bluuebunny/crossref_metadata_2025 huggingface dataset:
Water and Electrolyte Homeostasis in a Mouse Model with Reduced ENaC Gamma Subunit Expression
Authors: Ray Evan C. , Jordahl Alexa , Marciszyn Allison , Winfrey Aaliyah , Lam Tracey , Barak Yaacov , Sheng Shaohu , Kleyman Thomas R.
Published: January 2021

The epithelial Na+channel (ENaC) promotes the absorption of Na+in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding ENaC’s subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of the γ subunit. We use this hypomorphic (γmt) allele to explore the importance of ENaC’s γ subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ subunit expression in γmt/mtmice is markedly suppressed in kidney and lung, while electrolytes resemble those of littermate controls. Challenge with a high K+diet does not cause significant differences in blood K+, but provokes higher aldosterone in γmt/mtmice than controls. Quantitative magnetic resonance (QMR) measurement of body composition reveals similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mtmice and controls. Surprisingly, euvolemia is sustained without significant changes in aldosterone or atrial natriuretic peptide. γmt/mtmice exhibit a more rapid decline in body water and lean tissue mass in response to a low Na+diet than controls. Replacement of drinking water with 2% saline induces dramatic increases in body fat in both genotypes, and a selective transient increase in body water and lean tissue mass in γmt/mtmice. While ENaC in renal tubules and colon work to prevent extracellular fluid volume depletion, our observations suggest that ENaC in non-epithelial tissues may have a role in preventing extracellular fluid volume overload.
Axial-circular magnetic levitation assisted biofabrication and manipulation of cellular structures
Authors: Anil-Inevi Muge , Delikoyun Kerem , Mese Gulistan , Tekin H. Cumhur , Ozcivici Engin
Published: January 2021

Diamagnetic levitation is an emerging technology for remote manipulation of cells in cell and tissue level applications. Low-cost magnetic levitation configurations using permanent magnets are commonly composed of a culture chamber physically sandwiched between two block magnets that limit working volume and applicability. This work describes a single ring magnet-based magnetic levitation system to eliminate physical limitations for biofabrication. Developed configuration utilizes sample culture volume for construct size manipulation and long-term maintenance. Furthermore, our configuration enables convenient transfer of liquid or solid phases during the levitation. Prior to biofabrication, we first calibrated the platform for levitation with polymeric beads, considering the single cell density range of viable cells. By taking advantage of magnetic focusing and cellular self-assembly, millimeter-sized 3D structures were formed and maintained in the system allowing easy and on-site intervention in cell culture with an open operational space. We demonstrated that the levitation protocol could be adapted for levitation of various cell types (i.e., stem cell, adipocyte and cancer cell) representing cells of different densities by modifying the paramagnetic ion concentration that could be also reduced by manipulating the density of the medium. This technique allowed the manipulation and merging of separately formed 3D biological units, as well as the hybrid biofabrication with biopolymers. In conclusion, we believe that this platform will serve as an important tool in broad fields such as bottom-up tissue engineering, drug discovery and developmental biology.
Genetic depletion of BDNF impairs both context-dependent and context-independent extinction learning of a spatial appetitive task
Authors: Méndez-Couz Marta , Manahan-Vaughan Denise
Published: January 2021

Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent learning, as well as hippocampus-dependent learning. Extinction learning (EL) comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. Concordantly, the participation of BDNF in hippocampus-dependent memory is experience-dependent. BDNF has been associated with synaptic plasticity needed for acquisition and extinction learning of fear conditioning. However, little is known about its influence on the extinction and renewal of spatial appetitive extinction learning (EL). In this study, in BDNF+/−-mice we evaluated to what extent BDNF contributes to spatial appetitive EL in the presence (ABA) or absence (AAA) of a context change. Daily training, to reach acquisition criterion in a T-maze, resulted in a similar outcome in BDNF+/−-mice or their wildtype (wt) littermates. EL was delayed in the AAA, and significantly impaired in the ABA-context compared to EL in wt littermates. When renewal was tested in the ABA paradigm we detected a significant response in wt controls, but not in BDNF+/−-mice. Taken together, these results support an important role for BDNF in EL in AAA and ABA context, as well as renewal of a spatial appetitive task, processes that relate to information updating and retrieval.
Predicting the current and future distribution of four original plants of Gentianae Macrophyllae Radix in China under climate change scenarios
Authors: Cao Houkang , Ma Xiaohui , Liu Li , Xi Shaoyang , Guo Yanxiu , Jin Ling
Published: January 2021

The wild resources of the four original plants (Gentiana crasicaulisDuthie ex Burk,Gentiana dauricaFisch,Gentiana stramineaMaxim, andGentiana macrophyllaPall) of Gentianae Macrophyllae Radix are becoming exhausted. Predicting the distribution under current and future climate scenarios is of significance for the sustainable utilization of resources and ecological protection. In this study, we constructed four species distribution models (SDMs) combining species distribution informations, 19 bioclimatic variables, and the maximum entropy (MaxEnt) model. The results showed that these 4 plants prefer a cool and humid climate. Under the future climate scenarios, the areas of the highly suitable habitats forGentiana crasicaulisDuthie ex Burk andGentiana dauricaFisch were likely to decrease, whileGentiana stramineaMaxim was likely to expand, andGentiana macrophyllaPall was less affected. In addition, the centroids of the highly suitable habitats for the four species shifted north or west. Most notably, most of the highly suitable habitats for the four species remained unchanged, which would be the preferred area for semi-artificial cultivation. The above information in this study would contribute to the development of reasonable strategies to reduce the impact of climate change on the four original plants.
The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome
Authors: Hendriks Ivo A. , Buch-Larsen Sara C. , Prokhorova Evgeniia , Rebak Alexandra K.L.F.S. , Ahel Ivan , Nielsen Michael L.
Published: January 2021

Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyzed human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, we quantified 1,596 ADPr sites, displaying a thousand-fold regulation across investigated knockout cells. We find that HPF1 and ARH3 inversely and homogenously regulate the serine ADP-ribosylome on a proteome-wide scale with consistent adherence to lysine-serine (KS)-motifs suggesting targeting is independent of HPF1 and ARH3. Our data reveal that ADPr globally exists as mono-ADP-ribosylation, and we detail a remarkable degree of histone co-modification with ADPr and other post-translational modifications. Strikingly, no HPF1-dependent target residue switch from serine to glutamate/aspartate was detectable in cells, which challenges current dogma related to PARP1 target residues. Collectively, we elucidate hitherto unappreciated processes related to cellular PARP1 activity.
Population structure limits parallel evolution
Authors: Fang Bohao , Kemppainen Petri , Momigliano Paolo , Merilä Juha
Published: January 2021

Population genetic theory predicts that small effective population sizes (Ne) and restricted gene flow limit the potential for local adaptation. In particular, the probability of evolving similar phenotypes based on shared genetic mechanisms (i.e. parallel evolution), is expected to be reduced. We tested these predictions in a comparative genomic study of two ecologically similar and geographically co-distributed stickleback species(viz. Gasterosteus aculeatusandPungitius pungitius). We found thatP. pungitiusharbours less genetic diversity and exhibits higher levels of genetic differentiation and isolation-by-distance thanG. aculeatus.Conversely,G. aculeatusexhibits a stronger degree of genetic parallelism across freshwater populations thanP. pungitius:2996vs.379 SNPs located within 26vsnine genomic regions show evidence of selection in multiple freshwater populations ofG. aculeatusandP. pungitius, respectively. Most regions involved in parallel evolution inG. aculeatusshowed increased levels of divergence, suggestive of selection on ancient haplotypes. In contrast, regions involved in freshwater adaptation inP. pungitiuswere younger, and often associated with reduced diversity. In accordance with theory, the results suggest that connectivity and genetic drift play crucial roles in determining the levels and geographic distribution of standing genetic variation, providing evidence that population subdivision limits local adaptation and therefore also the likelihood of parallel evolution.
Identification of TIA1 mRNA targets during human neuronal development
Authors: Byres Loryn P. , Mufteev Marat , Yuki Kyoko E. , Wei Wei , Piekna Alina , Wilson Michael D. , Rodrigues Deivid C. , Ellis James
Published: January 2021

Background

Neuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment is still unknown.

Methods and Results

To identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels.

Conclusion

Our results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.
Emergent signal execution modes in biochemical reaction networks calibrated to experimental data
Authors: Ortega Oscar O. , Ozen Mustafa , Wilson Blake A. , Pino James C. , Irvin Michael W. , Ildefonso Geena V. , Garbett Shawn P. , Lopez Carlos F.
Published: January 2021

Mathematical models of biomolecular networks are commonly used to study cellular processes; however, their usefulness to explain and predict dynamic behaviors is often questioned due to the unclear relationship between parameter uncertainty and network dynamics. In this work, we introduce PyDyNo (Python Dynamic analysis of biochemical NetwOrks), a non-equilibrium reaction-flux based analysis to identify dominant reaction paths within a biochemical reaction network calibrated to experimental data. We first show, in a simplified apoptosis execution model, that Bayesian parameter optimization can yield thousands of parameter vectors with equally good fits to experimental data. Our analysis however enables us to identify the dynamic differences between these parameter sets and identify three dominant execution modes. We further demonstrate that parameter vectors from each execution mode exhibit varying sensitivity to perturbations. We then apply our methodology to JAK2/STAT5 network in colony-forming unit-erythroid (CFU-E) cells to identify its signal execution modes. Our analysis identifies a previously unrecognized mechanistic explanation for the survival responses of the CFU-E cell population that would have been impossible to deduce with traditional protein-concentration based analyses.

Impact Statement

Given the mechanistic models of network-driven cellular processes and the associated parameter uncertainty, we present a framework that can identify dominant reaction paths that could in turn lead to unique signal execution modes (i.e., dominant paths of flux propagation), providing a novel statistical and mechanistic insights to explain and predict signal processing and execution.
Maternal lineages from 10-11thcentury commoner cemeteries of the Carpathian Basin
Authors: Maár Kitti , Varga Gergely I. B. , Kovács Bence , Schütz Oszkár , Maróti Zoltán , Kalmár Tibor , Nyerki Emil , Nagy István , Latinovics Dóra , Tihanyi Balázs , Marcsik Antónia , Pálfi György , Bernert Zsolt , Gallina Zsolt , Varga Sándor , Költő László , Raskó István , Török Tibor , Neparáczki Endre
Published: January 2021

Background

Nomadic groups of conquering Hungarians played a predominant role in Hungarian prehistory, but genetic data are available only from the immigrant elite strata. Most of the 10-11th century remains in the Carpathian Basin belong to common people, whose origin and relation to the immigrant elite has been widely debated.

Methods

Mitogenome sequences were determined from 202 individuals with Next Generation Sequencing combined with hybridization capture. Median Joining networks were used for phylogenetic analysis. The commoner population was compared to 87 ancient Eurasian populations with sequence based (Fst) and haplogroup based population genetic methods.

Results

Haplogroup composition of the commoner population markedly differs from the elite and in contrast to the elite, commoners cluster with European populations. Besides, detectable sub-haplogroup sharing indicates admixture between the elite and commoners.

Conclusions

Majority of the 10-11thcentury commoners most likely represent local populations of the Carpathian Basin, which admixed with the eastern immigrant groups including conquering Hungarians.
An active finite viscoelastic model for gastric smooth muscle contraction
Authors: Panda Satish Kumar , Buist Martin Lindsay
Published: January 2021

A coupled electromechanical model to describe the transduction process of cellular electrical activity into mechanical deformation has been presented. The model consolidates a biophysical smooth muscle cell model, a biophysical actin-myosin interaction model, a sliding filament model and a viscoelastic constitutive model to construct an active finite viscoelastic model. The key input to this model is an electrical pulse which then estimates the resulting stress and deformation in the cell. The proposed model was used to recreate experimental observations performed on canine and porcine gastric tissue strips. In all cases, the simulation results were well matched with the experimental data (R2>0.9).
Resource selection by the Endangered Arabian tahr: identifying critical habitats for conservation and climate change adaptation
Authors: Ross S , Rawahi H. , Jahdhami M.H.
Published: January 2021

The Arabian tahr is an Endangered mountain ungulate endemic to the Hajar Mountains of Arabia. The Arabian tahr population is in decline and threats to tahr habitat are intensifying, in addition new potential challenges from climate change are emerging. Fundamental to future conservation planning is understanding tahr habitat selection patterns, so we can prioritise habitat protection, and understand how habitat may be used to provide thermal refuge and allow adaptation to climate change impacts. We used GPS collars and resource selection functions to characterise Arabian tahr habitat preferences in Wadi Sareen Nature Reserve, Oman. We found tahr habitat selection was dependent on scale, sex and season. Vegetation resources were only selected at the smallest scales of selection and avoided at other scales. Habitat providing low heat load and thermal refuge were intensely selected at small and medium scales, by both sexes and in both seasons, suggesting the importance of thermal refuges in facilitating thermoregulation. Higher elevations, steep slopes and rugged habitats were selected across all scales tested here, and in previous landscape-scale studies, indicating the fundamental importance of these habitats in supporting Arabian tahr populations. Our results identified critical habitats required to sustain Arabian tahr, and demonstrated the importance of thermal refuges to species living in the hot climates such as the Arabian Peninsula. Given the accessibility of habitat layers, and ease in which the identified habitats can be mapped using a geographical information system, understanding the habitat selection of tahr and other species is a crucial step to increasing conservation management capacity of threatened species. Given our uncertainty of how to conserve wildlife under future climate change, understanding the availability and distribution of wildlife habitat is an important baseline from where we can plan, connect and preserve the resources necessary for wildlife conservation.
Multiple Mutualist Effects generate synergistic selection and strengthen fitness alignment in a tripartite interaction between legumes, rhizobia, and mycorrhizal fungi
Authors: Afkhami Michelle E. , Friesen Maren L. , Stinchcombe John R.
Published: January 2021

Nearly all organisms interact with multiple mutualists, and complementarity within these complex interactions can result in synergistic fitness effects. However, it remains largely untested how multiple mutualists impact eco-evolutionary dynamics. We tested how multiple microbial mutualists-- N-fixing bacteria and mycorrrhizal fungi-- affected selection and heritability in their shared host plant (Medicago truncatula), as well as fitness alignment between partners. Our results demonstrate for the first time that multispecies mutualisms synergistically affect selection and heritability of host traits and enhance fitness alignment between mutualists. Specifically, we found that multiple mutualists doubled the strength of selection on a plant architectural trait, resulted in 2-3-fold higher heritability of reproductive success, and more than doubled the strength of fitness alignment between N-fixing bacteria and plants. Taken together, these findings show that synergism generated by multiple mutualisms extends to key components of microevolutionary change, and emphasizes the importance of multiple mutualist effects in understanding evolutionary trajectories.
Paths to annihilation: Genetic and demographic consequences of range contraction patterns
Authors: Rogan Jordan , Parker Mickey Ray , Hancock Zachary B. , Earl Alexis D. , Buchholtz Erin K. , Chyn Kristina , Martina Jason , Fitzgerald Lee A.
Published: January 2021

Species range contractions are important contributors to biological annihilation, yet typically do not receive the same attention as extinctions. Range contractions can lead to marked impacts on populations but are often only characterized by measurements of reduced extent. For effective conservation efforts, it is critical to recognize that not all range contractions are the same. We propose four distinct patterns of range contraction:shrinkage,amputation,hollow, andfragmentation. We tested their impact on populations of a generic generalist species using forward-time simulations. Results showed that all four patterns differentially reduced population abundance (declines of 60-80%) and significantly increased average relatedness, with differing patterns in nucleotide diversity (π) declines relative to the contraction pattern. The fragmentation pattern resulted in the strongest effects on post-contraction genetic diversity and structure. Defining and quantifying range contraction patterns and their consequences for the planet’s biodiversity provides necessary information to combat biological annihilation in the Anthropocene.
PRESENILIN 1mutations causing early-onset familial Alzheimer’s disease or familial acne inversa differ in their effects on genes facilitating energy metabolism and signal transduction
Authors: Barthelson Karissa , Dong Yang , Newman Morgan , Lardelli Michael
Published: January 2021

Background

The most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations inPRESENILIN 1(PSEN1) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation inPSEN1causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored.

Objective

To analyse brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity forpsen1mutations causing EOfAD or fAI.

Methods

RNA sequencing was performed on mRNA isolated from the brains of a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenouspsen1gene.

Results

Both mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signalling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signalling revealed possible increases in γ-secretase activity due to heterozygosity for eitherpsen1mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident.

Conclusion

We observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases.
Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling
Authors: Tanaka Tatsuhide , Okuda Hiroaki , Terada Yuki , Shinjo Takeaki , Banja Mitsuko , Nishimura Kazuya , Isonishi Ayami , Furue Hidemasa , Takemura Shoko , Tatsumi Kouko , Wanaka Akio
Published: January 2021

Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identifiedsorting nexin 25(Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior.Snx25conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activatesNgfmRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.
A mean-field approach for modeling the propagation of perturbations in biochemical reaction networks
Authors: Przedborski Michelle , Sharon David , Chan Steven , Kohandel Mohammad
Published: January 2021

Often, the time evolution of a biochemical reaction network is crucial for determining the effects of combining multiple pharmaceuticals. Here we illustrate a mathematical framework for modeling the dominant temporal behaviour of a complicated molecular pathway or biochemical reaction network in response to an arbitrary perturbation, such as resulting from the administration of a therapeutic agent. The method enables the determination of the temporal evolution of a target protein as the perturbation propagates through its regulatory network. The mathematical approach is particularly useful when the experimental data that is available for characterizing or parameterizing the regulatory network is limited or incomplete. To illustrate the method, we consider the examples of the regulatory networks for the target proteins c-Myc and Chop, which play an important role in venetoclax resistance in acute myeloid leukemia. First we show how the networks that regulate each target protein can be reduced to a mean-field model by identifying the distinct effects that groups of proteins in the regulatory network have on the target protein. Then we show how limited proteinlevel data can be used to further simplify the mean-field model to pinpoint the dominant effects of the network perturbation on the target protein. This enables a further reduction in the number of parameters in the model. The result is an ordinary differential equation model that captures the temporal evolution of the expression of a target protein when one or more proteins in its regulatory network have been perturbed. Finally, we show how the dominant effects predicted by the mathematical model agree with RNA sequencing data for the regulatory proteins comprising the molecular network, despite the model not having a priori knowledge of this data. Thus, while the approach gives a simplified model for the expression of the target protein, it allows for the interpretation of the effects of the perturbation on the regulatory network itself. This method can be easily extended to sets of target proteins to model components of a larger systems biology model, and provides an approach for partially integrating RNA sequencing data and protein expression data. Moreover, it is a general approach that can be used to study drug effects on specific protein(s) in any disease or condition.
PilB fromStreptococcus sanguinisis a bimodular type IV pilin with a direct role in adhesion
Authors: Raynaud Claire , Sheppard Devon , Berry Jamie-Lee , Gurung Ishwori , Pelicic Vladimir
Published: January 2021

Type IV pili (T4P) are functionally versatile filamentous nanomachines, nearly ubiquitous in prokaryotes. They are predominantly polymers of one major pilin, but also contain minor pilins whose functions are often poorly defined, and likely to be diverse. Here, we show that the minor pilin PilB from the T4P ofS. sanguinisdisplays an unusual bimodular 3D structure, with a bulky von Willebrand factor A-like (vWA) module “grafted” onto a small pilin module via a short unstructured loop. Structural modelling suggests that PilB is only compatible with a localisation at the tip of T4P. By performing a detailed functional analysis, we found that (i) the vWA module contains a canonical metal ion-dependent adhesion site (MIDAS), preferentially binding Mg2+and Mn2+, (ii) abolishing metal-binding has no impact on the structure of PilB or piliation, (iii) metal-binding is important forS. sanguinisT4P-mediated twitching motility and adhesion to eukaryotic cells, and (iv) the vWA module shows an intrinsic binding ability to several host proteins. These findings reveal an elegant, yet simple, evolutionary tinkering strategy to increase T4P functional versatility, by grafting an adhesive module onto a pilin for presentation by the filaments. This strategy appears to have been extensively used by bacteria, in which modular pilins are widespread and exhibit an astonishing variety of architectures.
Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model
Authors: Joaquín Cáceres C. , Cardenas-Garcia Stivalis , Carnaccini Silvia , Seibert Brittany , Rajao Daniela S. , Wang Jun , Perez Daniel R.
Published: January 2021

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mproinhibitor with antiviral activity against SARS-CoV-2in vitro. Using the K18-hACE2 mouse model, thein vivoantiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18-hACE2 mice and produced milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls, most notably in the brain in mice challenged with a low virus dose. Although GC-376 was not sufficient to improve neither clinical symptoms nor survival, it did show a positive effect against SARS-CoV-2in vivo. This study supports the notion that the K18-hACE2 mouse model is suitable to study antiviral therapies against SARS-CoV-2, and GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection.
The crystal structure and thermal decomposition kinetics of cis-hexanitrostilbene
Authors: Liu Yunzhang , Chen Lizhen , Wang Jianlong , Chen Jun , Wang Jingqi , Pan Hongxia
Published: January 2021

Hexanitrostilbene (HNS) is an energetic material with wide application and excellent comprehensive performance. cis-HNS is successfully prepared using crude HNS with a purity of 95% as the raw material and N-methyl pyrrolidone (NMP) as the solvent. After separation and purification, acetone is used as a solvent to obtain light-yellow crystals at room temperature. The molecular structure of cis-HNS is determined through analysis of Fourier transform infrared, 13C NMR and 1H NMR spectroscopy and single-crystal X-ray diffraction data. The thermal decomposition properties of cis and trans-HNS are studied using differential scanning calorimetry (DSC). When the heating rate is low, cis-HNS will undergo a crystal transformation after melting, from liquid cis-HNS to liquid trans-HNS, and then it will solidify and release heat. According to the results of DSC data, the apparent kinetic parameters of thermal decomposition of cis- and trans-HNS were obtained by Kissinger method [Kissinger (1957). Anal. Chem.
29, 1702–1706] and Ozawa method [Ozawa (1965). Bull. Chem. Soc. Jpn.
38, 1881–1886], respectively. The spontaneous combustion temperature and self-accelerating decomposition temperature of cis and trans-HNS are calculated by the Zhang-Hu-Xie-Li method [Zhang et al. (1994). Thermochim. Acta, 244, 171–176].
Hospital‐physician integration and Medicare’s site‐based outpatient payments
Authors: Post Brady , Norton Edward C. , Hollenbeck Brent , Buchmueller Thomas , Ryan Andrew M.
Published: January 2021

Objective

To determine the relationship between Medicare's site‐based outpatient billing policy and hospital‐physician integration.

Data sources

National Medicare claims data from 2010 to 2016.

Study Design

For each physician‐year, we calculated the disparity between Medicare reimbursement under hospital ownership and under physician ownership. Using logistic regression analysis, we estimated the relationship between these payment differences and hospital‐physician integration, adjusting for region, market concentration, and time fixed effects. We measured integration status using claims data and legal tax names.

Data Collection

The study included integrated and non‐integrated physicians who billed Medicare between January 1, 2010, and December 31, 2016 (n = 2 137 245 physician‐year observations).

Principal Findings

Medicare reimbursement for physician services would have been $114 000 higher per physician per year if a physician were integrated compared to being non‐integrated. Primary care physicians faced a 78% increase, medical specialists 74%, and surgeons 224%. These payment differences exhibited a modest positive relationship to hospital‐physician vertical integration. An increase in this outpatient payment differential equivalent to moving from the 25th to 75th percentile was associated with a 0.20 percentage point increase in the probability of integrating with a hospital (95% CI: 0.0.10‐0.30). This effect was slightly larger among primary care physicians (0.27, 95% CI: 0.18 to 0.35) and medical specialists (0.26, 95% CI: 0.05 to 0.48), while not significantly different from zero among surgeons (−0.02; 95% CI: −0.27 to 0.22).

Conclusions

The payment differences between outpatient settings were large and grew over time. Even routine annual outpatient payment updates from Medicare may prompt some hospital‐physician vertical integration, particularly among primary care physicians and medical specialists.
Forensic analysis of anabolic steroids tablets composition using attenuated total reflection Fourier transform infrared microspectroscopy (µATR‐FTIR) mapping
Authors: Lemos Vanessa Ferreira , Ortiz Rafael Scorsatto , Limberger Renata Pereira
Published: January 2021

The use of falsified and unregistered drugs is a worldwide public health problem. Because these global market products usually do not follow the Good Manufacturing Practices required by health legislation, its composition may be completely different from the original or may contain relevant concentrations of impurities and toxic contaminants. Since anabolic steroids are among the main irregular therapeutic classes seized in Brazil, here we propose a new methodology for analyzing these products, in tablets form, using Attenuated Total Reflection Fourier Transform Infrared Microspectroscopy (µATR‐FTIR) mapping. Spectra were acquired from solid tablets by attenuated total reflection, through point mapping methodology. In data processing, a characteristic absorption band for each Active Pharmaceutical Ingredient (API) was integrated and plotted to create its distribution map. This technique was applied in an unprecedented way for the forensic analysis of anabolic steroids and proved to be effective in distinguishing falsified products based on the detection of their APIs. It was possible to detect APIs in 26 out of 30 samples, five of which were classified as falsified only through µATR‐FTIR analysis. We were able to create distribution maps of the detected substances associating the microspectroscopic results with characteristic band integration method, which can be used to detect substances and to study samples’ homogeneity. We concluded that this methodology is promising for the analysis of anabolic steroid tablets, and can be used in a complementary way with techniques already consolidated in forensic laboratory routine for a better classification of questioned samples between authentic and falsified ones.
Identification of small proline‐rich protein 1B (SPRR1B) as a prognostically predictive biomarker for lung adenocarcinoma by integrative bioinformatic analysis
Authors: Zhang Zihe , Shi Ruifeng , Xu Songlin , Li Yongwen , Zhang Hongbing , Liu Minghui , Zhu Guangsheng , Chen Chen , Pan Zhenhua , Liu Hongyu , Chen Jun
Published: January 2021

Background

With the ongoing development of targeted therapy and immunotherapy in recent years, the overall five‐year survival rate of NSCLC patients has not improved, and the search for novel diagnostic and prognostic markers for lung adenocarcinoma continues.

Methods

Lung adenocarcinoma (LUAD) gene expression data and relevant clinical information were obtained from the TCGA. Hub genes were identified with weighted gene co‐expression network analysis (WGCNA) and protein–protein interaction network (PPI). Survival analyses were also performed using GEPIA. The 536 LUAD patients were divided into two groups according to the SPRR1B expression level and analyzed by gene set enrichment analysis (GSEA) and verified by immunoblotting. The effects of SPRR1B on cell proliferation and cell metastasis and apoptosis were evaluated by 5‐ethynyl‐2′‐deoxyuridine (EdU) staining, colony formation assay, transwell migration and invasion assay, and flow cytometry, respectively.

Results

A total of 2269 DEGs were analyzed by WGCNA and five hub genes (CCK, FETUB, PCSK9, SPRR1B, and SPRR2D) were identified. Among them, SPRR1B was selected as one of the most significant prognostic genes in LUAD. SPRR1B was found to be highly expressed in lung adenocarcinoma cells compared with that in normal bronchial epithelial cells. In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro. The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer.

Conclusions

Our findings demonstrate that SPRR1B may function as a prognosis predictor in lung adenocarcinoma.
Primary mediastinal germ cell tumors ‐ A retrospective analysis of >30 years of experience in a single institution
Authors: Koizumi Tomonobu , Kanda Shintaro , Nihonmatu Ryo , Gomi Daisuke , Sekiguchi Nodoka , Noguchi Takuro , Fukushima Toshirou , Kobayashi Takashi , Yamamoto Hiroshi , Takeda Tetsu
Published: January 2021

Background

This study was performed to clarify the treatment outcome of patients with primary mediastinal germ cell tumors (PMGCTs), focusing on the clinical manifestations and management during definitive therapy and long‐term follow‐up.

Methods

In this study, we retrospectively reviewed the medical records of patients with PMGCTs treated at Shinshu University School of Medicine, and examined the clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal GCTs treated at our hospital between 1983 and 2019.

Results

Five patients were diagnosed with pure seminoma and 17 had nonseminomatous GCT. A total of 21 patients were treated with cisplatin‐based chemotherapy and 15 patients (68.2%) underwent thoracic surgery after chemotherapy. Although all cases of nonseminomatous GCT were negative for tumor markers after cisplatin‐based chemotherapy, two cases showed variable GCT cells and two had somatic components (angiosarcoma and rhabdomyosarcoma) in resected specimens. Three relapsed soon after surgery. Growing teratoma syndrome developed during chemotherapy in four cases. Urgent thoracic surgery was performed in three patients, but one case was inoperable. The calculated 10‐year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. During follow‐up, second non‐GCT malignancies developed in three patients (colon cancer, 190 months; thyroid cancer, 260 months; non‐small cell lung cancer, 250 months after the initial chemotherapy) and one patient with primary mediastinal seminoma was associated with multiple type I endocrine tumors.

Conclusions

Our experiences demonstrated that long‐term survival and/or cure can be achieved with adequate chemotherapy followed by local surgical treatment even in patients with mediastinal GCTs. However, the clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied. In addition, the development of secondary malignancies should be taken into consideration for long‐term follow‐up. Clinicians should be aware of the various clinical features and secondary malignancies in primary mediastinal GCTs.
A visualisation approach for pitching research
Authors: Faff Robert W. , Kernbach Sebastian
Published: January 2021

Based on a simple template tool, Faff’s ‘pitching’ framework provides a succinct and methodical approach to conveying a new research proposal to an academic expert. Some potential users are discouraged by a mistaken belief that it is just a ‘form‐filling’ exercise. We argue that one fruitful way to make the proposed ‘pitching’ process more inviting, support researchers' thinking process and enable a fruitful communication with others is to invoke a visualisation strategy. Accordingly, we propose a visualisation enhancement through visual templates with a particular focus on a ‘canvas’ technique – which we label the ‘Pitching Research Canvas’.
Trajectories of suicidal ideation after first‐episode psychosis: a growth mixture modeling approach
Authors: Salagre Estela , Grande Iria , Jiménez Esther , Mezquida Gisela , Cuesta Manuel J. , Llorente Cloe , Amoretti Sílvia , Lobo Antonio , González‐Pinto Ana , Carballo Juan José , Corripio Iluminada , Verdolini Norma , Castro‐Fornieles Josefina , Legido Teresa , Carvalho Andre F. , Vieta Eduard , Bernardo Miquel ,   PEPs Group
Published: January 2021

Objective

The period immediately after the onset of first‐episode psychosis (FEP) may present with high risk for suicidal ideation (SI) and attempts, although this risk may differ among patients. Thus, we aimed to identify trajectories of SI in a 2‐years follow‐up FEP cohort and to assess baseline predictors and clinical/functional evolution for each trajectory of SI.

Methods

We included 334 FEP participants with data on SI. Growth mixture modeling was used to identify trajectories of SI. Putative sociodemographic, clinical, and cognitive predictors of the distinct trajectories were examined using multinomial logistic regression.

Results

We identified three distinct trajectories:Non‐SItrajectory (85.53% sample),Improving SItrajectory (9.58%), andWorsening SItrajectory (6.89%). Multinomial logistic regression model revealed that greater baseline pessimistic thoughts, anhedonia, and worse perceived family environment were associated with higher baseline SI followed by anImprovingtrajectory. Older age, longer duration of untreated psychosis, and reduced sleep predictedWorsening SItrajectory. Regarding clinical/functional evolution, individuals within theImproving SItrajectory displayed moderate depression at baseline which ameliorated during the study period, while theWorsening SIsubgroup exhibited persistent mild depressive symptoms and greater functional impairment at follow‐up assessments.

Conclusion

Our findings delineated three distinct trajectories of SI among participants with FEP, one experiencing no SI, another in which SI might depend on acute depressive symptomatology, and a last subset where SI might be associated with mild but persistent clinical and functional impairments. These data provide insights for the early identification and tailored treatment of suicide in this at‐risk population.
An evaluation of the variation and underuse of clozapine in the United Kingdom
Authors: Whiskey Eromona , Barnard Alex , Oloyede Ebenezer , Dzahini Olubanke , Taylor David M. , Shergill Sukhwinder S.
Published: January 2021

Background

Clozapine is the only licensed treatment for treatment refractory schizophrenia. Despite this, it remains grossly underused relative to the prevalence of refractory schizophrenia. The extent of underuse and the degree of regional variation in prescribing in the United Kingdom is unknown. It is also unclear, how the UK compares with other European countries in rates of clozapine prescribing.

Methods

We obtained data relating to all clozapine prescribing in the UK from the relevant clozapine registries. We examined regional variation in clozapine use across England, corrected for the known prevalence of severe mental illness (SMI). We also compared the UK rate of clozapine use per 100,000 population to that described in other European countries.

Findings

There is substantial variation in clozapine prescribing across different regions of England and only about a third of potentially eligible patients were prescribed the drug in the UK. Clozapine prescribing rate in the UK was lower than in several European countries.

Interpretation

There is clear regional inequity in access to the most effective treatment in refractory schizophrenia in England. Strategies to increase clozapine use, by overcoming both real and perceived barriers, are urgently necessary to reduce treatment inequity for patients with refractory schizophrenia.
Accidental injury, self‐injury, and assault among children of women with schizophrenia: a population‐based cohort study
Authors: Taylor Clare L. , Brown Hilary K. , Saunders Natasha R. , Barker Lucy C. , Chen Simon , Cohen Eyal , Dennis Cindy‐Lee , Ray Joel G. , Vigod Simone N.
Published: January 2021

Objective

We aimed to compare the risk for injury overall and by intent (accidental injury, self‐injury, and assault) among children born to women with versus without schizophrenia.

Methods

Using health administrative data from Ontario, Canada, children born from 2003 to 2017 to mothers with (n = 3769) and without (n = 1,830,054) schizophrenia diagnosed prior to their birth were compared on their risk for child injury, captured via emergency department, hospitalization, and vital statistics databases up to age 15 years. Cox proportional hazard models generated hazard ratios for time to first injury event (overall and by intent), adjusted for potential confounders (aHR). We stratified by child sex and age at follow‐up: 0–1 (infancy), 2–5 (pre‐school), 6–9 (primary school), and 10–15 (early adolescence) planning to collapse age categories as needed to obtain stable and reportable estimates.

Results

Maternal schizophrenia was associated with elevated risk for child injury overall (105.4 vs. 89.4/1000 person‐years (py), aHR 1.08, 95% CI 1.03–1.14), accidental injury (104.7 vs. 88.1/1000py, 1.08, 1.03–1.14), for self‐injury (0.4 vs. 0.2/1000py, 2.14 1.18–3.85), and assault (1.0 vs. 0.3/1000py, 2.29, 1.45–3.62). By child sex, point estimates were of similar magnitude and direction, though not all remained statistically significant. For accidental injury and self‐injury, the risk associated with maternal schizophrenia was most elevated in 10–15‐year‐olds. For assault, the risk associated with maternal schizophrenia was most elevated among children in the 0–1 and 2–5‐year‐old age groups.

Conclusion

The elevated risk of child injury associated with maternal schizophrenia, especially for self‐injury and assault, suggests that targeted monitoring and preventive interventions are warranted.
Concerns regarding the use of the vulnerability concept in research on people with intellectual disability
Authors: Snipstad Øyvind Ibrahim Marøy
Published: January 2021

Accessible Summary

People with intellectual disability are often described as “vulnerable” or a “vulnerable group.”

The paper focuses on vulnerability as part of an ethical discussion in research.

The paper says that people with intellectual disability are not necessarily more vulnerable than others in all areas of life but, like everyone else, experience many social contexts that may or may not place them in vulnerable positions.

The paper is concerned with how the negative attributes often related to the label intellectual disability and vulnerability affect the decisions and views of researchers.

Background

People with intellectual disability are often defined as a vulnerable group. The feminist philosopher Jackie Scully argues that vulnerability is often associated with qualities such as immaturity, helplessness, victimhood, passivity and so forth. As research is a social activity, the qualities associated with vulnerability affect researchers’ decisions about who to include and exclude from their research project as well as influencing their interpretations of the research participants’ answers, behaviour and actions. This may result in excluding people with intellectual disability from research or that their ways of being becomes interpreted as mere symptoms of their diagnosis rather than subjective opinions and experiences.

Conclusion

By addressing these issues through the work of Norwegian philosopher Hans Skjervheim, this paper contests traditional interpretations of vulnerability and instead argues that vulnerability should be related more specifically to each individual research project and prompt questions such as: How do we protect these particular participants from harm?