bluuebunny/crossref_metadata_2025 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

Sex 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 significance

Immunotherapies 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

Solid-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

In 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

The 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

Smoking-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

Natural 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.

Importance

Horizontal 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

Direct 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

Suicidal 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.
Association of Vitamin D deficiency and vitamin D receptor gene polymorphisms with type 1 diabetes risk: A South Indian familial study
Authors: Thirunavukkarasu Ramasamy , Chitra Ayyappan , Asirvatham Arthur , Jayalakshmi Mariakuttikan
Published: August 2022

“The authors have withdrawn their manuscript because they identified errors in the vitamin D levels and VDR gene polymorphisms section. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
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

Introduction

The 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.

Methods

Using 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.

Results

The 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.

Conclusions

These 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

Background

Morphometric image analysis enables the quantification of differences in the shape and size of organs between individuals.

Methods

Here 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.

Results

We 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.

Conclusions

The 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

The 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

Audiovisual 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

Sulfoquinovosyl 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.
Methylglyoxal-derived hydroimidazolone, MG-H1, increases food intake by altering tyramine signaling via the GATA transcription factor ELT-3 in Caenorhabditis elegans
Authors: Shanmugam Muniesh Muthaiyan , Chaudhuri Jyotiska , Sellegounder Durai , Sahu Amit Kumar , Guha Sanjib , Chamoli Manish , Hodge Brian , Roberts Charis , Lithgow Gordon , Sarpong Richmond , Kapahi Pankaj
Published: August 2022

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food almost everywhere, from the baking industry to our everyday life. However, the Maillard reaction also takes place in all cells, from prokaryotes to eukaryotes, leading to the formation of Advanced Glycation End-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNA-seq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGEs (MG-H1) induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream factor for increased feeding upon accumulation of AGEs by partially regulating the expression of tdc-1 and tyra-2 genes. Further, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MGO and associated AGEs. Understanding this signaling pathway is essential to modulate hedonistic overfeeding behavior observed in modern AGEs rich diets.
Investigating the relationship between CRISPR-Cas content and growth rate in bacteria
Authors: Liu Zhi-Ling , Hu En-Ze , Niu Deng-Ke
Published: August 2022

CRISPR-Cas systems provide adaptive immunity for prokaryotic cells by recognizing and eliminating the recurrent genetic invaders whose sequences had been captured in a prior infection and stored in the CRISPR arrays as spacers. However, the biological/environmental factors determining the efficiency of this immune system have yet to be fully characterized. Recent studies in cultured bacteria showed that slowing the growth rate of bacterial cells could promote their acquisition of novel spacers. This study examined the relationship between the CRISPR-Cas content and the minimal doubling time across the bacteria and the archaea domains. Every completely sequenced genome could be used to predict a minimal doubling time. With a large dataset of 4142 bacterial samples, we found that the predicted minimal doubling times are positively correlated with spacer number and other parameters of the CRISPR-Cas systems, like array number,Casgene cluster number, andCasgene number. Different datasets gave different results. Weak results were obtained in analyzing bacterial empirical minimal doubling times and the archaea domain. Still, the conclusion of more spacers in slowly-grown prokaryotes was supported. In addition, we found that the minimal doubling times are negatively correlated with the occurrence of prophages, and the spacer numbers per array are negatively associated with the number of prophages. These observations support the existence of an evolutionary trade-off between bacterial growth and adaptive defense against virulent phages.
Phage-antibiotic combinations to control Pseudomonas aeruginosa-Candida two-species biofilms
Authors: Manohar Prasanth , Loh Belinda , Nachimuthu Ramesh , Leptihn Sebastian
Published: August 2022

Phage-antibiotic combinations to treat bacterial infections are gaining increased attention due to the synergistic effects often observed when applying both components together. This synergy has also been observed for bacteria embedded in biofilms as many phages are capable of degrading the heterogeneous material, often preventing antibiotic compounds from reaching the embedded bacteria. Most studies however focus on a single pathogen, although in many clinical cases multiple species are present at the site of infection. The aim of this study was to investigate the anti-biofilm activity of phage-antibiotic/antifungal combinations on single- and dual-species biofilms formed by the bacterium P. aeruginosa and the fungal pathogen Candida albicans, two microorganisms commonly found together in cystic fibrosis patients. The Pseudomonas phage Motto in combination with ciprofloxacin had significant anti-biofilm activity in disintegrating 24-hour-old pseudomonal biofilms. Also, other antibiotic combinations, such as cefotaxime, gentamicin, meropenem and tetracycline showed substantial effects on biofilms. We then compared biofilms formed by P. aeruginosa alone with the dual-species biofilms formed by bacteria and C. albicans. Here, we found that the phage together with the antifungal fluconazole was active against 6-hour-old dual-species biofilms but showed only negligible activity against 24-hour-old biofilms. Similarly, the combination of antibacterial compounds together with the phage showed no synergistic effects on biofilms formed by P. aeruginosa and C. albicans. This study lays the first foundation for potential therapeutic approaches to treat infections caused by bacteria and fungi using phage-antibiotic combinations.
Golgi localized Arl15 regulates cargo transport, cell adhesion and motility
Authors: Sharma Prerna , Venkatesh Pooja Hoovina , Paddillaya Neha , Shah Nikita , Rajeshwari BR , Dakua Archishman , Penmatsa Aravind , Balasubramanian Nagaraj , Gundiah Namrata , Setty Subba Rao Gangi
Published: August 2022

Arf-like GTPases (Arls) regulate membrane trafficking and cytoskeletal organization. Genetic studies predicted a role for Arl15 in type-2 diabetes, insulin resistance, adiposity, and rheumatoid arthritis. Recent studies indicate a possible role for Arl15 in multiple physiological processes, including magnesium homeostasis. However, the molecular function of Arl15 is poorly defined. We evaluated the role of Arl15 in vesicular transport using techniques to quantify cargo trafficking, to mechanobiology. Fluorescence microscopy of stably expressing Arl15-GFP HeLa cells showed its localization to the Golgi and cell surface, including filopodia, and a cohort to recycling endosomes. The dissociation of Golgi, using small molecular inhibitors or the expression of Arf1 dominant-negative mutant, completely mislocalized Arl15 to the cytosol. Interestingly, site-directed mutagenesis analysis identified a novel V80A mutation in the GTP-binding domain that turns Arl15 into a dominant-negative form with reduced number of filopodia. Depletion of Arl15 in HeLa cells caused mislocalization of cargo, such as caveolin-2 and STX6, from the Golgi. Arl15 knockdown cells displayed reduced filopodial number, altered focal adhesion kinase organization, and enhanced soluble and receptor-mediated cargo uptake without affecting the TfR recycling. Arl15 knockdown decreased cell migration and enhanced cell spreading and adhesion strength. Traction force microscopy experiments revealed that Arl15 depleted cells exert higher tractions and generate multiple focal adhesion points during the initial phase of cell adhesion as compared to control cells. Collectively, these studies demonstrated a functional role for Arl15 in the Golgi, which includes regulating cargo transport to organize membrane domains at the cell surface.

Key points

Arl15 primarily localizes to Golgi and plasma membrane, including filopodia

Membrane localization of Arl15 is dependent on Golgi integrity or Arf1 activation

Arl15 knockdown mislocalizes STX6-dependent Golgi localized cargo required for cell surface organization and reduces the filopodial number

Arl15 is involved in cell spreading, adhesion, and migration
A Web-based Software Resource for Interactive Analysis of Multiplex Tissue Imaging Datasets
Authors: Creason Allison L. , Watson Cameron , Gu Qiang , Persson Daniel , Sargent Luke , Chen Yu-An , Lin Jia-Ren , Sivagnanam Shamilene , Wünnemann Florian , Nirmal Ajit J. , Chin Koei , Feiler Heidi S. , Coussens Lisa M. , Schapiro Denis , Grüning Björn , Sorger Peter K. , Sokolov Artem , Goecks Jeremy
Published: August 2022

Highly multiplexed tissue imaging (MTI) are powerful spatial proteomics technologies that enablein situsingle-cell characterization of tissues. However, analysis and visualization of MTI datasets remains challenging, and we developed the Galaxy-ME software hub to address this challenge.Galaxy-ME is a web-based, interactive software hub that enables end-to-end analysis and visualization of MTI datasets and is accessible to everyone. To demonstrate its utility, Galaxy-ME was used to analyze datasets obtained from multiple MTI assays and evaluate assay concordance in both normal and cancerous tissues. Galaxy-ME is a publicly available web resource.
Disentangling the effects of eutrophication and natural variability on macrobenthic communities across French coastal lagoons
Authors: Jones Auriane G. , Schaal Gauthier , Boyé Aurélien , Creemers Marie , Derolez Valérie , Desroy Nicolas , Fiandrino Annie , Mouton Théophile L. , Simier Monique , Smith Niamh , Ouisse Vincent
Published: August 2022

Coastal lagoons are transitional ecosystems that host a unique diversity of species and support many ecosystem services. Owing to their position at the interface between land and sea, they are also subject to increasing human impacts, which alter their ecological functioning. Because coastal lagoons are naturally highly variable in their environmental conditions, disentangling the effects of anthropogenic disturbances like eutrophication from those of natural variability is a challenging, yet necessary issue to address. Here, we analyze a dataset composed of macrobenthic invertebrate abundances and environmental variables (hydro-morphology, water, sediment and macrophytes) gathered across 29 Mediterranean coastal lagoons located in France, to characterize the main drivers of community composition and structure. Using correlograms, linear models and variance partitioning, we found that lagoon hydro-morphology (connection to the sea and lagoon surface), which affects the level of environmental variability (salinity and temperature), as well as lagoon-scale benthic habitat diversity (using macrophyte morphotypes) seemed to regulate macrofauna distribution, while eutrophication and associated stressors like low dissolved oxygen, acted upon the existing communities, mainly by reducing species richness and diversity. Furthermore, M-AMBI, a multivariate index composed of species richness, Shannon diversity and AMBI (AZTI’s Marine Biotic Index) and currently used to evaluate the ecological state of French coastal lagoons, was more sensitive to eutrophication (18%) than to natural variability (9%), with nonetheless 49% of its variability explained jointly by both. To improve the robustness of benthic indicators like M-AMBI and increase the effectiveness of lagoon benthic habitat management, we call for a revision of the ecological groups at the base of the AMBI index and of the current lagoon typology which could be inspired by the lagoon-sea connection levels used in this study.
First Record of Aedes (Stegomyia) albopictus (Diptera: Culicidae) in the state of Acre, Brazil
Authors: da Costa Rocha Ricardo , da Silva Cardoso Acigelda , de Souza Janis Lunier , da Silva Pereira Eliana , de Amorim Marcio Fernandes , de Souza Maria Socorro Martins , de Lima Medeiros Cleomar , Monteiro Maria Francisca Mendes , de Oliveira Meneguetti Dionatas Ulises , de Paula Marcia Bicudo , Brilhante Andreia Fernandes , Lima-Camara Tamara Nunes
Published: August 2022

Introduction

Aedes (Stegomyia) albopictus (Skuse, 1854) was reported in Brazil for the first time in 1986, and has displayed successful expansion throughout the Brazilian territory.

Methods

During a routine activity to control dengue conducted by the Division of Entomology of the Municipal Health Department in Rio Branco, adults and immatures of Culicidae were collected in a peri-urban area.

Results

The Culicidae forms identified indicated that they belonged to the species Ae. albopictus.

Conclusions

This is the first official record of the presence of Ae. albopictus in the state of Acre, confirming its current presence in all Brazilian states.
Diversity and function of methyl-coenzyme M reductase-encoding archaea in Yellowstone hot springs revealed by metagenomics and mesocosm experiments
Authors: Lynes Mackenzie M. , Krukenberg Viola , Jay Zackary J. , Kohtz Anthony J. , Gobrogge Christine A. , Spietz Rachel L. , Hatzenpichler Roland
Published: August 2022

Metagenomic studies on geothermal environments have been central in recent discoveries on the diversity of archaeal methane and alkane metabolism. Here, we investigated the methanogenic populations inhabiting terrestrial geothermal features in Yellowstone National Park (YNP) by combining amplicon sequencing with metagenomics and mesocosm experiments. Detection of gene amplicons of methyl-coenzyme M reductase subunit A (mcrA) indicated a wide diversity of Mcr-encoding archaea across geothermal features with differing physicochemical regimes. From three selected hot springs we recovered twelve Mcr-encoding metagenome assembled genomes (MAGs) affiliated with lineages of cultured methanogens as well as Candidatus (Ca.) Methanomethylicia, Ca. Hadesarchaeia, and Archaeoglobi. These MAGs encoded the potential for hydrogenotrophic, aceticlastic, or hydrogen-dependent methylotrophic methanogenesis, or anaerobic short-chain alkane oxidation. While Mcr-encoding archaea represented a minor fraction of the microbial community of hot springs, mesocosm experiments with methanogenic precursors resulted in stimulation of methanogenic activity and the enrichment of lineages affiliated with Methanosaeta and Methanothermobacter as well as with uncultured Mcr-encoding archaea including Ca. Korarchaeia, Ca. Nezhaarchaeia, and Archaeoglobi. Altogether, we revealed that diverse Mcr-encoding populations with the metabolic potential to produce methane from different precursors persist in the geothermal environments of YNP. This study highlights the importance of combining environmental metagenomics with laboratory-based experiments to expand our understanding of uncultured Mcr-encoding archaea and their potential impact on microbial carbon transformations in geothermal environments and beyond.
In airway epithelium, basal stem cells and their stress fibers remodel during the unjamming transition
Authors: Phung Thien-Khoi N. , Mitchel Jennifer A. , O’Sullivan Michael J. , Park Jin-Ah
Published: August 2022

Under homeostatic conditions, epithelial cells remain non-migratory. However, during embryonic developmental and pathological processes, they become migratory. The mechanism underlying the transition between non-migratory and migratory epithelial cells is a fundamental question of cellular biology. In well-differentiated primary human bronchial epithelial cell layers, non-migratory epithelial cells become migratory through an unjamming transition (UJT). We have previously identified the hallmarks of UJT: apical cell elongation and collective cellular migration. These indicate that UJT is driven by intercellular force modulation, but the nature of these forces in pseudostratified epithelia is unknown. Here, we identify structural characteristics of basal stem cells that are indicative of force generation. During the UJT, basal stem cells elongate and enlarge, and their stress fibers lengthen and align. These morphological changes in basal stem cells correspond to the previously defined hallmarks of the UJT. Moreover, basal cell elongation and stress fiber lengthening precedes apical cell elongation. Together, these structural changes in basal stem cells suggest that in pseudostratified airway epithelium, basal stem cells may be the origin of the traction forces through stress fiber modeling during the UJT.

Summary Statement

Our image analysis of pseudostratified airway epithelium reveals basal stem cells as the likely source of traction forces driving collective cellular migration during an unjamming transition.
Egocentric value maps of the near-body environment
Authors: Bufacchi Rory John , Somervail Richard , Fitzpatrick Aoife Maria , Caminiti Roberto , Iannetti Gian Domenico
Published: August 2022

Body-part centric response fields are pervasive: they are observed in single neurons, fMRI, EEG, and multiple behavioural measures. This prevalence across scales and measures makes them excellent candidates for studying systems-level neuroscience. Nonetheless, they remain poorly understood because we lack a unifying formal explanation of their origins and role in wider brain function. Here, we provide such explanation.

We use reinforcement learning to analytically explain the existence of body-part centric receptive fields, also known as peripersonal field. We then simulate multiple experimental findings considered foundational in the peripersonal space literature. Our results demonstrate that peripersonal fields naturally arise from two simple and plausible assumptions about living agents: 1) they experience reward when they contact objects in the environment, and 2) they act to maximise reward. These simple assumptions are enough to explain empirical findings on stimulus kinematics, tool use, valence, and network-architecture.

Our explanation provides further insight. First, it offers multiple empirically testable predictions. Second, it offers a formal description of the notion that the world-agent state is encoded in parieto-premotor cortices, using motor primitives: peripersonal fields provide building blocks that together create a short-term model of the world near the agent in terms of its future states; a successor representation. This short-term, close-range egocentric peripersonal map is analogous to the long-term, long-range allocentric spatial map of place and grid cells, which underlie locomotion and navigation to reach distant objects. Together, these allocentric and egocentric maps allow efficient interactions with a changing environment across multiple spatial and temporal scales.

Abstract Figure
SiGra: Single-cell spatial elucidation through image-augmented graph transformer
Authors: Tang Ziyang , Zhang Tonglin , Yang Baijian , Su Jing , Song Qianqian
Published: August 2022

The recent advances in high-throughput molecular imaging push the spatial transcriptomics technologies to the subcellular resolution, which breaks the limitations of both single-cell RNA-seq and array-based spatial profiling. The latest released single-cell spatial transcriptomics data from NanoString CosMx and MERSCOPE platforms contains multi-channel immunohistochemistry images with rich information of cell types, functions, and morphologies of cellular compartments. In this work, we developed a novel method, Single-cell spatial elucidation through image-augmented Graph transformer (SiGra), to reveal spatial domains and enhance the substantially sparse and noisy transcriptomics data. SiGra applies hybrid graph transformers over a spatial graph that comprises high-content images and gene expressions of individual cells. SiGra outperformed state-of-the-art methods on both single-cell spatial profiles and spot-level spatial transcriptomics data from complex tissues. The inclusion of immunohistochemistry images improved the model performance by 37% (95%CI: 27% – 50%). SiGra improves the characterization of intratumor heterogeneity and intercellular communications in human lung cancer samples, meanwhile recovers the known microscopic anatomy in both human brain and mouse liver tissues. Overall, SiGra effectively integrates different spatial modality data to gain deep insights into the spatial cellular ecosystems.
Autophagy is associated with survival and resiliency of fibroblasts in long-term decaying post-mortem parenchymal tissue
Authors: McAndrews Kathleen M. , McGrail Daniel J. , Gansmo Liv B. , Che Sara P.Y. , Chakravarti Deepavali , LeBleu Valerie S. , Kalluri Raghu
Published: August 2022

Fibroblasts are spindle-shaped mesenchymal cells and an abundantly studied cell type that are easy to culture. Their adaptive response in culture conditions allows for use in many different cell biological experiments, including their utility in generating induced pluripotent stem cells. Despite extensive use of fibroblasts in cell and molecular biology and genetics experiments, fundamental evaluation of their resiliency and survival programs, in comparison with other cell types, is undetermined. Here, we demonstrate that fibroblasts exhibit remarkable survival capacity in post-mortem tissue decaying at room temperature and can be cultured from ear, tail, kidney, lung, fetal, and mammary tumor tissue after 12-hours of post-mortem tissue decay. Fibroblasts can be cultured from ear and lung tissue after 24-hours, and from ear after up to 120-hours of post-mortem tissue decay. Gene expression profiling of post-mortem lung tissue fibroblasts compared to fresh tissue cultured fibroblasts suggested a transition to a more quiescent phenotype with activation of nutrient scavenging pathways as evidenced by downregulation of genes associated with DNA replication, ribosomes, cell cycle, and spliceosomes as well as upregulation of genes associated metabolism, autophagy, and lysosomes. Measurement of light chain 3B (LC3B)-I/LC3B-II ratio and lysosomal-associated membrane protein (LAMP)-1 indicate that autophagy is increased in post-mortem fibroblasts, with evidence for potential increase in autolysosomes and senescence program. Our study provides evidence for the ability of normal fibroblasts to overcome extreme stress conditions and offers new insights into cell survival mechanisms and aging, with potential utility in tissue regeneration and repair.