bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-specific T cell exhaustion drives differential immune responses in glioblastoma
Authors: Lee Juyeun , Nicosia Michael , Silver Daniel J. , Li Cathy , Bayik Defne , Watson Dionysios C. , Lauko Adam , Johnson Sadie , McGraw Mary , Grabowski Matthew M. , Kish Danielle D. , Desai Amar , Goodman Wendy , Cameron Scott J. , Okada Hideo , Valujskikh Anna , Fairchild Robert L. , Ahluwalia Manmeet S. , Lathia Justin D. 
Published: August 2022

AbstractSex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Using GBM models, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased T cell infiltration and increased T cell exhaustion. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, which was further corroborated by in vitro exhaustion assays. Moreover, increased T cell exhaustion was observed in male GBM patients. These findings demonstrate sex-specific pre-determined behavior of T cells is critical in inducing sex differences in GBM progression and immunotherapy response.Statement of significanceImmunotherapies in GBM patients have been unsuccessful due to a variety of factors including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-specific T cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve therapeutic efficacy of immunotherapy in GBM.
Asymmetric Ion Mobility and Interface Displacement Drive the Signal Enhancement in a polymer-electrolyte nanopore
Authors: Marcuccio Fabio , Soulias Dimitrios , Chau Chalmers C. , Radford Sheena E. , Hewitt Eric W. , Actis Paolo , Edwards Martin A. 
Published: August 2022

ABSTRACTSolid-state nanopores have been widely employed in the detection of biomolecules, but low signal-to-noise ratios still represent a major obstacle to enable the discrimination of short nucleic acid and protein sequences. The addition of 50% polyethylene glycol (PEG) to the bath solution was recently demonstrated as a simple way to enhance the detection of such biomolecules translocating through a model solid-state nanopore. Here, we provide a comprehensive description of the physics describing a nanopore measurement carried out in 50% PEG that is supported by finite-element modelling and experiments. We demonstrate that the addition of PEG to the external solution introduces a strong imbalance in the transport properties of cations and anions, drastically affecting the characteristic current response of the nanopore. We further show that the strong asymmetric current response is due to a polarity-dependent ion distribution and transport at the nanopipette tip region, leading to either ion depletion or enrichment for few tens of nanometers across the aperture. Under negative potential, when double-stranded DNA molecules translocate, the depleted region (sensing region) significantly improves the sensitivity compared to systems without PEG. We then introduce a displacement of the interface between pore and external solution to simulate the mechanical interactions between analyte and PEG molecules. We found that this displacement affects the ion distribution in the sensing region, enhancing the detection current during the translocation of biomolecules.
Mapping Cellular Response to Destabilized Transthyretin Reveals Cell- and Amyloidogenic Protein-Specific Signatures
Authors: Ghosh Sabrina , Villacorta-Martin Carlos , Lindstrom-Vautrin Jonathan , Kenney Devin , Golden Carly S. , Edwards Camille V. , Sanchorawala Vaishali , Connors Lawreen H. , Giadone Richard M. , Murphy George J. 
Published: August 2022

AbstractIn ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive. In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTRV122I and TTRL55P) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock). In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR which resolved upon pre-incubation with kinetic stabilizer tafamidis. Collectively, these data provide insight into the mechanisms underlying amyloid-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.
Habitat suitability modeling of Himalayan Monal and Koklass Pheasant in Western Himalayas and Hindukush, Pakistan
Authors: AzharJameel Muhammad , Nadeem Muhammad Sajid , Kabir Muhammad , Mahmood Tariq , Akrim Faraz , Khan Muazzam Ali , Awan Muhammad Naeem , Khan Muhammad Fiaz , Anjum Muhammad Zubair , Aslam Shahzad 
Published: August 2022

AbstractThe Himalayan pheasants are under the greatest threat due to habitat degradation, and loss. Quantifying geographical range and suitable habitat of a species can help in better management and conservation decisions. Himalayan Monal (Lophophorus impejanus) and Koklass (Pucrasia macrolopha) are endemic to the Himalayas and Hindukush mountains. This study aims to investigate habitat suitability of these pheasants in the western Himalayas and Hindukush. MaxEnt and Cringing models were used to document habitat suitability and to identify valleys with most suitable habitat. MaxEnt model displayed excellent predictive performance showing a strong prediction of the probability distribution and habitat. The area under cover (AUC) values quantified for the replicate runs were 0.994 (±0.001) and 0.991 (±0.005) for Himalayan Monal and Koklass pheasant respectively. The climatic parameters including temperature, precipitation of the warmest quarter (bio_18) contributed the maximum 21.3% and 23.5%, followed by annual precipitation (bio_12) 12.3% and 8.9% for habitat prediction of Monal and Koklass. The topographical variables, altitude, slope, and distance to settlements contributed 15.2%, 2.6%, and 16% in the Monal habitat prediction model while 8.4%, 10.5%, and 15.8% for the Koklass habitat prediction model respectively. We quantified highly suitable (844.4 sq. km), moderately suitable (2819.42 sq. km), and less suitable (3933.09 sq. km) habitat for Monal pheasant. Whereas, highly suitable habitat for Koklass pheasant was (611.5 sq. km), followed by moderately suitable (2551.3 sq. km), and less suitable (4494.11 sq. km). Bar Palas region of Koli Palas district, Jalkot and Kandia valley of district upper Kohistan and Kayal valley of district lower Kohistan were identified as core zones or hot spots for these pheasant species. Areas identified as core zone/hotspot and suitable habitat for the pheasant species should be legally protected for the conservation of pheasants.
Genome-wide DNA methylation profiles in smoking discordant and concordant monozygotic twin pairs
Authors: van Dongen Jenny , Willemsen Gonneke ,   BIOS Consortium, de Geus Eco J.C. , Boomsma Dorret I. , Neale Michael C. 
Published: August 2022

AbstractSmoking-associated DNA methylation levels identified through epigenome-wide association studies (EWAS) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for. We exploited a strong within-family design, i.e., the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age=36 years,range=18-78, 70% female), including pairs discordant or concordant for current or former smoking. In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in CACNA1D and GNG12, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles. In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking.
Random transposon mutagenesis identifies genes essential for transformation in naturally competent archaea
Authors: Fonseca Dallas R. , Loppnow Madison B. , Day Leslie A. , Kelsey Elisa L. , Abdul Halim Mohd Farid , Costa Kyle C. 
Published: August 2022

AbstractNatural transformation, the process whereby a cell acquires DNA directly from the environment, is an important driver of evolution in microbial populations. While transformation is well characterized in bacteria, relatively little is known about this process in archaea. Here, we leverage an optimized method to generate transposon mutants inMethanococcus maripaludisto screen for genes essential to natural transformation. A screen of 5,376 mutant strains identified 25 candidate genes. Among these are genes encoding components of the type IV-like pilus, transcription/translation associated genes, putative membrane bound transport proteins, and genes of unknown function. Interestingly, similar genes were identified regardless of whether replicating or integrating plasmids were provided as substrate for transformation. Using allelic replacement mutagenesis, we confirmed that several genes identified in these screens are essential for transformation. Finally, we identified a homolog of a membrane bound substrate transporter inMethanoculleus thermophilusand verified its importance using allelic replacement mutagenesis, suggesting a conserved mechanism for DNA transfer in multiple archaea. These data provide an initial catalog of genes important for transformation in the archaea and can inform efforts to understand gene flow in this domain.ImportanceHorizontal gene transfer (HGT) is an important driver of evolution in microbial populations. One of the primary ways microorganisms acquire genetic material through HGT is transformation, the direct uptake of DNA from the environment. While transformation is well-studied in bacteria, little is known about this process in archaea. Using a random mutagenesis screen to identify components of the archaeal transformation pathway, we identify a catalog of genes important to transformation inMethanococcus maripaludisand show that a subset of these genes is functionally conserved across diverse archaea. This is a key step in understanding mechanisms of gene flow in natural populations, and identification of the DNA uptake system will assist in establishing new model genetic systems for studying the archaea.
Demographic and Outcome Characteristics of Children Hospitalized with Acute COVID-19 versus Multisystem Inflammatory Syndrome in Children in Canada
Authors: Farrar Daniel S. , Hepburn Charlotte Moore , Drouin Olivier , Tal Tala El , Morin Marie-Paule , Berard Roberta A. , King Melanie , Thibodeau Melanie Laffin , Haddad Elie , Scuccimarri Rosie , Yeung Rae S. M. , Kakkar Fatima , Morris Shaun K. ,   the Canadian Paediatric Surveillance Program COVID-19 Study Team
Published: August 2022

ABSTRACTDirect comparisons of pediatric hospitalizations for acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C) can inform health system planning. While there were more hospitalizations and deaths from acute COVID-19 amongst Canadian children between March 2020–May 2021, MIS-C cases were more severe, requiring more intensive care and vasopressor support.
Polygenic contributions to suicidal thoughts and behaviors in a sample ascertained for alcohol use disorders
Authors: Colbert Sarah MC , Mullins Niamh , Chan Grace , Meyers Jacquelyn L , Schulman Jessica , Kuperman Samuel , Lai Dongbing , Nurnberger John , Plawecki Martin H , Kamarajan Chella , Anokhin Andrey P , Bucholz Kathleen K , Hesselbrock Victor , Edenberg Howard J , Kramer John , Dick Danielle M , Porjesz Bernice , Agrawal Arpana , Johnson Emma C 
Published: August 2022

ABSTRACTSuicidal thoughts and behaviors have partially distinct genetic etiologies. We used PRS-CS to create polygenic risk scores (PRS) from GWAS of non-suicidal self-injury, broad sense self-harm ideation, non-fatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRS were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N = 7,526). All PRS were significantly associated with suicidal ideation and suicide attempt (betas=0.08-0.44, FDR<0.023). All PRS except non-suicidal self-injury PRS were associated with active suicidal ideation and severity of suicidality (betas=0.04-0.22, FDR<0.034). Several associations remained significant in models where all significant PRS were included as simultaneous predictors, and when all PRS predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRS and persistent suicidal ideation, non-suicidal self-injury, attempt severity and desire to die. Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.
Does your measure matter? A comparison of alcohol availability measures in Great Britain
Authors: Angus Colin , Holmes John , Purshouse Robin , Meier Petra , Brennan Alan 
Published: August 2022

AbstractIntroductionThe relationship between the spatial availability of alcohol and alcohol-related harm is well established; however the specific components of availability which drive this relationship and how availability may best be measured remains unclear. This study applies a range of alternative measures of availability to selected areas in Great Britain to establish to what extent they are related to each other.MethodsUsing a database giving low-level geographic location (full postcode) and type e.g. (bar, supermarket) of every licensed outlet selling alcohol across 4 times points (2003, 07, 10, 14) we calculated low-level measures of alcohol availability for three Local Authorities covering a spectrum of population density and deprivation. Measures were calculated based proximity, outlet density, outlet clustering and so-called ‘gravity’ measures. The relationships between measures are explored descriptively and through correlation and factor analysis.ResultsThe availability of alcohol is high in the selected Local Authorities, with an average of 45 outlets within 1km of any individual postcode and a mean distance of 400m to an on-trade and 900m to an off-trade outlet. Different measures display different temporal trends with the density and gravity measures having close agreement with each other while proximity measures suggest different trends. Socioeconomic patterning varies both between Local Authorities and measures chosen, with similar agreement between density and gravity measures and different patterns displayed for proximity measures.ConclusionsThese findings highlight that different measures applied to different geographies may give fundamentally different characterisations of availability. The choice of availability measure used in any study does, therefore, matter and should not be made without appropriate regard to theoretical considerations
Liver Shape Analysis using Statistical Parametric Maps at Population Scale
Authors: Thanaj Marjola , Basty Nicolas , Cule Madeleine , Sorokin Elena P , Whitcher Brandon , Bell Jimmy D , Thomas E Louise 
Published: August 2022

AbstractBackgroundMorphometric image analysis enables the quantification of differences in the shape and size of organs between individuals.MethodsHere we have applied morphometric methods to the study of the liver by constructing surface meshes from liver segmentations from abdominal MRI images in 33,434 participants in the UK Biobank. Based on these three dimensional mesh vertices, we evaluated local shape variations and modelled their association with anthropometric, phenotypic and clinical conditions, including liver disease and type-2 diabetes.ResultsWe found that age, body mass index, hepatic fat and iron content, as well as, health traits were significantly associated with regional liver shape and size. Interaction models in groups with specific clinical conditions showed that the presence of type-2 diabetes accelerates age-related changes in the liver, while presence of liver fat further increased shape variations in both type-2 diabetes and liver disease.ConclusionsThe results suggest that this novel approach may greatly benefit studies aiming at better categorisation of pathologies associated with acute and chronic clinical conditions.
Lipidomic profiling reveals age-dependent changes in complex plasma membrane lipids that regulate neural stem cell aging
Authors: Zhao Xiaoai , Yan Xin , Contrepois Kévin , Vallania Francesco , Ellenberger Mathew , Kashiwagi Chloe M. , Gagnon Stephanie D. , Siebrand Cynthia J. , Cabruja Matias , Traber Gavin M. , McKay Andrew , Hornburg Daniel , Khatri Purvesh , Snyder Michael P. , Zare Richard N. , Brunet Anne 
Published: August 2022

AbstractThe aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs), which may underlie age-associated defects in sensory and cognitive functions1–6. While mechanisms that restore old NSC function have started to be identified7–23, the role of lipids – especially complex lipids – in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related lipidomic signatures in young and old quiescent NSCs in vitro and in vivo. These analyses reveal drastic changes in several complex membrane lipid classes, including phospholipids and sphingolipids in old NSCs. Moreover, poly-unsaturated fatty acids (PUFAs) strikingly increase across complex lipid classes in quiescent NSCs during aging. Age-related changes in complex lipid levels and side chain composition are largely occurring in plasma membrane lipids, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we find that aging is accompanied by modifications in plasma membrane biophysical properties, with a decrease in plasma membrane order in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knockout of Mboat2, which encodes a phospholipid acyltransferase, exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. As Mboat2 expression declines with age, Mboat2 deficiency may drive NSC decline during aging. Interestingly, supplementation of plasma membrane lipids derived from young NSCs boosts the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs in old individuals, which has important implications for countering brain decline during aging.
Humans rely more on talker identity than temporal coherence in an audiovisual selective attention task using speech-like stimuli
Authors: Cappelloni Madeline S , Mateo Vincent S , Maddox Ross K 
Published: August 2022

AbstractAudiovisual integration of speech can benefit the listener by not only improving comprehension of what a talker is saying but also helping a listener pick a particular talker’s voice out of a mix of sounds. Binding, an early integration of auditory and visual streams that helps an observer allocate attention to a combined audiovisual object, is likely involved in audiovisual speech processing. Although temporal coherence of stimulus features across sensory modalities has been implicated as an important cue for non-speech stimuli (Maddox et al., 2015), the specific cues that drive binding in speech are not fully understood due to the challenges of studying binding in natural stimuli. Here we used speech-like artificial stimuli that allowed us to isolate three potential contributors to binding: temporal coherence (are the face and the voice changing synchronously?), articulatory correspondence (do visual faces represent the correct phones?), and talker congruence (do the face and voice come from the same person?). In a trio of experiments, we examined the relative contributions of each of these cues. Normal hearing listeners performed a dual detection task in which they were instructed to respond to events in a target auditory stream and a visual stream while ignoring events in a distractor auditory stream. We found that viewing the face of a talker who matched the attended voice (i.e., talker congruence) offered a performance benefit. Importantly, we found no effect of temporal coherence on performance in this task, a result that prompts an important recontextualization of previous findings.
Formation of sulfoquinovosyl diacylglycerol by acylation of sulfoquinovosyl glycerol
Authors: Cuevas-Rivas Jessica Y. , Rodriguez-Terrones Diego , González-Silva Napoleón , Moreno-Ocampo Ángeles , Guerrero Gabriela , Bergström Ed , Thomas-Oates Jane E. , Geiger Otto , López-Lara Isabel M. 
Published: August 2022

ABSTRACTSulfoquinovosyl diacylglycerol (SQDG) is a membrane-forming lipid present in photosynthetic organisms as well as in distinct bacteria growing in phosphate-limited environments. Four genes for SQDG biosynthesis were previously identified in Rhodobacter sphaeroides, the operon sqdBDC and sqdA. In this work, we found that SMc02490 of Sinorhizobium meliloti is an SqdA orthologue. Expression of the S. meliloti sqdBDC operon in Escherichia coli results in formation of sulfoquinovosyl glycerol (SQGro), while co-expression of this operon together with smc02490 (sqdA) results in formation of SQDG. Furthermore, SqdA allows for incorporation of exogenous SQGro into SQDG in S. meliloti and in E. coli cultures, suggesting that presence of SqdA in bacteria permit them to use environmental SQGro for the biosynthesis of the membrane lipid SQDG. An in vitro enzymatic assay for the acyltransferase SqdA was developed. Cell-free crude extracts of E. coli expressing sqdA can efficiently convert [35S]-sulfoquinovosyl monoacylglycerol into SQDG using as acyl donor acyl carrier protein. Bioinformatic analyses reveal that this sulfoquinovose acylation pathway for SQDG biosynthesis is delimited to the Hyphomicrobiales (Rhizobiales) and Rhodobacterales orders of Alphaproteobacteria.