bluuebunny/crossref_metadata_2025 huggingface dataset:
intSDM: anRpackage for building a reproducible workflow for the field of integrated species distribution models
Authors: Mostert Philip , Bjørkås Ragnhild , Bruls Angeline J.H.M. , Koch Wouter , Martin Ellen C. , Perrin Sam W.
Published: September 2022

1

There has been an exponential increase in quantity and type of biodiversity data in recent years, including presence-absence, counts, and presence-only citizen science data. Species Distribution Models (SDMs) have typically been used in ecology to estimate current and future ranges of species, and are a common tool used when making conservation prioritisation decisions. However integration of these data in a model-based framework is needed to address many of the current large-scale threats to biodiversity.

Current SDM practice typically underutilizes the large amount of publicly available biodi-versity data and does not follow a set of standard best practices. Integrating different data types with open-source tools and reproducible workflows saves time, increases collaboration opportunities, and increases the power of data inference in SDMs.

We aim to address this issue by (1) proposing methods and (2) generating a reproducible workflow to integrate different available data types to increase the power of SDMs. We provide theRpackageintSDM, as well as guidance on how to accommodate users’ diverse needs and ecological questions with different data types available on the Global Biodiversity Information Facility (GBIF), the largest biodiversity data aggregator in the world.

Finally, we provide a case study of the application of our proposed reproducible workflow by creating SDMs for vascular plants in Norway, integrating presence-only and presence-absence species occurrence data and climate data.
Circadian rhythms in the gut microbiota shape sex differences in host gene expression and metabolism
Authors: Munyoki Sarah K. , Goff Julie P. , Kolobaric Antonija , Long Armari , Mullett Steven J. , Burns Jennifer K. , Jenkins Aaron K. , DePoy Lauren , Wendell Stacy G. , McClung Colleen A. , Morrison Kathleen E. , Jašarević Eldin
Published: September 2022

Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific microbial circadian rhythms in host metabolism using germ-free and conventionalized female and male mice, dietary manipulations, coupled with a systems biology approach. Sex differences in circadian rhythms of genes involved in immunity and metabolism are dependent on oscillations in the microbiota, microbial metabolic functions, and microbial metabolites. Further, dietary factors modify the magnitude of sex differences in host-microbe circadian dynamics. We show that consuming an obesogenic high-fat, low-fiber diet produced sex-specific changes in circadian rhythms in microbiota, metabolites, and host gene expression, which were linked to sex differences in the severity of metabolic dysfunction. These results reveal that microbial circadian rhythms contribute to sex differences in metabolism, emphasizing the need to consider sex as a biological variable in research on microbial contributions to metabolic dysfunction.

HIGHLIGHTS

Microbial circadian rhythms differ by sex.

Sex-specific rhythms in host transcriptional networks are microbiome-dependent.

Diet-induced obesity entrains new sex-specific rhythms in microbiome and host genes.

Timing of data collection influences magnitude of sex differences.
Parvalbumin protein controls inhibitory tone in the spinal cord
Authors: Qiu Haoyi , Miraucourt Lois , Petitjean Hugues , Davidova Albena , Levesque-Damphousse Philipa , Estall Jennifer L. , Sharif-Naeini Reza
Published: September 2022

The nervous system processes sensory information by relying on the precise coordination of neuronal networks and their specific synaptic firing patterns. In the spinal cord, disturbances to the firing pattern of the tonic firing parvalbumin (PV)-expressing inhibitory interneuron (PV neurons) disrupt the ability of the dorsal horn to integrate touch information and may result in pathological phenotypes. The parvalbumin protein (PVp) is a calcium (Ca2+)-binding protein that buffers the accumulation of Ca2+ following a train of action potential to allow for tonic firing. Here, we find that peripheral nerve injury causes a decrease in PVp expression in PV neurons and makes them transition from tonic to adaptive firing. We also show that reducing the expression of PVp causes otherwise healthy adult mice to develop mechanical allodynia and causes their PV neurons to lose their high frequency firing pattern. We show that this frequency adaptation is mediated by activation of SK channels on PV neurons. Further, we show their tonic firing can be partially restored after nerve injury by selectively inhibiting the SK2 channels of PV neurons. We also reveal that a decrease in the transcriptional coactivator, PGC-1α, causes decrease PVp expression and the development of mechanical allodynia. By preventing the decrease in PVp expression before nerve injury, we were able to protect mice from developing mechanical allodynia. Our results indicate an essential role for PVp-mediated calcium buffering in PV neuron firing activity and the development of mechanical allodynia after nerve injury.
Insights into the molecular mechanism of translation inhibition by the ribosome-targeting antibiotic thermorubin
Authors: Paranjpe Madhura N. , Marina Valeria I. , Grachev Aleksandr A. , Maviza Tinashe P. , Tolicheva Olga A. , Paleskava Alena , Osterman Ilya A. , Sergiev Petr V. , Konevega Andrey L. , Polikanov Yury S. , Gagnon Matthieu G.
Published: September 2022

Thermorubin (THR) is an aromatic anthracenopyranone antibiotic active against both Gram-positive and Gram-negative bacteria. It is known to bind to the 70S ribosome at the intersubunit bridge B2a and was thought to inhibit factor-dependent initiation of translation and obstruct the accommodation of tRNAs into the A site. Here, we show that thermorubin causes ribosomes to stall in vivo and in vitro at internal and termination codons, thereby allowing the ribosome to initiate protein synthesis and translate at least a few codons before stalling. Our biochemical data show that THR affects multiple steps of translation elongation with a significant impact on the binding stability of the tRNA in the A site, explaining premature cessation of translation. Our high-resolution crystal and cryo-EM structures of the 70S-THR complex show that THR can co-exist with P- and A-site tRNAs, explaining how ribosomes can elongate in the presence of the drug. Remarkable is the ability of THR to arrest ribosomes at the stop codons. Our data suggest that by causing structural re-arrangements in the decoding center, THR interferes with the accommodation of tRNAs or release factors into the ribosomal A site.

HIGHLIGHTS

Thermorubin is a potent inhibitor of protein synthesis both in vivo and in vitro;

Thermorubin does not prevent the binding of P- and A-site tRNAs;

Thermorubin affects multiple steps of translation elongation with a major impact on binding stability of the A-site tRNA;

Thermorubin can act as an inhibitor of translation termination on some ORFs.
Geological drivers of diversification in Papuan microhylid frogs
Authors: Hill Ethan C. , Gao Diana F. , Polhemus Dan A. , Fraser Claire J. , Iova Bulisa , Allison Allen , Butler Marguerite A.
Published: September 2022

Abstract

Studies of the Papuan region have provided fundamental insights into both the evolutionary processes generating its exceptional biodiversity, as well support for alternative hypotheses of geological history. Lying at the junction of five tectonic plates, this region has experienced a turbulent geological history that has not only produced towering mountains allowing elevational specialization, and island archipelagos of varying distance promoting vicariance, but also active margins where land masses have collided and been subsequently rifted apart creating a mosaic of intermixed terranes with vastly different geological histories which may influence the evolutionary history of its biota. Asterophryine frogs are a hyperdiverse clade representing half the world’s microhylid diversity (over 360 species) centered on New Guinea and its satellite islands. We show that vicariance facilitated by geological history, and not elevational specialization best explain this far and wide distribution of a clade that should have poor dispersal abilities. Thus, some of the predictions of island biogeography theory are supported if informed by geological history. We recovered a mainland tectonic unit, the East Papua Composite Terrane (EPCT), as the center of origin for Asterophryinae and no fewer than 71 instances of what appear to be long-distance dispersal events, 29 of which are between mainland regions, with 42 from the mainland to the islands, some presently as far as 200 km away from source populations over open ocean. Furthermore, we find strong support for a “Slow and Steady” hypothesis for the formation of the northern margin of New Guinea by many separate accretion events during the Miocene, over other major geological alternatives, consistent with the 20 M year age of the clade and arrival via the EPCT. In addition, the historical biogeography of our frogs strongly support an affiliation of the Louisiade Archipelago and Woodlark Island with the Owen Stanley Mountain range on the EPCT, and the recent proximity of the large New Britain island. Our results show that Asterophryinae did not have to repeatedly and independently disperse across and large ocean barriers to the offshore islands, but that the current distribution can be explained through vicariance and short-distance oceanic dispersal as historical land connections disappeared and islands slowly became separated from each other. We show that islands have a life history, undergoing changes in area through island-building and erosion, but also change in distance from other land masses, with consequent opportunities for dispersal, isolation, and cladogenesis of their biotas. More broadly, we can begin to see how the geological history of the Papuan region can result in the rapid accumulation and staggering number of extant species.
Glucocorticoids negatively relate to body mass on the short-term in a free-ranging ungulate
Authors: Lalande Lucas D. , Gilot-Fromont Emmanuelle , Carbillet Jeffrey , Débias François , Duhayer Jeanne , Gaillard Jean-Michel , Lemaître Jean-François , Palme Rupert , Pardonnet Sylvia , Pellerin Maryline , Rey Benjamin , Vuarin Pauline
Published: September 2022

Environmental fluctuations force animals to adjust glucocorticoids (GCs) secretion and release to current conditions. GCs are a widely used proxy of an individual stress level. While short-term elevation in GCs is arguably beneficial for fitness components, previous studies have documented that the relationship between long-term baseline GCs elevation and fitness components can vary according to ecological and individual factors and according to the life-history of the species studied. Using longitudinal data on roe deer (Capreolus capreolus) from two populations facing markedly different environmental contexts, we tested whether baseline GC levels negatively correlate with body mass – a trait positively associated with demographic individual performance – on the short- to long-term. In support, higher baseline GC concentrations were associated to lighter body mass, both measured during the same capture event, in adults of both populations. Overall, we showed that despite the marked environmental and demographic differences between populations and despite the between-sex differences in life history (i.e. reproductive tactics), the relationship between body mass and GCs is consistent across environmental contexts, but might differ according to the life history stage of an individual. This work opens promising perspectives to further explore the relationship between GC and fitness-related traits according to life history stages in free-ranging mammals across seasonal and environmental contexts. The timing and context-dependence of GC levels highlight the complexity of studying stress responses in the wild.
MEF2A suppresses replicative stress responses that trigger DDX41-dependent IFN production
Authors: Smith Julian R. , Dowling Jack W. , Karp Andrew , Schwerk Johannes , Savan Ram , Forero Adriana
Published: September 2022

Interferons (IFN) are induced by sensing of self- and non-self DNA or genomic lesions by pathogen recognition receptors (PRR) that activate STING. These pathways must be kept in check by negative regulators to prevent unscheduled activation of IFN, which contributes to autoinflammation. Here we show that MEF2A as a novel negative regulator of inflammation that suppresses homeostatic induction of IFNs. Indeed, MEF2A deficiency results in the spontaneous production of type I IFN and robust downstream IFN-stimulated gene expression that coincided with a robust cellular antiviral state. Mechanistically, MEF2A depletion promoted the accumulation of R-loops that activate the DDX41/STING pathway. This pro-inflammatory pathway was dependent on ATR kinase activity, hallmark of the replicative stress response, was necessary for the activation of STING upon loss of MEF2A expression. Thus, our study connects MEF2A with protection from maladaptive type I IFN responses triggered by R-loop accumulation and links the DDX41-dependent activation of STING to the DNA damage response.
Can root systems redistribute soil water to mitigate the effects of drought?
Authors: Mair Andrew , Dupuy Lionel X , Ptashnyk Mariya
Published: September 2022

Plants adapt both morphologically and physiologically in response to drought. This work considers another potential mechanism of plant drought resistance. Namely, the capacity of root systems to modify the hydraulic properties of surrounding soil, and extend the post-precipitation lifetime of water in the rooted zone.

In studies of plant drought resistance, the effect of root-oriented preferential soil water transport is seldom considered, despite experimental evidence that it occurs. We developed a model for water transport through soil that incorporates preferential flow induced by a root system. Bayesian optimisation was employed to calibrate the model against experimental data, and the finite element method was used to obtain model simulations for the influence of different root architectures on post-precipitation water lifetime.

When increasing preferential flow strength, simulations indicated a trade-off between evaporation and deep percolation losses. It was also observed that the soil surrounding root systems with a reduced gravitropic response, retained the most water following precipitation.

This work provides new insight into the role of root system traits in plant drought resistance, and identifies potential crop phenotypes for improved water use efficiency.
Cell-type-specific roles of inhibitory interneurons in the rehabilitation of auditory cortex after peripheral damage
Authors: Kumar Manoj , Handy Gregory , Kouvaros Stylianos , Ljungqvist Brinson Lovisa , Bizup Brandon , Doiron Brent , Tzounopoulos Thanos
Published: September 2022

Peripheral sensory organ damage leads to compensatory cortical plasticity that supports a remarkable recovery of perceptual capabilities. A major knowledge gap is the lack of precise mechanisms that explain how this plasticity is implemented and distributed over a diverse collection of excitatory and inhibitory cortical neurons. Here, we explored these mechanisms in mouse A1. After peripheral damage, we found recovered sound-evoked activity of excitatory principal neurons (PNs) and parvalbumin (PVs) interneurons (INs), reduced activity in somatostatin-INs (SOMs), and recovered activity in vasoactive intestinal peptide-INs (VIPs). Given the sequentially organized cortical network where VIPs inhibit INs, SOMs inhibit PVs and PNs, and PVs inhibit PNs, our results suggest that PVs contribute to PN stability, SOMs allow for increased PN and PV activity, and VIPs enable the PN and PV recovery by inhibiting SOMs. These results highlight a strategic, cooperative, and cell-type-specific plasticity program that restores cortical sound processing after peripheral damage.
Translating DNA origami Nanotechnology to Middle School, High School, and Undergraduate Laboratories
Authors: Beshay P. E. , Kucinic A. , Wile N. , Halley P. , Des Rosiers L. , Chowdhury A. , Hall J. L. , Castro C. E. , Hudoba M. W.
Published: September 2022

DNA origami is a rapidly emerging nanotechnology that enables researchers to create nanostructures with unprecedented geometric precision that have tremendous potential to advance a variety of fields including molecular sensing, robotics, and nanomedicine. Hence, many students could benefit from exposure to basic knowledge of DNA origami nanotechnology. However, due to the complexity of design, cost of materials, and cost of equipment, experiments with DNA origami have been limited mainly to research institutions in graduate level laboratories with significant prior expertise and well- equipped laboratories. This work focuses on overcoming critical barriers to translating DNA origami methods to educational laboratory settings. In particular, we present a streamlined protocol for fabrication and analysis of DNA origami nanostructures that can be carried out within a 2-hour laboratory course using low-cost equipment, much of which is readily available in educational laboratories and science classrooms. We focus this educational experiment module on a DNA origami nanorod structure that was previously developed for drug delivery applications. In addition to fabricating nanostructures, we demonstrate a protocol for students to analyze structures via gel electrophoresis using classroom-ready gel equipment. These results establish a basis to expose students to DNA origami nanotechnology and can enable or reinforce valuable learning milestones in fields such as biomaterials, biological engineering, and nanomedicine. Furthermore, introducing students to DNA nanotechnology and related fields can also have the potential to increase interest and future involvement by young students.

GRAPHICAL ABSTRACT
Visual-motor integration deficits in 3q29 deletion syndrome
Authors: Pollak Rebecca M , Burrell T Lindsey , Cubells Joseph F , Klaiman Cheryl , Murphy Melissa M , Saulnier Celine A , Walker Elaine F , White Stormi Pulver , Mulle Jennifer G
Published: September 2022

Purpose

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population.

Methods

Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function.

Results

Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment.

Conclusion

The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability, and that all individuals with 3q29del may benefit from early interventions, including occupational therapy.
The Slingshot phosphatase 2 is required for acrosome biogenesis during spermatogenesis in mice
Authors: Xu Ke , Su Xianwei , Fang Kailun , Lv Yue , Lu Gang , Chan Waiyee , Chen Zi-Jiang , Ma Jinlong , Liu Hongbin
Published: September 2022

The acrosome is a membranous organelle positioned in the anterior portion of sperm head and is essential for male fertility. Acrosome biogenesis requires the dynamic cytoskeletal shuttling of vesicles towards nascent acrosome which is regulated by a series of accessory proteins. However, much remains unknown about the molecular basis underlying this process. Here, we generatedSsh2knock-out (KO) mice and show that Slingshot phosphatase 2 (SSH2), a regulator of actin remodeling, is essential for acrosome biogenesis and male fertility. InSsh2KO males, spermatogenesis was arrested at the early spermatid stage with enhanced germ cell apoptosis and the impaired acrosome biogenesis was characterized by defective transport/fusion of proacrosomal vesicles. Moreover, disorganized F-actin structures accompanied by excessive phosphorylation of COFILIN were observed in testes ofSsh2KO mice. Collectively, our data reveal a modulatory role for SSH2 in acrosome biogenesis through COFILIN-mediated actin remodeling and the indispensability of this phosphatase in male fertility in mice.
Dehydration alters transcript levels in the mosquito midgut, likely facilitating rapid rehydration
Authors: Holmes Christopher J. , Brown Elliott S. , Sharma Dhriti , Warden Matthew , Pathak Atit , Payton Blaine , Nguyen Quynh , Spangler Austin , Sivakumar Jaishna , Hendershot Jacob M. , Benoit Joshua B.
Published: September 2022

The mosquito midgut is an important site for bloodmeal regulation while also acting as a primary site for pathogen exposure within the mosquito. Recent studies show that exposure to dehydrating conditions alters mosquito bloodfeeding behaviors as well as post-feeding regulation, likely altering how pathogens interact with the mosquito. Unfortunately, few studies have explored the underlying dynamics between dehydration and bloodmeal utilization, and the overall impact on disease transmission dynamics remains veiled. In this study, we find that dehydration-based feeding in the yellow fever mosquito,Aedes aegypti, prompts alterations to midgut gene expression, as well as subsequent physiological factors involving water control and post-bloodfeeding (pbf) regulation. Altered expression of ion transporter genes in the midgut of dehydrated mosquitoes and rapid reequilibration of hemolymph osmolality after a bloodmeal indicate an ability to expedite fluid and ion processing. These alterations ultimately indicate that femaleA. aegyptiemploy mechanisms to ameliorate the detriments of dehydration by imbibing a bloodmeal, providing an effective avenue for rehydration. Continued research into bloodmeal utilization and the resulting effects on arthropod-borne transmission dynamics becomes increasingly important as drought prevalence is increased by climate change.
Chronic Gq activation of ventral hippocampal neurons and astrocytes differentially affects memory and behavior
Authors: Suthard Rebecca L. , Jellinger Alexandra L. , Surets Michelle , Shpokayte Monika , Pyo Angela Y. , Buzharsky Michelle D. , Senne Ryan A. , Dorst Kaitlyn , Leblanc Heloise , Ramirez Steve
Published: September 2022

Network dysfunction is implicated in numerous diseases and psychiatric disorders, and the hippocampus serves as a common origin for these abnormalities. To test the hypothesis that chronic modulation of neurons and astrocytes induces impairments in cognition, we activated the hM3D(Gq) pathway in CaMKII+ neurons or GFAP+ astrocytes within the ventral hippocampus across 3, 6 and 9 months. CaMKII-hM3Dq activation impaired fear extinction at 3 months and acquisition at 9 months. Both CaMKII-hM3Dq manipulation and aging had differential effects on anxiety and social interaction. GFAP-hM3Dq activation impacted fear memory at 6 and 9 months. GFAP-hM3Dq activation impacted anxiety in the open field only at the earliest time point. CaMKII-hM3Dq activation modified the number of microglia, while GFAP-hM3Dq activation impacted microglial morphological characteristics, but neither affected these measures in astrocytes. Overall, our study elucidates how distinct cell types can modify behavior through network dysfunction, while adding a more direct role for glia in modulating behavior.

Highlights

CaMKII- and GFAP-Gq activation impacted memory, anxiety, and social behaviors.

Novel environment exploration was affected by CaMKII- and GFAP-Gq activation.

CaMKII-Gq modified microglial number, while GFAP-Gq affected microglial morphology.

Neither cell manipulation affected astrocytic number or morphology.
Illuminating histidine phosphorylation in the pancreatic tumor microenvironment
Authors: Luhtala Natalie , Lytle Nikki , DelGiorno Kathleen E. , Shi Yu , Naeem Razia , Hollingsworth Michael A. , Kaech Susan M. , Wahl Geoffrey M. , Hunter Tony
Published: September 2022

Development of phosphohistidine (pHis) antibodies has significantly advanced our understanding of pHis contributions to tumor biology, including a tumor suppressive role for a pHis phosphatase, a metastasis suppressive role for His kinases, and pHis regulation of T cell receptor signaling. Using these antibodies, we investigated pHis pathway regulation in the mouse pancreatic tumor microenvironment. We identified deregulated expression of pHis and pHis phosphatases that correlated with mouse pancreatic tumor progression. We developed a protocol to circumvent the acid and heat-sensitivity of pHis signals, enabling their co-staining with other proteins in FFPE tissue, identifying a significant enrichment of 1-pHis and a subtype of 3-pHis signals (Gly-3-pHis) in the stroma. We discovered increased Gly-3-pHis levels in tumor-associated myeloid cells mainly resulting from elevated ATP citrate lyase 3-pHis levels and predicted the existence of pHis in cell-cell adhesion proteins. We provide evidence that mitochondrial delocalization of PGAM5, a pHis phosphatase with increased expression during pancreatic tumorigenesis, occurs in tumor cells as compared to stromal cells, enabling access to PGAM5’s known cytoplasmic substrate, pHis-NME (Non-MEtastatic), and two potential Gly-3-pHis substrates, SCSα (Succinyl CoA Synthetase) and β-catenin. Overall, we introduce a new method and possible targets for future studies of pHis pathway deregulation during tumorigenesis.
CTCF and R-loops are boundaries of cohesin-mediated DNA looping
Authors: Zhang Hongshan , Shi Zhubing , Banigan Edward J. , Kim Yoori , Yu Hongtao , Bai Xiao-chen , Finkelstein Ilya J.
Published: September 2022

Cohesin and CCCTC-binding factor (CTCF) are key regulatory proteins of three-dimensional (3D) genome organization. Cohesin extrudes DNA loops that are anchored by CTCF in a polar orientation. Here, we present direct evidence that CTCF binding polarity controls cohesin-mediated DNA looping. Using single-molecule imaging of CTCF-cohesin collisions, we demonstrate that a critical N-terminal motif of CTCF blocks cohesin translocation and DNA looping. The cryo-electron microscopy structure of the intact cohesin-CTCF complex reveals that this CTCF motif ahead of zinc-fingers can only reach its binding site on the STAG1 cohesin subunit when the N-terminus of CTCF faces cohesin. Remarkably, a C-terminally oriented CTCF accelerates DNA compaction by cohesin. DNA-bound Cas9 and Cas12a ribonucleoproteins are also polar cohesin barriers, indicating that stalling is intrinsic to cohesin itself, and other proteins can substitute for CTCF in fruit flies and other eukaryotes. Finally, we show that RNA-DNA hybrids (R-loops) block cohesin-mediated DNA compaction in vitro and are enriched with cohesin subunits in vivo, likely forming TAD boundaries. Our results provide direct evidence that CTCF orientation and R-loops shape the 3D genome by directly regulating cohesin.
ReproTox-KG: Toxicology Knowledge Graph for Structural Birth Defects
Authors: Evangelista John Erol , Clarke Daniel J. B. , Xie Zhuorui , Marino Giacomo B. , Utti Vivian , Ahooyi Taha M. , Jenkins Sherry L. , Taylor Deanne , Bologa Cristian G. , Yang Jeremy J. , Binder Jessica L. , Kumar Praveen , Lambert Christophe G. , Grethe Jeffrey S. , Wenger Eric , Oprea Tudor I. , de Bono Bernard , Ma’ayan Avi
Published: September 2022

Birth defects are functional and structural abnormalities that impact 1 in 33 births in the United States. Birth defects have been attributed to genetic as well as other factors, but for most birth defects there are no known causes. Small molecule drugs, cosmetics, foods, and environmental pollutants may cause birth defects when the mother is exposed to them during pregnancy. These molecules may interfere with the process of normal fetal development. To characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with an initial focus on associations between birth defects, drugs, and genes. Specifically, to construct ReproTox-KG we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression data, known drug targets, genetic burden scores for all human genes, and placental crossing scores for all small molecules in ReproTox-KG. Using the data stored within ReproTox-KG, we scored 30,000 preclinical small molecules for their potential to induce birth defects. Querying the ReproTox-KG, we identified over 500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG is provided as curated tables and via a web-based user interface that can enable users to explore the associations between birth defects, approved and preclinical drugs, and human genes.
Using Generalized Structured Additive Regression Models to determine factors associated with and clusters for COVID-19 hospital deaths in South Africa
Authors: Maposa Innocent , Welch Richard , Ozougwu Lovelyn , Arendse Tracy , Mudara Caroline , Blumberg Lucille , Jassat Waasila
Published: September 2022

Background

The first case of COVID-19 in South Africa was reported in March 2020 and the country has since recorded over 3.6 million laboratory-confirmed cases and 100 000 deaths as of March 2022. Transmission and infection of SARS-CoV-2 virus and deaths in general due to COVID-19 have been shown to be spatially associated but spatial patterns in in-hospital deaths have not fully been investigated in South Africa. This study uses national COVID-19 hospitalization data to investigate the spatial effects on hospital deaths after adjusting for known mortality risk factors.

Methods

COVID-19 hospitalization data and deaths were obtained from the National Institute for Communicable Diseases (NICD). Generalized structured additive logistic regression model was used to assess spatial effects on COVID-19 in-hospital deaths adjusting for demographic and clinical covariates. Continuous covariates were modelled by assuming second-order random walk priors, while spatial autocorrelation was specified with Markov random field prior and fixed effects with vague priors respectively. The inference was fully Bayesian.

Results

The risk of COVID-19 in-hospital mortality increased with patient age, with admission to intensive care unit (ICU) (aOR=4.16; 95% Credible Interval: 4.05-4.27), being on oxygen (aOR=1.49; 95% Credible Interval: 1.46-1.51) and on invasive mechanical ventilation (aOR=3.74; 95% Credible Interval: 3.61-3.87). Being admitted in a public hospital (aOR= 3.16; 95% Credible Interval: 3.10-3.21) was also significantly associated with mortality. Risk of in-hospital deaths increased in months following a surge in infections and dropped after months of successive low infections highlighting crest and troughs lagging the epidemic curve. After controlling for these factors, districts such as Vhembe, Capricorn and Mopani in Limpopo province, and Buffalo City, O.R. Tambo, Joe Gqabi and Chris Hani in Eastern Cape province remained with significantly higher odds of COVID-19 hospital deaths suggesting possible health systems challenges in those districts.

Conclusion

The results show substantial COVID-19 in-hospital mortality variation across the 52 districts. Our analysis provides information that can be important for strengthening health policies and the public health system for the benefit of the whole South African population. Understanding differences in in-hospital COVID-19 mortality across space could guide interventions to achieve better health outcomes in affected districts.
Observational assessments of the relationship of dietary and pharmacological treatment on continuous measures of dysglycemia over 24 hours in women with gestational diabetes
Authors: Dingena Cassy F. , Holmes Melvin J. , Campbell Matthew D. , Cade Janet E. , Scott Eleanor M. , Zulyniak Michael A.
Published: September 2022

Objectives

Studies that use continuous glucose monitoring (CGM) to monitor women with gestational diabetes (GDM) highlight the importance of managing dysglycemia over a 24-hour period. However, the effect of current treatment methods on dysglycemia over 24-hrs are currently unknown. This study aimed to characterise CGM metrics over 24-hrs in women with GDM and the moderating effect of treatment strategy.

Methods

Retrospective analysis of CGM data from 128 women with GDM in antenatal diabetes clinics. CGM was measured for 7-days between 30-32 weeks gestation. Non-parametric tests were used to evaluate differences of CGM between periods of day (morning, afternoon, evening, and overnight) and between treatment methods (i.e., diet alone or diet+metformin). Exploratory analysis in a subgroup of 34 of participants was performed to investigate the association between self-reported macronutrient intake and glycaemic control.

Results

Glucose levels significantly differed during the day (i.e., morning to evening; P<0.001) and were significantly higher (i.e., mean blood glucose and AUC) and more variable (i.e., SD and CV) than overnight glucose levels. Morning showed the highest amount of variability (CV; 8.4% vs 6.5%, P<0.001 and SD; 0.49 mmol/L vs 0.38 mmol/L, P<0.001). When comparing treatment methods, mean glucose (6.09 vs 5.65 mmol/L; P<0.001) and AUC (8760.8 vs 8115.1 mmol/L.hr; P<0.001) were significantly higher in diet+metformin compared to diet alone. Finally, the exploratory analysis revealed a favourable association between higher protein intake (+1SD or +92 kcal/day) and lower mean glucose (-0.91 mmol/L p, P=0.02) and total AUC (1209.6 mmol/L.h, P=0.021).

Conclusions

Glycemia varies considerably across a day, with morning glycemia demonstrating greatest variability. Additionally, our work confirms that individuals assigned to diet+metformin have greater difficulty managing glycemia and results suggest that increased dietary protein may assist with management of dysglycemia. Future work is needed to investigate the benefit of increased protein intake on management of dysglycemia.
Real World Effectiveness of Tixagevimab/cilgavimab (Evusheld) in the Omicron Era
Authors: Chen Benjamin , Haste Nina , Binkin Nancy , Law Nancy , Horton Lucy E. , Yam Nancy , Chen Victor , Abeles Shira
Published: September 2022

Background

Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based off of results from a clinical trial conducted prior to the Omicron variant. Its clinical effectiveness has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all cases.

Methods

We used the electronic medical record to identify patients who received T/C at our institution. Among these patients, we assessed for cases of symptomatic COVID-19 and associated hospitalizations before and after receiving T/C. We used chi square tests and Fishers exact p-values to examine differences between characteristics of those who got COVID before and after T/C prophylaxis.

Results

Of 1295 T/C recipients, 121 (9.3%) developed symptomatic COVID-19 before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Among those with infection prior to T/C, 36/121 (29.8%) were hospitalized, including 8 (6.6%) admitted to the ICU. Among those with COVID-19 after receiving T/C, 6/102 (5.9%) were hospitalized but none required ICU admission. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected prior to T/C treatment occurred during Omicron BA.1 surge, while the majority of cases among post-T/C recipients occurred when BA.5 was predominant. Patients infected with COVID-19 prior to receiving T/C had received fewer vaccine doses and were less likely to receive COVID-19 therapeutics compared to those with COVID-19 after having received T/C.

Conclusion

We identified COVID-19 infections after T/C prophylaxis. Among persons eligible for T/C, COVID-19 illnesses occurring after T/C were less likely to require hospitalization compared to those with COVID-19 prior to T/C. In the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.
New primer sets to detect recent human adenovirus F41 variants in wastewater: Is it linked to the new acute hepatitis?
Authors: Perez-Zabaleta Mariel , Williams Cecilia , Cetecioglu Zeynep
Published: September 2022

Human adenovirus type F-41 has been pursued as one of the potential reasons for the new acute hepatitis cases of unknown cause in young children. Tracking the spread of this virus in the population using wastewater-based epidemiology tools can help clinical investigations to determine its relation to this new hepatitis outbreak.

In this study, methods to detect human adenovirus type F (40 and 41) and specifically type F41 were designed and implemented to quantify the amount of these pathogens in wastewater samples from Stockholm, Sweden. An assay based on reverse transcriptase quantitative polymerase chain reaction using TaqMan technology and primers targeting the three main capsid genes of adenoviruses: hexon, penton and fiber, was designed. The hexon primers were specific to adenovirus F41, while fiber primers could quantify both adenoviruses, F40 and F41. Wastewater samples from Stockholm were used to validate the designed assay and, in addition, pepper mild mottle virus (PMMoV) levels were quantified to study the data normalization.

Our results can help link the occurrence of the virus variant with new cases of acute hepatitis and contribute to a better understanding of the possible causes. It can also provide valuable information that can be used in future investigations on the monitoring of human adenovirus type F in wastewater.
A Novel Machine Learning Systematic Framework and Web Tool for Breast Cancer Survival Rate Assessment
Authors: Ji Jonathan M. , Shen Wen H.
Published: September 2022

Cancer research, including that of breast cancer, has increasingly relied on molecular profiling based on advances in genomic technology. Although these techniques have permitted scientists to unravel the process by which cancer develops, scientists still struggle to effectively translate the vast amounts of patient data into clinically meaningful results. As a result, tasks such as predicting the human response to differing treatments remains a major challenge in cancer treatment.

There have been many studies attempting to determine the survival indicators of breast cancer patients. However, most of these analyses were predominantly performed using traditional statistical methods, which are imperfect and inadequate in tackling vast amounts of data or unstructured data on human breast cancer. With the exponential progress in computing power and artificial intelligence approaches, we believe that there is an opportunity for machine learning to supersede our current capabilities in fully understanding the correlations between geneset alterations, drug responses, and the prognosis of breast cancer patients. This information would greatly benefit scientists and physicians in developing clinical therapeutic strategies, such as performing personalized treatment.

This machine learning project employs multiple machine learning approaches, including a novel deep learning algorithm, in building models for the detection and visualization of significant prognostic indicators of breast cancer patient survival rate. The clinical and genomic data of 1,980 primary breast cancer samples used in this project were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database of cBioPortal. The data was preprocessed and then split to train eight classical machine learning models and the aforementioned deep learning Convolutional Neural Network (CNN) model.

These models were evaluated using the recall scores, the accuracy scores, the receiver operating characteristic (ROC) curve, and the area under the ROC curve (AUC) on the training dataset and confirmed using the rest of the data of the dataset. Both the deep learning and machine learning methods produced desirable prediction accuracies. However, the deep learning model noticeably outperformed all other classifiers and achieved the highest accuracy (AUC = 0.900). This project was constructed in the Google Colab environment based on python and its programming libraries with data visualization, Tensorflow, and Keras.

The CNN model demonstrates a powerful ability to be used as a systematic framework for real time prediction by end users. A web application for the breast cancer survival rate prediction was designed and developed using streamlit, Tensorflow, Keras and python libraries to allow end-users to interact with the model with ease and obtain quick and accurate prediction.
Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism
Authors: Arbogast Florent , Sal-Carro Raquel , Boufenghour Wacym , Frenger Quentin , Bouis Delphine , De La Palavesa Louise Filippi , Fauny Jean-Daniel , Griso Olivier , Puccio Hélène , Fima Rebecca , Huby Thierry , Gautier Emmanuel L. , Molitor Anne , Carapito Raphaël , Bahram Seiamak , Romani Nikolaus , Clausen Björn E. , Voisin Benjamin , Mueller Christopher G. , Gros Frédéric , Flacher Vincent
Published: September 2022

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of eitherAtg5orAtg7in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.
Utilizing Evolutionary Conservation to Detect Deleterious Mutations and Improve Genomic Prediction in Cassava
Authors: Long Evan M , Romay M. Cinta , Buckler Edward S. , Robbins Kelly R
Published: September 2022

Cassava (Manihot esculenta) is an annual root crop which provides the major source of calories for over half a billion people around the world. Since its domestication ∼10,000 years ago, cassava has been largely clonally propagated through stem cuttings. Minimal sexual recombination has led to an accumulation of deleterious mutations made evident by heavy inbreeding depression. To locate and characterize these deleterious mutations, and to measure selection pressure across the cassava genome, we aligned 52 related Euphorbiaceae and other related species representing millions of years of evolution. With single base-pair resolution of genetic conservation, we used protein structure models, amino acid impact, and evolutionary conservation across the Euphorbiaceae to estimate evolutionary constraint. With known deleterious mutations, we aimed to improve genomic evaluations of plant performance through genomic prediction. We first tested this hypothesis through simulation utilizing multi-kernel GBLUP to predict simulated phenotypes across separate populations of cassava. Simulations showed a sizable increase of prediction accuracy when incorporating functional variants in the model when the trait was determined by <100 quantitative trait loci (QTL). Utilizing deleterious mutations and functional weights informed through evolutionary conservation, we saw improvements in genomic prediction accuracy that were dependent on trait and prediction. We showed the potential for using evolutionary information to track functional variation across the genome, in order to improve whole genome trait prediction. We anticipate that continued work to improve genotype accuracy and deleterious mutation assessment will lead to improved genomic assessments of cassava clones.
A Coarse-Grained Molecular Dynamics Investigation on Spontaneous Binding of Aβ1-40Fibrils with Cholesterol-mixed DPPC Bilayers
Authors: Agrawal Nikhil , Skelton Adam A , Parisini Emilio
Published: September 2022

Alzheimer’s disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Whereas experimental studies have suggested that Aβ oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 μs-long simulations to investigate the interaction between trimeric or hexameric Aβ1-40fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50 % cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous Aβ1-40fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the Aβ1-40fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help Aβ1-40fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against Aβ oligomer/fibril-membrane interaction.