Miracle-dz/UniFAR-FTUs huggingface dataset:
New Human Follitropin Preparations: How Glycan Structural Differences May Affect Biochemical and Biological Function and Clinical Effect

It is well accepted that pituitary follitropin is secreted into the circulation as a mixture of variants, which differ not in primary structure but rather at the level of glycosylation. These glycosidic forms vary in the number of glycosylation sites filled, complexity of glycosidic chains, and sialylation and sulfation. It is generally agreed that high sialylation, 2,3 sialic acid capping of terminal N-acetyl galactosamine or galactose leads to longer circulating half-life, by blocking binding of asialoglycoprotein receptor (ASGPR) in the liver. In contrast, 2,6 sialic acid found in humans does not prevent recognition of galactose and N-acetyl galactosamine by ASGPR. Few studies on clinical outcomes comparing differences in sialylation of follitropin found in commercially available preparations are available. Thus, there is a clear need for a consortium of open data to address this unmet need. Recently, FSH glycosylation, primarily on the β-subunit, which varies as women age, has emerged as a key modifier of follitropin action, with profound biological effects in vivo in animal models. To date, limited information of recombinant follitropin hormone preparations is available. Thus, most of the studies with FSH that is well characterized biochemically have been done in vitro, with engineered non gonadal host cells bearing recombinant receptors or in animal models. Since limited studies in human granulosa cells are available, a question is whether structural differences in glycosylation in commercially available follitropin affects biological function and clinical effect in humans. The presence of fucose, for example, has not been studied greatly even though, in the case of antibody therapy it has been shown to have a large effect on antibody targeting. This review on glycosidic variability of follitropin from the biochemical/structural point of view reflects on this question and presents an assessment in the context of available published data. If clinical differences are to be expected or not, the readers will have a better understanding of the evidence for and limitations of such expectations.
Protective Effects of Sodium-Glucose Transporter 2 Inhibitors on Atrial Fibrillation and Atrial Flutter: A Systematic Review and Meta- Analysis of Randomized Placebo-Controlled Trials

Background Hyperglycemia is associated with an increased risk of developing atrial fibrillation (AF) and atrial flutter (AFL). Sodium-glucose transporter 2 inhibitors (SGLT2i) have been reported to prevent AF/AFL in some studies, but not others. Therefore, a meta-analysis was performed to investigate whether SGLT2i use is associated with lower risks of AF/AFL. Methods PubMed, Scopus, Web of Science, Cochrane library databases were searched for randomized placebo-controlled trials comparing SGLT2i and placebo. Results A total of 33 trials involving 66,685 patients were included. The serious adverse events (SAEs) of AF/AFL occurrence were significantly lower in the SGLT2i group than the placebo group (0.96% vs. 1.19%; RR 0.83; 95% CI 0.71–0.96; P = 0.01; I2 25.5%). Similarly, the SAEs of AF occurrence was significantly lower in the SGLT2i group (0.82% vs. 1.06%; RR 0.81; 95% CI 0.69–0.95; P = 0.01; I2 10.2%). The subgroup analysis showed that the reduction in AF/AFL was significant only for dapagliflozin (1.02% vs. 1.49%; RR 0.73; 95% CI 0.59–0.89; P = 0.002; I2 0%), but not for canagliflozin (1.00% vs 1.08%; RR 0.83; 95% CI 0.62–1.12; P = 0.23; I2 0%), empagliflozin (0.88% vs 0.70%; RR 1.20; 95% CI 0.76–1.90; P = 0.43; I2 0%), ertugliflozin (1.01% vs 0.96%; RR 1.08; 95% CI 0.66–1.75; P = 0.76; I2 0%), and sotagliflozin (0.16% vs 0.10%; RR 1.09; 95% CI 0.13–8.86; P = 0.93; I2 0%). Conclusions SGLT2i use is associated with a 19.33% lower SAEs of AF/AFL compared with the placebo. Dapagliflozin users had the lowest SAEs of AF/AFL incidence. Further studies are needed to determine whether canagliflozin, empagliflozin, ertugliflozin, and sotagliflozin similarly exert protective effects against AF/AFL development.
Comparing Dynamic and Static Time-Area Closures for Bycatch Mitigation: A Management Strategy Evaluation of a Swordfish Fishery

Time-area closures are a valuable tool for mitigating fisheries bycatch. There is increasing recognition that dynamic closures, which have boundaries that vary across space and time, can be more effective than static closures at protecting mobile species in dynamic environments. We created a management strategy evaluation to compare static and dynamic closures in a simulated fishery based on the California drift gillnet swordfish fishery, with closures aimed at reducing bycatch of leatherback turtles. We tested eight operating models that varied swordfish and leatherback distributions, and within each evaluated the performance of three static and five dynamic closure strategies. We repeated this under 20 and 50% simulated observer coverage to alter the data available for closure creation. We found that static closures can be effective for reducing bycatch of species with more geographically associated distributions, but to avoid redistributing bycatch the static areas closed should be based on potential (not just observed) bycatch. Only dynamic closures were effective at reducing bycatch for more dynamic leatherback distributions, and they generally reduced bycatch risk more than they reduced target catch. Dynamic closures were less likely to redistribute fishing into rarely fished areas, by leaving open pockets of lower risk habitat, but these closures were often fragmented which would create practical challenges for fishers and managers and require a mobile fleet. Given our simulation’s catch rates, 20% observer coverage was sufficient to create useful closures and increasing coverage to 50% added only minor improvement in closure performance. Even strict static or dynamic closures reduced leatherback bycatch by only 30–50% per season, because the simulated leatherback distributions were broad and open areas contained considerable bycatch risk. Perfect knowledge of the leatherback distribution provided an additional 5–15% bycatch reduction over a dynamic closure with realistic predictive accuracy. This moderate level of bycatch reduction highlights the limitations of redistributing fishing effort to reduce bycatch of broadly distributed and rarely encountered species, and indicates that, for these species, spatial management may work best when used with other bycatch mitigation approaches. We recommend future research explores methods for considering model uncertainty in the spatial and temporal resolution of dynamic closures.
Relationship between Work of Adhesion and Equilibrium Interatomic Distance at the Interface

In previous work concerning fiber−matrix junctions in single-fiber composites, a linear relationship has been established between the interfacial shear strength τ and the reversible adhesion energy W at the interface, which takes into account dispersive and acid−base interactions. In the present study, the validity of such a relationship is examined from a theoretical point of view. It appears that its mathematical form is entirely justified in terms of “static friction”, if τ is considered as the resistance to the interfacial slipping due to the existence of molecular interactions. The most important parameter in this approach appears to be the equilibrium intermolecular or interatomic distance λ at the interface. It is shown, in good agreement with results available in the literature, that λ decreases when the work of adhesion increases, in particular when strong acid−base interactions are involved at the interface. To a first approximation, it appears that the reversible work of adhesion W varies like .
Vanadium Oxide Supported on Mesoporous MCM-41 as Selective Catalysts in the Oxidative Dehydrogenation of Alkanes

The application of different techniques (51V NMR, diffuse reflectance, and TPR-H2) in the characterization of vanadia supported on mesoporous MCM-41 catalysts shows that the nature of the vanadium species depends on the V loading. In dehydrated catalysts with V content lower than 7 wt%, vanadium is mainly in a tetrahedral environment. In the presence of moisture, most V5+, placed in accessible positions, binds to water molecules, becoming hexacoordinated, while some V5+ species, probably located within the pore walls, keep their tetrahedral coordination. Higher V contents in the catalyst leads to the formation of polymeric V2O5-like species. Both XRD and textural results indicate that the mesoporous structure of the support is mostly maintained after the vanadium incorporation, and therefore high surface areas were obtained on the final catalysts. MCM-41-suppported vanadia catalysts are active and selective in the oxidative dehydrogenation of propane and ethane, although the catalytic behavior depends on the V loading. A high rate of formation of propylene or ethylene per unit mass of catalyst per unit time have also been observed as a consequence of the high dispersion of V atoms achieved on the surface of the support.
FIGO (International Federation of Gynecology and Obstetrics) initiative on fetal growth: Best practice advice for screening, diagnosis, and management of fetal growth restriction

Nir Melamed1 | Ahmet Baschat2 | Yoav Yinon3 | Apostolos Athanasiadis4 | Federico Mecacci5 | Francesc Figueras6 | Vincenzo Berghella7 | Amala Nazareth8 | Muna Tahlak9 | H. David McIntyre10 | Fabrício Da Silva Costa11 | Anne B. Kihara12 | Eran Hadar13,14 | Fionnuala McAuliffe15 | Mark Hanson16,17 | Ronald C. Ma18,19 | Rachel Gooden20 | Eyal Sheiner21 | Anil Kapur22 | Hema Divakar23 | Diogo Ayres-de-Campos24 | Liran Hiersch25 | Liona C. Poon26 | John Kingdom27 | Roberto Romero28 | Moshe Hod13,14*
Germination alters the microstructure, in vitro protein digestibility, α‐glucosidase and dipeptidyl peptidase‐IV inhibitory activities of bioaccessible fraction of pigeon pea (Cajanus cajan) seeds

Germination was investigated as a bioprocess for enhancing the digestibility and bioactivity of pigeon pea (Cajanus cajan). Pigeon pea seeds were germinated for 0, 4, 24 and 48 h. Electrophoresis revealed that the 7S vicilin subunits were the most abundant proteins in control and germinated seeds. FTIR showed a loss of β sheet and a gain of α‐helix contents, and microscopy showed cell wall degradation in germinated seeds. Germination decreased the seed protein yield due to partial hydrolysis of proteins. After in vitro digestion, 48‐h germination increased the protein digestibility‐corrected amino acid score of the pigeon pea flour and isolated protein. Germination also enhanced the inhibitory activity of the seed digesta against α‐glucosidase but not dipeptidyl peptidase IV. Taken together, germination could be used to enhance the nutritional quality and bioactivity of pigeon pea towards improving its future utilization as novel healthy food for mitigating food insecurity.
Spray Scrubbing of Particulates with a Critical Flow Atomizer

Wet scrubbers are gaining importance over other devices for particulate collection with the increasing stringency of pollution regulations. The scrubbing of particulates (soot and fly-ash) in a spray tower with a two-phase critical flow atomizer using water is reported in this article. The atomizer is capable of generating droplets with a high degree of spray uniformity. Preliminary studies reveal that the atomizer deployed in the present investigation is energetically more favorable than existing atomizers. With this atomizer, the scrubbing performances of a model spray tower are determined experimentally in terms of different operating variables. Various physical interactions with the exception of electrostatic effects are found to significantly influence the removal efficiency. The removal efficiency is found to increase with the inlet particle loading, gas flow rate and liquid to gas flow rate ratio. Experiments reveal that the present system collects finer (soot) particles (with a Sauter Mean Diameter (SMD) of 1.43 μm) more efficiently than the relatively coarse (fly-ash) particles (SMD of 6.38 μm) under similar experimental conditions. Further investigation reveals that almost 100% removal efficiency (zero penetration) of both soot and fly-ash particles can be attained at a much lower Q L /Q G ratio of 3 m 3 /1000 actual cubic meters (ACM) than for the existing systems. A unique correlation is developed for predicting the performance of the spray tower in terms of various pertinent variables of the system. The predicted values agree very well with the experimental values (± 10 % deviation). A comparison of the performance of the present system with the existing systems indicates that the spray tower developed is techno-enviro-economically more favorable than existing systems.
A NEW CASE OF DIPLOIDY WITHIN A HAPLOID GENUS OF ENTOMOPATHOGENIC FUNGI

Fungi in the genus Metarhizium are soil-borne plant-root endophytes and rhizosphere colonisers, but also potent insect pathogens with highly variable host ranges. These ascomycete fungi are predominantly asexually reproducing and ancestrally haploid, but two independent origins of persistent diploidy within the Coleoptera-infecting M. majus species complex are known and has been attributed to incomplete chromosomal segregation following meiosis during the sexual cycle. There is also evidence for infrequent sexual cycles in the locust-specific pathogenic fungus Metarhizium acridum (Hypocreales: Clavicipitaceae), which is an important entomopathogenic biocontrol agent used for the control of grasshoppers in agricultural systems as an alternative to chemical control. Here, we show that the genome of the M. acridum isolate ARSEF 324, which is formulated and commercially utilised under the name ‘Green Guard’, is functionally diploid. We used single-molecule real-time (SMRT) sequencing technology to complete a high-quality assembly of ARSEF 324. Kmer frequencies, intragenomic collinearity between contigs and single nucleotide variant read depths across the genome revealed the first incidence of diploidy described within the species M. acridum. The haploid assembly of 44.7 Mb consisting of 20.8% repetitive elements, which is the highest proportion described of any Metarhizium species. The genome assembly and the inferred diploid state, can shed light on past research on this strain and could fuel future investigation into the fitness landscape of aberrant ploidy levels, not least in the contest of biocontrol agents.
Drug-bound and -free outward-facing structures of a multidrug ABC exporter point to a swing mechanism

Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved two ATP-Mg2+-bound outward-facing (OF) conformations of the Bacillus subtilis (homodimeric) BmrA, one by X-ray crystallography without drug, and another by single-particle cryo-EM with rhodamine 6G (R6G). Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5’-6’ of the other. R6G induces a rearrangement of TM1-2, highlighting a flexibility that was confirmed by H/D exchange and molecular dynamics simulations. The latter also shows a fast post-release occlusion of the cavity driven by hydrophobicity. Altogether, these data support a new swing mechanism for drug transport.
Prolonged development of long-term potentiation at lateral entorhinal cortex synapses onto adult-born neurons

Critical period plasticity at adult-born neuron synapses is widely believed to contribute to the learning and memory functions of the hippocampus. Experience regulates circuit integration and for a transient interval, until cells are ~6 weeks old, new neurons display enhanced long-term potentiation (LTP) at afferent and efferent synapses. Since neurogenesis declines substantially with age, this raises questions about the extent of lasting plasticity offered by adult-born neurons. Notably, however, the hippocampus receives sensory information from two major cortical pathways. Broadly speaking, the medial entorhinal cortex conveys spatial information to the hippocampus via the medial perforant path (MPP), and the lateral entorhinal cortex, via the lateral perforant path (LPP), codes for the cues and items that make experiences unique. While enhanced critical period plasticity at MPP synapses is relatively well characterized, no studies have examined long-term plasticity at LPP synapses onto adult-born neurons, even though the lateral entorhinal cortex is uniquely vulnerable to aging and Alzheimer’s pathology. We therefore investigated LTP at LPP inputs both within (4-6 weeks) and beyond (8+ weeks) the traditional critical period. At immature stages, adult-born neurons did not undergo significant LTP at LPP synapses, and often displayed long-term depression after theta burst stimulation. However, over the course of 3-4 months, adult-born neurons displayed increasingly greater amounts of LTP. Analyses of short-term plasticity point towards a presynaptic mechanism, where transmitter release probability declines as cells mature, providing a greater dynamic range for strengthening synapses. Collectively, our findings identify a novel form of new neuron plasticity that develops over an extended interval, and may therefore be relevant for maintaining cognitive function in aging.
The role of ventromedial prefrontal cortex in reward valuation and future thinking during intertemporal choice

Intertemporal choices require trade-offs between short-term and long-term outcomes. Ventromedial prefrontal cortex (vmPFC) damage causes steep discounting of future rewards (delay discounting; DD) and impoverished episodic future thinking (EFT). The role of vmPFC in reward valuation, EFT, and their interaction during intertemporal choice is still unclear. Here, twelve patients with lesions to vmPFC and forty-one healthy controls chose between smaller-immediate and larger-delayed hypothetical monetary rewards while we manipulated reward magnitude and the availability of EFT cues. In the EFT condition, participants imagined personal events to occur at the delays associated with the larger-delayed rewards. We found that DD was steeper in vmPFC patients compared to controls, and not modulated by reward magnitude. However, EFT cues downregulated DD in vmPFC patients as well as controls. These findings indicate that vmPFC integrity is critical for the valuation of (future) rewards, but not to instill EFT in intertemporal choice.
AKAP79 enables calcineurin to directly suppress protein kinase A activity

Interplay between the second messengers cAMP and Ca2+ is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca2+-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD). AKAP79 supports signaling of this type by anchoring PKA and calcineurin in tandem. In this study, we discovered that AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory subunits by an order of magnitude. Fluorescent PKA activity reporter assays, supported by kinetic modeling, show how AKAP79-enhanced calcineurin activity enables suppression of PKA without altering cAMP levels by increasing PKA catalytic subunit capture rate. Experiments with hippocampal neurons indicate that this mechanism contributes towards LTD. This non- canonical mode of PKA regulation may underlie many other cellular processes.
Tracing evolution history of 100 whole genome sequences of diffuse stem brain tumor

Diffuse intrinsic pontine glioma (DIPG) is a deadly disease among young children. The evolution path and mutational processes giving rise to DIPG remain elusive. We analyzed 100 whole genome sequences (WGS) from 60 DIPG patients. This revealed 25% DIPGs acquired whole-genome duplications (WGD) early during tumor evolution. WGD samples are associated with loss of TP53 and poorer survival. In addition, almost all WGD samplers harbor complex structural variations (SVs) and show characteristic short microhomology at SV breakpoints. Mutation analysis revealed that H3K27M driver mutation is acquired early during tumor clonal evolution. Mutation signature analysis identified a unique mutational process at a late stage of tumor evolution. This study revealed that tumor evolution of DIPG is characterized by chromosomal instability shaped by DNA repair defects and dynamic mutational processes. Our work shed new insights on the disease pathogenesis of DIPG and provided rationale for designing novel therapy for this deadly disease.
Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion

Synchronous release at neuronal synapses is accomplished by a machinery that senses calcium influx and fuses the synaptic vesicle and plasma membranes to release neurotransmitters. Previous studies suggested the calcium sensor Synaptotagmin (Syt) is a facilitator of vesicle docking and both a facilitator and inhibitor of fusion. On phospholipid monolayers, the Syt C2AB domain spontaneously oligomerized into rings that are disassembled by Ca2+, suggesting Syt rings may clamp fusion as membrane-separating “washers” until Ca2+-mediated disassembly triggers fusion and release (Wang et al., 2014). Here we combined mathematical modeling with experiment to measure mechanical properties of Syt rings and to test this mechanism. Consistent with experiment, the model quantitatively recapitulates observed Syt ring-induced dome and volcano shapes on phospholipid monolayers, and predicts rings are stabilized by anionic phospholipid bilayers or bulk solution with ATP. The selected ring conformation is highly sensitive to membrane composition and bulk ATP levels, a property that may regulate vesicle docking and fusion in ATP-rich synaptic terminals. We find the Syt molecules hosted by a synaptic vesicle oligomerize into a halo, unbound from the vesicle, but in proximity to sufficiently PIP2-rich plasma membrane (PM) domains the PM-bound trans Syt ring conformation is preferred. Thus, the Syt halo serves as landing gear for spatially directed docking at PIP2-rich sites that define the active zones of exocytotic release, positioning the Syt ring to clamp fusion and await calcium. Our results suggest the Syt ring is both a Ca2+-sensitive fusion clamp and a high-fidelity sensor for directed docking. Significance Synchronous neurotransmitter release relies on directed docking of synaptic vesicles at active zones in axon terminals, where calcium influx activates membrane fusion and release. In vitro, the calcium sensor Synaptotagmin oligomerizes into rings disassembled by calcium. Here, experiment and modeling suggest the Synaptotagmin molecules hosted by an undocked vesicle oligomerize into a tethered, unbound halo in ATP-rich synaptic terminals. The halo directs vesicle docking to PIP2-rich plasma membrane domains in active zones, where the trans-bound ring conformation is favored, interposed between the membranes to clamp fusion until calcium triggers ring disassembly and neurotransmitter release. The mechanism exploits the extreme sensitivity of Synaptotagmin ring binding preferences to solution and membrane composition, with ~15 -fold-enhanced sensitivity for rings of ~15 molecules.