bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-specific Effects of SGLT2 Inhibition in a Kidney with Reduced Nephron Number: Modeling and Analysis
Authors: Layton Anita T. 
Published: December 2021

AbstractThe kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.
Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function
Authors: Knox Kevin M. , Beckman Megan , Smith Carole L. , Jayadev Suman , Barker-Haliski Melissa 
Published: December 2021

AbstractPatients with early-onset Alzheimer’s disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p<0.02; females: p<0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p=0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p=0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.
Nanoscale patterning of in vitro neuronal circuits
Authors: Mateus José C. , Weaver Sean , van Swaay Dirk , Renz Aline F. , Hengsteler Julian , Aguiar Paulo , Vörös János 
Published: December 2021

ABSTRACTMethods for patterning neurons in vitro have gradually improved and are used to investigate questions difficult to address in or ex vivo. Though these techniques guide axons between groups of neurons, multiscale control of neuronal connectivity, from circuits to synapses, is yet to be achieved in vitro. As studying neuronal circuits with synaptic resolution in vivo poses significant challenges, an in vitro alternative could serve as a testbed for in vivo experiments or as a platform for validating biophysical and computational models. In this work we use a combination of electron beam and photolithography to create polydimethylsiloxane (PDMS) structures with features ranging from 150 nanometers to a few millimeters. Leveraging the difference between average axon and dendritic spine diameters, we restrict axon growth while allowing spines to pass through nanochannels to guide synapse formation between small groups of neurons (i.e. nodes). We show this technique can be used to generate large numbers of isolated feed-forward circuits where connections between nodes are restricted to regions connected by nanochannels. Using a genetically encoded calcium indicator in combination with fluorescently tagged post synaptic protein, PSD-95, we demonstrate functional synapses can form in this region. Although more work needs to be done to control connectivity in vitro, we believe this is a significant step in that direction.
Amyloidogenesis of SARS-CoV-2 Spike Protein
Authors: Nyström Sofie , Hammarström Per 
Published: December 2021

ABSTRACTSARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 Spike protein (S-protein). Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates during incubation at 37°C. Three 20-amino acid long synthetic Spike peptides (sequence 191-210, 599-618, 1165-1184) fulfilled three amyloid fibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity and ultrastructural fibrillar morphology. Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 hours of S-protein co-incubation with the protease neutrophil elastase (NE) in vitro. NE efficiently cleaved S-protein rendering exposure of amyloidogenic segments and accumulation of the peptide 193-202, part of the most amyloidogenic synthetic Spike peptide. NE is overexpressed at inflamed sites of viral infection and at vaccine injection sites. Our data propose a molecular mechanism for amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The potential implications of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis and consequences following S-protein based vaccines should be addressed in understanding the disease, long COVID-19, and vaccine side effects.
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy
Authors: Lövestam Sofia , Koh Fujiet Adrian , van Knippenberg Bart , Kotecha Abhay , Murzin Alexey G. , Goedert Michel , Scheres Sjors H.W. 
Published: December 2021

AbstractAbundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.
A high-throughput neutralization assay for yellow fever serodiagnostics
Authors: Rasulova Madina , Vercruysse Thomas , Paulissen Jasmine , Coun Catherina , Suin Vanessa , Heyndrickx Leo , Ma Ji , Geerts Katrien , Timmermans Jolien , Mishra Niraj , Li Li-Hsin , Kum Dieudonné Buh , Coelmont Lotte , Van Gucht Steven , Karimzadeh Hadi , Thorn-Seshold Julia , Rothenfußer Simon , Ariën Kevin K. , Neyts Johan , Dallmeier Kai , Thibaut Hendrik Jan 
Published: December 2021

AbstractQuick and accurate detection of neutralizing antibodies (nAbs) against yellow fever is essential in serodiagnosis during outbreaks, for surveillance and to evaluate vaccine efficacy in population-wide studies. All this requires serological assays that can process a large number of samples in a highly standardized format. Albeit being laborious, time-consuming and limited in throughput, classical plaque reduction neutralization test (PRNT) is still considered gold standard for the detection and quantification of nAbs due to its sensitivity and specificity. Here we report the development of an alternative fluorescence-based serological assay (SNTFLUO) with an equally high sensitivity and specificity that is fit for high-throughput testing with the potential for automation. Finally, our novel SNTFLUO was cross-validated in several reference laboratories and against international WHO standards showing its potential to be implemented in clinical use. SNTFLUO assays with similar performance are available for the Japanese encephalitis, Zika and dengue viruses amenable for differential diagnostics.IMPORTANCEFast and accurate detection of neutralizing antibodies (nAbs) against yellow fever virus (YFV) is key in yellow fever serodiagnosis, outbreak surveillance and monitoring of vaccine efficacy. Although classical PRNT still remains gold standard for measuring YFV nAbs, this methodology suffers from inherent limitations such as a low throughput and an overall high labor intensity. We present a novel fluorescence-based serum neutralization test (SNTFLUO) with equally high sensitivity and specificity that is fit for processing large number of samples in a highly standardized manner and has the potential to be implemented in clinical use. In addition, we present SNTFLUO assays with similar performance for Japanese encephalitis, Zika and dengue viruses opening new avenues for differential diagnostics.
Classification and Regression Models for Genomic Selection of Skewed Phenotypes: A Case for Disease Resistance in Winter Wheat (Triticum aestivumL.)
Authors: Merrick Lance F. , Lozada Dennis N. , Chen Xianming , Carter Arron H. 
Published: December 2021

AbstractMost genomic prediction models are linear regression models that assume continuous and normally distributed phenotypes, but responses to diseases such as stripe rust (caused byPuccinia striiformisf. sp. tritici) are commonly recorded in ordinal scales and percentages. Disease severity (SEV) and infection type (IT) data in germplasm screening nurseries generally do not follow these assumptions. On this regard, researchers may ignore the lack of normality, transform the phenotypes, use generalized linear models, or use supervised learning algorithms and classification models with no restriction on the distribution of response variables, which are less sensitive when modeling ordinal scores. The goal of this research was to compare classification and regression genomic selection models for skewed phenotypes using stripe rust SEV and IT in winter wheat. We extensively compared both regression and classification prediction models using two training populations composed of breeding lines phenotyped in four years (2016-2018, and 2020) and a diversity panel phenotyped in four years (2013-2016). The prediction models used 19,861 genotyping-by-sequencing single-nucleotide polymorphism markers. Overall, square root transformed phenotypes using rrBLUP and support vector machine regression models displayed the highest combination of accuracy and relative efficiency across the regression and classification models. Further, a classification system based on support vector machine and ordinal Bayesian models with a 2-Class scale for SEV reached the highest class accuracy of 0.99. This study showed that breeders can use linear and non-parametric regression models within their own breeding lines over combined years to accurately predict skewed phenotypes.
Concerted modification of nucleotides at functional centers of the ribosome revealed by single-molecule RNA modification profiling
Authors: Bailey Andrew D. , Talkish Jason , Ding Hongxu , Igel Haller , Durán Alejandra , Mantripragada Shreya , Paten Benedict , Ares Manuel 
Published: December 2021

ABSTRACTNucleotides in RNA and DNA are chemically modified by numerous enzymes that alter their function. Eukaryotic ribosomal RNA (rRNA) is modified at more than 100 locations, particularly at highly conserved and functionally important nucleotides. During ribosome biogenesis, modifications are added at various stages of assembly. The existence of differently modified classes of ribosomes in normal cells is unknown because no method exists to simultaneously evaluate the modification status at all sites within a single rRNA molecule. Using a combination of yeast genetics and nanopore direct RNA sequencing, we developed a reliable method to track the modification status of single rRNA molecules at 37 sites in 18S rRNA and 73 sites in 25S rRNA. We use our method to characterize patterns of modification heterogeneity and identify concerted modification of nucleotides found near functional centers of the ribosome. Distinct, undermodified subpopulations of rRNAs accumulate upon loss of Dbp3 or Prp43 RNA helicases, suggesting overlapping roles in ribosome biogenesis. Modification profiles are surprisingly resistant to change in response to many genetic and acute environmental conditions that affect translation, ribosome biogenesis, and pre-mRNA splicing. The ability to capture single molecule RNA modification profiles provides new insights into the roles of nucleotide modifications in RNA function.Highlightsmethod enabling single-molecule profiling of RNA modifications is developed and reveals heterogeneous classes of modified ribosomes.rRNA 2’O methylation and pseudouridylation modifications are independent of each other.in functional centers of the ribosome are modified in a concerted fashion.of function for RNA helicases Dbp3 and Prp43 produce discrete overlapping subpopulations of incompletely modified ribosomes.modification profiles are resilient to rapidly changing nutrient conditions and perturbation of translation
Tryptophol acetate and tyrosol acetate, small molecule metabolites identified in a probiotic mixture, inhibit hyperinflammation
Authors: Malka Orit , Malishev Ravit , Bersudsky Marina , Rajendran Manikandan , Krishnamohan Mathumathi , Shaik Jakeer , Chamovitz Daniel A. , Tikhonov Evgeni , Sultan Eliya , Koren Omry , Apte Ron N. , Rosental Benyamin , Voronov Elena , Jelinek Raz 
Published: December 2021

AbstractProbiotic fermented foods are perceived as contributing to human health, however solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small molecule metabolites secreted by the probiotic milk-fermented yeastKluyveromyces marxianusinhibit hyperinflammation (e.g., “cytokine storm”). Comprehensivein vivoandin vitroanalyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the pro-inflammatory cytokines IL-6, IL-1α, IL-1β and TNF-α, and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress pro-inflammatory cytokine generation, rather brought their concentrations back to baseline levels thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.
3D-Strudel - a novel model-dependent map-feature validation method for high-resolution cryo-EM structures
Authors: Istrate Andrei , Wang Zhe , Murshudov Garib N , Patwardhan Ardan , Kleywegt Gerard J 
Published: December 2021

AbstractRecent technological advances in electron cryo-microscopy (cryo-EM) have led to significant improvements in the resolution of many single-particle reconstructions and a sharp increase in the number of entries released in the Electron Microscopy Data Bank (EMDB) every year, which in turn has opened new possibilities for data mining. Here we present a resolution-dependent library of rotamer-specific amino-acid map motifs mined from entries in the EMDB archive with reported resolution between 2.0 and 4.0Å. We further describe 3D-Strudel, a method for map/model validation based on these libraries. 3D-Strudel calculates linear correlation coefficients between the map values of a map-motif from the library and the experimental map values around a target residue. We also present “Strudel Score”, a plug-in for ChimeraX, as a user-friendly tool for visualisation of 3D-Strudel validation results.
Can Chemical Exchange Saturation Transfer (CEST MRI) be used as biomarker of disease progression in Prion Disease?
Authors: Demetriou Eleni , Tachrount Mohamed , Ellis Matthew , Linehan Jackeline , Brandner Sebastian , Collinge John , Mead Simon , Shmueli Karin , Farrow Mark , Golay Xavier 
Published: December 2021

AbstractHuman prion diseases are fatal neurodegenerative disorders that may have prolonged asymptomatic incubation periods. However, the underlying mechanism by which prions cause brain damage remains unclear. In turn, characterization of early pathological aspects would be of benefit for the diagnosis and potential treatment of these progressive neurodegenerative disorders. We investigated chemical exchange saturation transfer (CEST) MRI based on its exquisite sensitivity to cytosol protein content as a surrogate for prion disease pathology. Three groups of prion-infected mice at different stages of the disease underwent conventional magnetic resonance imaging and CEST MRI at 9.4T. For each mouse, chemical exchange contrasts were measured by applying five RF powers at various frequency offsets using magnetization transfer asymmetries. Relayed Nuclear Overhauser effects (NOE*) and amide proton transfer (APT*) were also assessed. For comparison, CEST MRI measurements were also made in healthy control mice brains. Here we show that alterations in CEST signal were detected before structural modifications or any clinical signs of prion disease. The detected CEST signal displayed different patterns at different stages of the disease indicating its potential for use as a longitudinal marker of disease progression. Highly significant correlations were found between CEST metrics and histopathological findings. A decline in NOE signal was positively correlated with abnormal prion protein deposition (R2 = 0.91) in the thalami of prion infected mice. Moreover, the NOE signal was negatively correlated with astrogliosis (R2 = 0.71) in the thalamus. No significant correlations were detected between NOE signals and spongiosis. MTR asymmetry at 3.5 ppm was also correlated with astrogliosis (R2 = 0.59), and prion protein deposition (R2 = 0.63) in thalamus. No significant changes were detected in APT* between prion-infected and control mice at all stages of the disease. Finally, MTR asymmetry between 2.8 and 3.2 ppm was correlated with prion protein deposition (R2 = 0.47) in the thalamus of prion -infected mice. To conclude, CEST MRI has potential utility as a biomarker of neurodegenerative processes in prion disease.
Sugar-rich larval diet promotes lower adult pathogen load and higher survival after infection in a polyphagous fly
Authors: Dinh Hue , Lundbäck Ida , Kumar Sheemal , Than Anh The , Morimoto Juliano , Ponton Fleur 
Published: December 2021

AbstractNutrition is a central factor influencing immunity and resistance to infection, but the extent to which nutrition during development affects adult responses to infections is poorly understood. Our study investigated how the nutritional composition of the larval diet affects the survival, pathogen load, and food intake of adult fruit flies, Bactrocera tryoni, after bacterial septic infection. We found a sex-specific effect of larval diet composition on survival post-infection: survival rate was higher and bacterial load was lower for infected females fed sugar-rich larval diet compared with females fed protein-rich larval diet, an effect that was absent in males. Both males and females were heavier when fed a balanced larval diet compared to protein- or sugar-rich diet, while body lipid reserves were higher in the sugar-rich larval diet compared with other diets. Body protein reserve was lower for sugar-rich larval diets compared to other diets in males, but not females. Both females and males shifted their nutrient intake to ingest a sugar-rich diet when infected compared with sham-infected flies without any effect of the larval diet, suggesting that sugar-rich diets can be beneficial to fight off bacterial infection. Overall, our findings show that nutrition during early life can shape individual fitness in adulthood.Summary statementDevelopmental conditions influence adulthood. Here we showed that when the larval diet is rich in sugar, resistance to infection is increased in females at adulthood, in a polyphagous fly.