteins as powerful tools to interrogate cell signaling mediated by protein ubiquitination. In this study, we highlight recent achievements of protein engineering on mapping, probing, and manipulating UB transfer in the cell.

This paper focuses on handheld and top-of-hole techniques which have appeared since 2007 or have undergone major improvements, and discusses their benefits, challenges and pitfalls, why we use them and what to expect from them. There is an ongoing need to be innovative with the way we undertake mineral exploration. Recent technological advances that have been applied to successful mineral exploration include on-site or portable instruments, on-site laboratory technologies, various core scanners, and technologies for fluid analysis. Portable or field technologies such as pXRF, pXRD, pNIR-SWIR, µRaman and LIBS aid in obtaining chemical and mineralogical information. Spectral gamma tools, a well-known technology, recently took advantage of improved ground and airborne (drone) instruments, to complement hyperspectral imagery. At mine and exploration sites, top-of-hole sensing technologies, such as Lab-at-Rig® and various core scanners (both spectral- and XRF-based) have become useful tools to analyse metres of core as it is being drilled. Fluid analyses are not as common as analyses of solid materials, but there are advances in such technologies as anodic stripping voltammetry, polarography and ion-exchange electrodes aiming for analysis of commodity or environmentally important elements.

Field-portable geochemical techniques and on-site technologies now offer instant response and flexibility for most exploration tasks. By providing relevant data within minutes, they allow safer field decisions and focus on the most promising finds, while saving valuable resources in sampling grids or drilling. More efficient laboratory analysis programs are supported by sample screening and homogeneity checking on-site. Field analyses are not always as accurate as laboratory ones, but most of the time can be correlated with them, enabling reliable decisions. The level of confidence in field-made decisions needs to be compared between later and less numerous laboratory analyses, and less precise but more abundant and immediate field analyses. It may be demonstrated that, in many cases, the fit–for-purpose nature of the latter allows a better confidence level. Quality compromises associated with field analyses can be reduced by the application of better sample preparation and quality assurance/quality control (QA/QC) procedures. Most of the further development of on-site chemical analysis is expected to be based on its integration with lab methods and on sound QA/QC practice, allowing a precise evaluation of its confidence level and uncertainties. Mineralogical analyses are constrained by our ability to interpret the data in near-real time but offer promising approaches in both surface and drilling exploration campaigns.

Thematic collection: This article is part of the Exploration 17 collection available at: https://www.lyellcollection.org/cc/exploration-17

OBJECTIVE

With rising health care costs and finite health care resources, understanding the population needs of different type 2 diabetes mellitus (T2DM) patient subgroups is important. Sparse data exist for the application of population segmentation on health care needs among Asian T2DM patients. We aimed to segment T2DM patients into distinct classes and evaluate their differential health care use, diabetes-related complications, and mortality patterns.

Most freshwater bacterial communities are characterized by a few dominant taxa that are often ubiquitous across freshwater biomes worldwide. Our understanding of the genomic diversity within these taxonomic groups is limited to a subset of taxa. Here, we investigated the genomic diversity that enables Limnohabitans, a freshwater genus key in funneling carbon from primary producers to higher trophic levels, to achieve abundance and ubiquity. We reconstructed eight putative Limnohabitans metagenome-assembled genomes (MAGs) from stations located along broad environmental gradients existing in Lake Michigan, part of Earth’s largest surface freshwater system. De novo strain inference analysis resolved a total of 23 strains from these MAGs, which strongly partitioned into two habitat-specific clusters with cooccurring strains from different lineages. The largest number of strains belonged to the abundant LimB lineage, for which robust in situ strain delineation had not previously been achieved. Our data show that temperature and nutrient levels may be important environmental parameters associated with microdiversification within the Limnohabitans genus. In addition, strains predominant in low- and high-phosphorus conditions had larger genomic divergence than strains abundant under different temperatures. Comparative genomics and gene expression analysis yielded evidence for the ability of LimB populations to exhibit cellular motility and chemotaxis, a phenotype not yet associated with available Limnohabitans isolates. Our findings broaden historical marker gene-based surveys of Limnohabitans microdiversification and provide in situ evidence of genome diversity and its functional implications across freshwater gradients.

IMPORTANCE Limnohabitans is an important bacterial taxonomic group for cycling carbon in freshwater ecosystems worldwide. Here, we examined the genomic diversity of different Limnohabitans lineages. We focused on the LimB lineage of this genus, which is globally distributed and often abundant, and its abundance has shown to be largely invariant to environmental change. Our data show that the LimB lineage is actually comprised of multiple cooccurring populations for which the composition and genomic characteristics are associated with variations in temperature and nutrient levels. The gene expression profiles of this lineage suggest the importance of chemotaxis and motility, traits that had not yet been associated with the Limnohabitans genus, in adapting to environmental conditions.

Obtaining blood and cerebrospinal fluid is generally less invasive than standard tumor biopsy, and are increasingly used to develop surrogate biomarkers. Leptomeningeal disease, a devastating complication of cancer, represents a unique opportunity for using liquid biopsies for diagnosis, treatment, and to elucidate underlying mechanisms of resistance to therapy.

See related article by Smalley et al., p. 2163

Unlike replicative senescence, oncogene-induced senescence caused heterochromatin-body formation.

A new method called MicroMapping can identify nanoscale protein–protein interactions on live cells.

Monoubiquitinated FANCI and FANCD2 constitute the ID complex, which forms a sliding clamp on DNA.

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.

Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ~71 million people worldwide. The limited host range of HCV, which robustly infects only humans and chimpanzees, has made studying this virus in vivo challenging and hampered the development of a desperately needed vaccine. The restrictions and ethical concerns surrounding biomedical research in chimpanzees has made the search for an animal model all the more important. In this review, we discuss different approaches that are being pursued toward creating small animal models for HCV infection. Although efforts to use a nonhuman primate species besides chimpanzees have proven challenging, important advances have been achieved in a variety of humanized mouse models. However, such models still fall short of the overarching goal to have an immunocompetent, inheritably susceptible in vivo platform in which the immunopathology of HCV could be studied and putative vaccines development. Alternatives to overcome this include virus adaptation, such as murine-tropic HCV strains, or the use of related hepaciviruses, of which many have been recently identified. Of the latter, the rodent/rat hepacivirus from Rattus norvegicus species-1 (RHV-rn1) holds promise as a surrogate virus in fully immunocompetent rats that can inform our understanding of the interaction between the immune response and viral outcomes (i.e., clearance vs. persistence). However, further characterization of these animal models is necessary before their use for gaining new insights into the immunopathogenesis of HCV and for conceptualizing HCV vaccines.