bluuebunny/crossref_metadata_2025 huggingface dataset:
HSP70 Promotes Pancreatic Cancer Cell Epithelial-Mesenchymal Transformation and Growth Via the NF-κB Signaling Pathway
Authors: Xiong Liumei , Li Danming , Xiao Gui , Tan Sipin , Xu Linfang , Wang Guiliang
Published: October 2024

Objective

To study the effects of HSP70 on proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) of pancreatic cancer cells and explore its underlying mechanisms.

Methods

Pancreatic cancer cell models with reduced HSP70 or increased HSP70 expression were established. Reverse transcription quantitative polymerase chain reaction and Western blot assays were used to determine mRNA and protein levels of HSP70, IKK/IκBa/NF-κB signaling pathway-related genes, and EMT markers. CCK-8 and cell cloning assays were used to evaluate cell proliferation and cloning abilities. Transwell and wound healing assays were used to assess the invasive and migratory properties of cells. Electrophoresis mobility shift assay (EMSA) and luciferase reporter assays were conducted to analyze NF-κB's promoter binding and transcriptional activities.

Results

HSP70 knockdown inhibited p-p65 nuclear translocation, the expression of p-p65, p-IKKα/β, p-IκBα, N-cadherin, Vimentin and Twist, NF-κB's promoter binding and transcriptional activities, pancreatic cancer cell proliferation, cloning, migration and invasion, while increased E-cadherin levels. HSP70 overexpression took the opposite effects. NF-κB signaling pathway modulation reversed EMT changes induced by altered HSP70 expression levels. rhHSP70 increased p-IKKα/β and p-IκBα protein levels.

Conclusions

HSP70 promotes EMT and enhances pancreatic cancer cell proliferation, migration, and invasion by activating NF-κB pathway.
Association between mitochondrial DNA copy number and neurodevelopmental outcomes among black and white preterm infants up to two years of age
Authors: Zhao Tingting , Li Aolan , Reese Bo , Cong Qianzi , Corwin Elizabeth J. , Taylor Sarah N. , Matson Adam , Chen Ming-Hui , Alder Nathan N. , Cong Xiaomei
Published: October 2024

Objectives:

Mitochondrial DNA copy number (mtDNAcn) is associated with mitochondrial function, with abnormal copy numbers having been linked to various disease states. Our study aims to understand the association between infant mtDNAcn and infant neurodevelopment, as well as the association with racial disparities.

Methods:

A longitudinal study was conducted with 55 preterm infants from whom a single blood sample was collected during their Neonatal intensive care unit (NICU) stay and used to analyze mtDNAcn. In addition, the NICU Network Neurobehavioral Scale at 36–38 postmenstrual age (PMA) and the Bayley Scale of Infant and Toddler Development (Bayley) Edition III at 1 and 2 years of corrected age were both conducted. Linear regression models were performed to investigate the relationship between infant clinical characteristics, infant neurobehavioral outcomes, and mtDNAcn.

Results:

The majority of infants studied were white (72.73%), non-Hispanic (70.91%), males (54.55%), delivered through C-section (72.73%), and without preterm premature rupture of membrane (76.36%). Increased mtDNAcn was associated with younger birth gestational age (<30.57 wk, P < 0.001). In addition, the opposite associations between mtDNAcn and neurodevelopmental outcomes were observed between white and black infants up to 1 year of gestational age.

Conclusions:

Increased mtDNAcn in white infants, and decreased mtDNAcn in black infants may be considered significant predictors of poor early-life neurodevelopmental outcomes in infants. A better understanding of the underlying mechanisms contributing to infant disparity in mtDNAcn and how low or high copy number impacts infant outcomes is essential.
Geometric constraint of mechanosensing by modification of hydrogel thickness prevents stiffness-induced differentiation in bone marrow stromal cells
Authors: Hernandez-Miranda Maria L. , Xu Dichu , Ben Issa Aya A. , Johnston David A. , Browne Martin , Cook Richard B. , Sengers Bram G. , Evans Nicholas D.
Published: October 2024

Extracellular matrix (ECM) stiffness is fundamental in cell division, movement and differentiation. The stiffness that cells sense is determined not only by the elastic modulus of the ECM material but also by ECM geometry and cell density. We hypothesized that these factors would influence cell traction-induced matrix deformations and cellular differentiation in bone marrow stromal cells (BMSCs). To achieve this, we cultivated BMSCs on polyacrylamide hydrogels that varied in elastic modulus and geometry and measured cell spreading, cell-imparted matrix deformations and differentiation. At low cell density BMSCs spread to a greater extent on stiff compared with soft hydrogels, or on thin compared with thick hydrogels. Cell-imparted matrix deformations were greater on soft compared with stiff hydrogels or thick compared with thin hydrogels. There were no significant differences in osteogenic differentiation relative to hydrogel elastic modulus and thickness. However, increased cell density and/or prolonged culture significantly reduced matrix deformations on soft hydrogels to levels similar to those on stiff substrates. This suggests that at high cell densities cell traction-induced matrix displacements are reduced by both neighbouring cells and the constraint imposed by an underlying stiff support. This may explain observations of the lack of difference in osteogenic differentiation as a function of stiffness.
Smaller islands, bigger appetites: evolutionary strategies of insular endemic skinks
Authors: Pinho Catarina J. , Dinis Herculano A. , Emerson Brent C. , Vasconcelos Raquel
Published: October 2024

Competitive dietary and morphological divergence among co-occurring species are fundamental aspects of ecological communities, particularly on islands. Cabo Verde (~570 km west of continental Africa) hosts several endemic reptiles descended from common ancestors, with sympatric species exhibiting wide morphological variation and competing for limited resources. To explore the mechanisms of resource partitioning between coexisting species, DNA metabarcoding was used to compare the diets of large and small skinks,
Chioninia vaillantii
and
Chioninia delalandii
, in sympatric and allopatric contexts on Fogo Island and in a more competitive context on the small and resource-poor Cima Islet. The morphological variation of all populations was also examined to test the character displacement hypothesis and to compare the effect of different competitive scenarios. Results showed significant differences in diet and linear measurements between species and populations. The two sympatric populations of
C. delalandii
on Fogo and Cima showed similar changes in head morphology compared to the allopatric population, supporting character displacement. The effect of higher competitive pressure on Cima was evidenced by the increased morphological and dietary variation observed. This study demonstrates how sister species develop dietary adaptations/morphologies to maintain stable coexistence, especially in highly competitive scenarios, providing useful insights for effective conservation strategies.
Effect of spider’s weight on signal transmittance in vertical orb webs
Authors: Yavuz Koray , Soler A. Mahy , Zaera Ramón , Jahangirov Seymur
Published: October 2024

Spider orb web is a sophisticated structure that needs to fulfil multiple roles, such as trapping prey and transmitting web-borne signals. When building their web, heavier spiders tend to increase the pretension on the web, which seems counterintuitive since a tighter web would decrease the chances of stopping and retaining prey. In this article, we claim that heavier orb-weaving spiders increase tension on the web in order to reduce the attenuation of the vibratory signal coming from the bottom part of the web. We support our claim by first building a detailed spider web model, which is tuned by a tension-adjusting algorithm to fit the experimentally observed profiles. Then, the effects of the spider weight and the web tension on the signal transmittance properties are investigated using state-of-the-art finite element analysis tools.
A Wearable Mindfulness Brain–Computer Interface for Alleviating Car Sickness
Authors: Zhu Jiawei , Bao Xiaoyu , Huang Qiyun , Wang Tao , Huang Li , Han Yupeng , Huang Haiyun , Zhu Junbiao , Qu Jun , Li Kendi , Chen Di , Jiang Ya , Xu Kailin , Wang Zijian , Wu Wei , Li Yuanqing
Published: October 2024

Car sickness, an enormous vehicular travel challenge, affects a significant pro-portion of the population. Pharmacological interventions are limited by adverse side effects, and effective nonpharmacological alternatives remain to be identified. Here, we introduce a novel closed-loop, artificial intelligence (AI)-driven, wear-able mindfulness brain–computer interface (BCI) to alleviate car sickness. As the user performs mindfulness meditation with a wearable headband, the BCI col-lects and analyses electroencephalography (EEG) data via a convolutional neural network to assess the user’s mindfulness state and provide real-time audiovisual feedback. This approach might efficiently redirect the user’s attention from phys-iological discomfort towards BCI-based mindfulness practices, thereby mitigating car sickness symptoms. The efficacy of the mindfulness BCI was rigorously evalu-ated in two real-world experiments, namely, short and long car rides, with a large cohort of more than 100 participants susceptible to car sickness. Remarkably, over 84% of the participants rated the mindfulness BCI intervention as effective, with significant reductions in car sickness severity, particularly in individuals with severe symptoms. Furthermore, EEG data analysis revealed prefrontal beta relative power as a neurobiological signature of car sickness, which, in conjunc-tion with attention shift theory and sensory conflict theory, provided mechanistic insights into the efficacy of the mindfulness BCI for alleviating car sickness. This study proposed the first nonpharmacological, wearable and effective car sickness intervention method and system with the potential to transform the travel expe-riences of hundreds of millions of people suffering from car sickness, which also represents a new application of BCI technology.
Histology-guided MRI segmentation of brainstem nuclei critical to consciousness
Authors: Olchanyi Mark , Augustinack Jean , Haynes Robin L. , Lewis Laura D. , Cicero Nicholas , Li Jian , Destrieux Christophe , Folkerth Rebecca D. , Kinney Hannah C. , Fischl Bruce , Brown Emery N. , Iglesias Juan Eugenio , Edlow Brian L.
Published: September 2024

While substantial progress has been made in mapping the connectivity of cortical networks responsible for conscious awareness, neuroimaging analysis of subcortical arousal networks that modulate arousal (i.e., wakefulness) has been limited by a lack of a robust segmentation procedures for brainstem arousal nuclei. Automated segmentation of brainstem arousal nuclei is an essential step toward elucidating the physiology of arousal in human consciousness and the pathophysiology of disorders of consciousness. We created a probabilistic atlas of brainstem arousal nuclei built on diffusion MRI scans of fiveex vivohuman brain specimens scanned at 750 µm isotropic resolution. Labels of arousal nuclei used to generate the probabilistic atlas were manually annotated with reference to nucleus-specific immunostaining in two of the five brain specimens. We then developed a Bayesian segmentation algorithm that utilizes the probabilistic atlas as a generative model and automatically identifies brainstem arousal nuclei in a resolution- and contrast-agnostic manner. The segmentation method displayed high accuracy in both healthy and lesionedin vivoT1 MRI scans and high test-retest reliability across both T1 and T2 MRI contrasts. Finally, we show that the segmentation algorithm can detect volumetric changes and differences in magnetic susceptibility within brainstem arousal nuclei in Alzheimer’s disease and traumatic coma, respectively. We release the probabilistic atlas and Bayesian segmentation tool in FreeSurfer to advance the study of human consciousness and its disorders.
Rare variant aggregation highlights rare disease genes associated with brain volume variation
Authors: Wightman Douglas P. , Maciel Bernardo A.P.C. , Brouwer Rachel M. , van den Heuvel Martijn P. , Posthuma Danielle
Published: September 2024

Variation in brain volume is associated with common and rare disorders. Investigating the genetics of brain volume may highlight overlap between diseases and biological mechanisms that explain disease symptoms. Previous studies examining genetic variants associated with brain volume have largely focused on common variants, with rare variant studies not primarily focusing on brain volume phenotypes or focusing on large structural variants. In this study, we aggregated rare variants within genes and associated genes with 44 brain volume phenotypes in the UK Biobank (N=40,374). We found convergence between genes within the same biological pathway and convergence between common and rare variants within the same gene. Seven of the genes associated with total or regional brain volume measures were also linked with rare brain disorders in previous literature. We successfully showed that rare variants in genes linked to rare brain disorders were also associated with sub-clinical brain volume variation.
The JAK inhibitor, Tofacitinib, Corrects the Overexpression of CEACAM6 and Limits Susceptibility to AIEC Caused by Reduced Activity of the IBD Associated Gene,PTPN2
Authors: Chatterjee Pritha , Canale Vinicius , King Stephanie J. , Shawki Ali , Lei Hillmin , Haddad Michael , Gries Casey M. , McGovern Dermot P.B. , Borneman James , McCole Declan F.
Published: September 2024

Background and Aims

A cohort of patients with inflammatory bowel disease (IBD) exhibit expansion of the gut pathobiont, adherent-invasiveE. coli(AIEC). Loss of activity of the IBD susceptibility gene, protein tyrosine phosphatase type 2 (PTPN2), results in dysbiosis of the gut microbiota both in human subjects and mice. Further, constitutivePtpn2knock-out (Ptpn2-KO) mice display expansion of AIEC compared to wildtype littermates. CEACAM6, a host cell surface glycoprotein, is exploited by AIEC to attach to and enter intestinal epithelial cells (IECs). Here, we investigate the role of IEC-specificPTPN2in restricting AIEC invasion.

Methods

Biopsies from IBD patients heterozygous (CT) or homozygous (CC) for thePTPN2SNP (single nucleotide polymorphism)rs1893217were processed for immunohistochemistry. HT-29 intestinal epithelial cells (IEC) were transfected with control shRNA (PTPN2-CTL), or a shRNA targeted towardsPTPN2(PTPN2-KD). Thers1893217SNP was inserted (PTPN2-KI), or a complete knock-out ofPTPN2(PTPN2- KO) was generated, with CRISPR-Cas9 gene editing of Caco-2BBe IEC lines. Adherence and invasion assays were performed with either the human IBD AIEC isolate, LF82, or a novel fluorescent-tagged mouse adherent-invasiveE. coli(mAIECred) at multiplicity of infection (MOI) of 10. IL-6 and the pan-JAK inhibitor tofacitinib were administered to interrogate JAK-STAT signaling. Protein expression was determined by western blotting and densitometry.

Results

CEACAM6 expression was elevated (colon and ileum) in IBD patients carrying thePTPN2 rs1893217SNP (CT, CC) compared to wildtype (TT) IBD patients. HT-29 and Caco-2BBe cell lines deficient inPTPN2expressed significantly higher levels of CEACAM6. Further,PTPN2-KI andPTPN2-KO cell lines also displayed greater adherence and invasion by AIEC LF82 and highermAIECredinvasion. CEACAM6 expression was further elevated after administration of IL-6 inPTPN2–deficient cell lines compared to untreated controls. Silencing of STAT1 and 3 partially reduced CEACAM6 protein expression. Tofacitinib significantly reduced the elevated CEACAM6 protein expression and the higher AIEC adherence and invasion inPTPN2-KI and PTPN2-KO cell lines compared to DMSO controls.

Conclusion

Our findings highlight a crucial role forPTPN2in restricting pathobiont entry into host cells. Our study also describes a role for the FDA-approved drug, tofacitinib (Xeljanz) in correcting the JAK-STAT- mediated over-expression of CEACAM6, used by pathobionts as an entry portal into host cells. These findings suggest a role for JAK-inhibitors in mitigating AIEC colonization in IBD-susceptible hosts.
Tissue resident memory CD4+T cells are sustained by site-specific levels of self-renewal and replacement from precursors
Authors: Chandler Jodie , Bullock M. Elise , Swain Arpit , Williams Cayman , van Dorp Christiaan H. , Seddon Benedict , Yates Andrew J.
Published: September 2024

Tissue-resident memory T cells (TRM) protect from repeated infections within organs and barrier sites. The breadth and duration of such protection is defined at minimum by three quantities; the rate at which new TRMare generated from precursors, their rate of self-renewal, and their loss rate through death, egress, or differentiation. Quantifying these processes in isolation is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4+TRMin skin and lamina propria (LP) of healthy adult mice. We show that CD69+CD4+TRMin skin reside for∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks; and approximately 2% of cells are replaced daily from precursors. CD69+CD4+TRMin LP have shorter residencies (∼ 14 days) and are maintained largely by immigration (4-6% per day). We also find evidence that the constitutive replacement of CD69+CD4+TRMat both sites derives from circulating effector-memory CD4+T cells, in skin possibly via a CD69−intermediate. Our integrated approach maps the ontogeny of CD4+TRMin skin and LP and exposes their dynamic and distinct behaviours, with continual seeding and erosion potentially impacting the duration of immunity at these sites.
Re-evaluation of some popular CRAC channel inhibitors – structurally similar but mechanistically different?
Authors: Gökçe Yasin , Mahzabeen Sinayat , Ghoorahoo Joshua , Harper Matthew Thomas , Yaras Nazmi , Rahman Taufiq
Published: September 2024

Ca2+-release activated Ca2+(CRAC) channels mediate the store-operated Ca2+entry (SOCE) that is used almost by all cells to replenish depleted intracellular Ca2+stores. Aberrant CRAC channel functions have been implicated in various diseases including autoimmune diseases and as such these channels and the resultant pathway (SOCE) have been intensively studied by academic and pharmaceutical scientists over decades. To date, several small molecule inhibitors and few antibodies have been developed against these ion channels. Some small molecule inhibitors of the CRAC channels, namely BTP2, Synta66, Pyr6 and GSK-7975A, are widely used as tool compounds in the field but their mode of action remains unclear. In this study, we used whole cell electrophysiology supported by in silico modelling to propose likely binding site and binding mode of these four popular CRAC channel inhibitors.
Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis
Authors: Bhattacharya Priyan , Linnenbach Alban , South Andrew P. , Martinez-Outschoorn Ubaldo , Curry Joseph M. , Johnson Jennifer M. , Harshyne Larry A. , Mahoney Mỹ G. , Luginbuhl Adam J. , Vadigepalli Rajanikanth
Published: September 2024

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. An exhaustive simulation of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8+ killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.
From tumor microenvironment to immuno-therapeutic outcomes for solid tumors: A systems theoretic approach
Authors: Bhattacharya Priyan , Vadigepalli Rajanikanth
Published: September 2024

Increasing evidence suggests the tumor microenvironment (TME) governs solid tumor response to immune checkpoint inhibition (ICI). Decoding the relationship between the cell compositional diversity of the tumor microenvironment (TME) and the therapeutic outcomes has been a longstanding problem in solid tumor research. In this work, we develop a systems-theoretic formalism to decipher the key mechanisms of growth, proliferation, immune evasion, and drug resistance that run common across solid tumors in the context of Immune Checkpoint Inhibitors (ICI). We reconstructed a core TME network in common across most solid tumors, containing multiple tumor and non-tumor cell types in distinct functional states, and molecular agents mediating cellular signaling and cell-cell interactions. Our analysis shows that the core TME network is sufficient to yield a multiplicity of attractors corresponding to clinically observed TME subtypes namely, immune or fibro dominated, immune or fibro desert, and immune and fibro deficient. Importantly, the reachability around the pre-ICI attractors governs the response to ICI explaining the TME subtype-specific therapy outcomes. We analyzed the attractor transition network to identify subtype-specific combination therapies that can drive unresponsive TME to a responsive subtype. We derived mathematical conditions relating TME balances to determine the limits of the efficacy of combination therapies. Our results hold for a large class of smooth biochemical kinetics with monotone and bounded interactions and (semi-)concave proliferation rules. The analytical findings have been verified with extensive simulation of different TME sub-types. Overall, we propose a generalized systems formalism that accounts for the TME properties governing ICI response and can aid in designing intervention strategies for improved tumor prognosis.

Significance Statement

Non-responsive therapy outcomes have been a persistent problem in cancer treatment. Predicting the possibility of non-responsiveness to a particular therapy from the pre-treatment composition of the tumor microenvironment (TME) aids in designing appropriate combination treatment strategies toward an improved prognosis. The present work develops a systems-theoretic formalism that aims to unfold the mechanisms behind solid tumors’ growth, non-responsiveness, and recurrence. Unlike a single model, the proposed formalism does not assume any particular kinetics, barring some minimal assumptions. This enables us to explain some of the relevant observations made by the recent experimental studies. Finally, the closed-form conditions obtained for responsivity and recurrence can also guide novel therapeutic strategies that may be able to restore responsiveness to immunotherapy.
Genomic insights into the successful invasion of the avian vampire fly (Philornis downsi) in the Galápagos Islands
Authors: Basnet Aarati , Palacios Catalina , Meng Hao , Nakhwa Dhruv , Farmer Thomas , Dahal Nishma , Anchundia David , Heimpel George E. , Causton Charlotte , Koop Jennifer A.H. , Lamichhaney Sangeet
Published: September 2024

Invasive species disrupt island ecosystems, posing significant threats to native species. The avian vampire fly(Philornis downsi), introduced into the Galápagos Islands, has become a major threat to endemic birds including Darwin’s finches, yet the genetic mechanisms of its invasion remain unclear. This study used whole-genome sequencing ofP. downsipopulations from Galápagos and its native range in mainland Ecuador, revealing reduced genetic diversity in Galápagos, indicative of a recent bottleneck. We found evidence of ongoing gene flow among island populations and identified regions under positive selection near genes related to neural signaling, muscle development, and metabolic processes, which may have contributed to the fly’s invasion success in Galápagos. These findings highlight the importance of genomic research for mitigating the impact ofP. downsion Galápagos biodiversity.
Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling
Authors: Nakagawa Rachel , Beardsley Andrew , Durney Sophia , Hayward Mary-Kate , Subramanyam Vishvak , Meyer Nathaniel P. , Wismer Harrison , Goodarzi Hani , Weaver Valerie M , Van de Mark Daniel , Goga Andrei
Published: September 2024

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C(G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127Amutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.

Graphical Abstract
Molecular Evolution and Functional Divergence of Heterodisulfide Reductase A (HdrA)
Authors: Banerjee Mousumi
Published: September 2024

Heterodisulfide reductase is a key enzyme in methanogenesis pathway in archaea, which helps to recycle the coenzymes after methane is formed from C1 carbon sources. Homologous enzymes are observed in non-methanogenic archaea and prokaryotes but their functional and evolutionary details are not fully explored. This report aims at understanding the distribution of one such homologous enzyme, heterodisulfide reductase A (HdrA); it’s domain architecture, overall structural contribution in biological function and evolutionary details in organisms other than methanogen. Exhaustive sequence analysis from both archaea and prokaryotic lineages reveals the presence of highly conserved homologues which probably have an altered oxido-reductase function. Phylogenetic analysis and co-clustering showed the differential diversity of the homologues enzyme in metabolically diverse groups. The distribution of Heterodisulfide homologues in both archaea and prokaryotes shows differential expansion of this protein by multiple horizontal gene transfer events. Conserved domain analysis and structural modelling of different phylogenetic clades shows sequence and structural diversity at the C-terminal domain. Bimolecular network analysis highlights the functional association and interactions of the heterodisulfide homologues with diverse protein partners which participate in different metabolic function. HdrA involved in species specific metabolic function while the functional conservation is evident between close related species. Analysis of structural domain within HdrA’s reveals that clade specific sequence which helps to differentiate structural domain arrangement and contributes to functional constrains. The presence of HdrA protein in methanogenic archaea and non-methanogens suggests that the protein function involving redox reaction and electron transfer shared a common history.
Dynamic cognitive differences between internal and external attention are associated with depressive and anxiety disorders
Authors: Oka Taiki , Koyama Yutaro , Sasaki Akihiro , Murakami Misa , Kobayashi Nao , Cortese Aurelio
Published: September 2024

The internal/external attention framework characterises attention focused on internal representations, such as emotions, versus external representations, such as perceptual stimuli. The inability to focus one’s attention is considered a critical factor in psychiatric disorders. While these different attentional foci are likely generated by the dynamic interplay of multiple cognitive processes, previous studies have generally examined single cognitive dimensions. We developed a new method, cognitive dynamic similarity analysis (C-DSA), to clarify how cognitive processes differ between experimental conditions. In an MR scanner, participants performed a word-processing task in which they focused on either their own emotions or the number of letters associated with a stimulus. To extract cognitive dynamics at the single-trial level, we applied cognitive dynamics estimation, a recently developed method that generates whole-brain activation maps for four cognitive dimensions (emotion processing, selective attention, self-referential thought, and working memory) using a meta-analytic platform. We then performed C-DSA to calculate the difference between internal and external attention for each cognitive dimension. C-DSA revealed significant differences between internal/external attention in all cognitive dimensions, but especially in emotion processing. Moreover, the difference between attention conditions of selective attention was negatively associated with the severity of depression and state-anxiety, but positively associated with trait-anxiety. Our findings suggest that C-DSA applies to both naturalistic and controlled dynamic processes and may be valuable in clinical settings by linking dynamic cognitive mechanisms with issues like ageing and psychiatric disorders.

Graphical abstract
Vibrio choleraeCsrA controls ToxR levels by increasing the stability and translation oftoxRmRNA
Authors: Mey Alexandra R. , Midgett Charles R. , Kull F. Jon , Payne Shelley M.
Published: September 2024

Regulation of colonization and virulence factor production in response to environmental cues is mediated through several regulatory factors inVibrio cholerae, including the highly conserved RNA-binding global regulatory protein CsrA. We have shown previously that CsrA increases synthesis of the virulence-associated transcription factor ToxR in response to specific amino acids (NRES) and is required for the virulence ofV. choleraein the infant mouse model of cholera. In this study, we mapped the 5’ untranslated region (5’ UTR) oftoxRand showed that CsrA can bind directly to an RNA sequence encompassing the 5’ UTR, indicating that the regulation of ToxR levels by CsrA is direct. Consistent with this observation, the 5’ UTR oftoxRcontains multiple putative CsrA binding sequences (GGA motifs), and mutating these motifs disrupted the CsrA-mediated increase in ToxR. Optimal binding of CsrA to a defined RNA oligonucleotide required the bridging of two GGA motifs within a single RNA strand. To determine the mechanism of CsrA regulation, we assayedtoxRtranscript levels, stability, and efficiency of translation. Both the amount oftoxRmRNA in NRES and the stability of thetoxRtranscript were increased by CsrA. Using an in vitro translation assay, we further showed that synthesis of ToxR was greatly enhanced in the presence of purified CsrA, suggesting a direct role for CsrA in the translation oftoxRmRNA. We propose a model in which CsrA binding to the 5’ UTR of thetoxRtranscript promotes ribosomal access while precluding interactions with RNA-degrading enzymes.

IMPORTANCE

Vibrio choleraeis uniquely adapted to life in marine environments as well as in the human intestinal tract. Global regulators such as CsrA, which help translate environmental cues into an appropriate cellular response, are critical for switching between these distinct environments. Understanding the pathways involved in relaying environmental signals is essential for understanding both the environmental persistence and the intestinal pathogenesis of this devastating human pathogen. In this study, we demonstrate that CsrA directly regulates synthesis of ToxR, a key virulence factor ofV. cholerae. Under conditions favoring high levels of active CsrA in the cell, such as in the presence of particular amino acids, CsrA increases ToxR protein levels by binding to thetoxRtranscript and enhancing both its stability and translation. By responding to nutrient availability, CsrA is perfectly poised to activate the virulence gene regulatory cascade at the preferred site of colonization, the nutrient-rich small intestinal mucosa.
The Harvard-Emory ECG Database
Authors: Koscova Zuzana , Li Qiao , Robichaux Chad , Moura Junior Valdery , Ghanta Manohar , Gupta Aditya , Rosand Jonathan , Aguirre Aaron , Hong Shenda , Albert David E. , Xue Joel , Parekh Aarya , Sameni Reza , Reyna Matthew A. , Westover M. Brandon , Cliford Gari D.
Published: October 2024

The Harvard-Emory ECG Database (HEEDB) is a large collection of 12-lead electrocardiogram (ECG) recordings, developed through a collaboration between Harvard University and Emory University. The database consists of 10,608,417 unique ECG recordings from 1,818,247 patients from Massachusetts General Hospital (MGH) and 1,452,964 recordings from 552,481 patients from Emory University Hospital (EUH) collected in clinical settings as part of routine patient care since the early 1990s. Continuously updated with new data, the recordings consist of 10-second, 12-lead ECGs sampled at 250 and 500 Hz, and stored in WFDB format. Future updates will include demographic information such as age, sex, race, and ethnicity. Additionally, 12SL annotations–encompassing ECG diagnoses, morphology, and rhythms–are available for 10,471,531 recordings from MGH and 1,268,277 recordings from EUH. Shortly, ICD-9/10 codes, CPT codes, and medication history will also be made publicly available.
Somatostatin interneurons select dorsomedial striatal representations of the initial learning phase
Authors: Rotariu S , Zalcman G , Badreddine N , Appaix F , Sarno S , Bureau I , Fino E
Published: September 2024

The dorsomedial striatum (DMS) is an associative node involved in the adaptation of ongoing actions to the environmental context and in the initial formation of motor sequences. In early associative or motor learning phases, DMS activity shows a global decrease in neuron firing, eventually giving rise to a select group of active cells, whose number is correlated with animal performance. Unveiling how those representation emerge from DMS circuits is crucial for understanding plasticity mechanisms of early adjustments to learning a task. Here, we hypothesized that inhibitory microcircuits formed by local interneurons are responsible for the genesis of early DMS representation and associated task performance. Despite the low density of somatostatin (SOM)-positive cells, we observed that selective manipulation of SOM cells disrupted reorganization of DMS activity and modulated initial phases of learning in two behavioral contexts. This effect was cell-specific as manipulation of parvalbumin-positive interneurons had no significant effect. Finally, we identified the high plasticity of SOM innervation in the DMS as a key modulator of the SPN excitability and firing activity. Hence, SOM interneurons set the pace of early learning by actively controlling the remapping of DMS network activity.
In situquantification of ribosome number by electron tomography
Authors: El Hankouri Mounir , Nousch Marco , Müller-Reichert Thomas , Fabig Gunar
Published: September 2024

Ribosomes, discovered in 1955 by George Palade, were originally described as small cytoplasmic particles preferentially associated with the endoplasmic reticulum (ER). Over the years, numerous studies were conducted on both ribosome structure and function. The basic question, however, how many ribosomes are contained within whole cells has not been addressed so far. Here we developed a microscopic method to determine the total number of ribosomes in human hTRET-RPE-1 and in nematode cells from different tissues inCaenorhabditis eleganshermaphrodites. Electron tomography of high-pressure frozen, freeze substituted and resin-embedded samples revealed that the number of ribosomes as determined by this electron tomographic approach closely matches the biochemical estimates for the hTRET-RPE-1 cells. In addition, RPOA-1-depleted worms compared to control worms showed an expected decrease in the number of ribosomes in two out of three different tissue types investigated. The application of our imaging-based approach to directly count the number of ribosomes in given samples will significantly enhance our basic understanding of ribosome localization and distribution within cells and tissues.
Microbial Metagenomes Across a Complete Phytoplankton Bloom Cycle: High-Resolution Sampling Every 4 Hours Over 22 Days
Authors: Nunn Brook L. , Timmins-Schiffman Emma , Mudge Miranda C. , Plubell Deanna , Chebli Gabriella , Kubanek Julia , Riffle Michael , Noble William S. , Harvey Elizabeth , Nunn Tasman A. , Huntemann Marcel , Clum Alicia , Foster Brian , Foster Bryce , Roux Simon , Palaniappan Krishnaveni , Mukherjee Supratim , Reddy T.B.K. , Daum Chris , Copeland Alex , Chen I-Min A. , Ivanova Natalia N. , Kyrpides Nikos C. , del Rio Tijana Glavina , Eloe-Fadrosh Emiley A.
Published: September 2024

In May and June of 2021, marine microbial samples were collected for DNA sequencing in East Sound, WA, USA every 4 hours for 22 days. This high temporal resolution sampling effort captured the last 3 days of aRhizosoleniasp. bloom, the initiation and complete bloom cycle of Chaetoceros socialis (8 days), and the following bacterial bloom (2 days). Metagenomes were completed on the time series, and the dataset includes 128 size-fractionated microbial samples (0.22-1.2µm), providing gene abundances for the dominant members of bacteria, archaea, and viruses. This dataset also has time-matched nutrient analyses, flow cytometry data, and physical parameters of the environment at a single point of sampling within a coastal ecosystem that experiences regular bloom events, facilitating a range of modeling efforts that can be leveraged to understand microbial community structure and their influences on the growth, maintenance, and senescence of phytoplankton blooms.
Meta-analytic Review of Bacteria and Parasites in Elasmobranchs Provides Insight into Research Gaps
Authors: Modzelesky Alexis
Published: September 2024

Elasmobranchs have conservational and commercial importance. There is a need for a more complete understanding of their health, due to their ability to shape trophic webs and their money-making potential with fishers and ecotourists. Sharks have been known to influence the strength of food webs, including reef ecosystems where many fish species are harvested for food. The investigation of pathogenic agents and diseases in elasmobranchs has been biased to favor those natural enemies that inhabit the digestive system and epidermal surfaces. Certain groups of parasites such as cestodes, copepods, and monogeneans, were most often recorded in this review. The bacterial microbiota of elasmobranchs is currently being researched, but much information is lacking in the field, with the exception of certain well-known strains, such as members of the genus Vibrio. In addition, information on the 22 species of sharks included in this study is more in depth than that which can be found for the 11 ray species and three skates. A quantitative study was undertaken to investigate relationships between taxonomic Order and Family, as well as the relationship between diet and number of natural enemies with the use of the statistical software R. It was found that number of natural enemies present in an elasmobranch species correlates with the number of sources available. This first attempt at an exhaustive review of elasmobranch natural enemies from Florida waters includes over 400 pathogens as well as indicates the 14 most under-studied elasmobranch species.
The utility of explainable A.I. for MRI analysis: Relating model predictions to neuroimaging features of the aging brain
Authors: Hofmann Simon M. , Goltermann Ole , Scherf Nico , Müller Klaus-Robert , Löffler Markus , Villringer Arno , Gaebler Michael , Witte A. Veronica , Beyer Frauke
Published: October 2024

Introduction

Deep learning models highly accurately predict brain-age from MRI but their explanatory capacity is limited. Explainable A.I. (XAI) methods can identify relevant voxels contributing to model estimates, yet, they do not reveal which biological features these voxels represent. In this study, we closed this gap by relating voxel-based contributions to brain-age estimates, extracted with XAI, to human-interpretable structural features of the aging brain.

Methods

To this end, we associated participant-level XAI-based relevance maps extracted from two ensembles of 3D-convolutional neural networks (3D-CNN) that were trained on T1-weighted and fluid attenuated inversion recovery images of 2016 participants (age range 18-82 years), respectively, with regional cortical and subcortical gray matter volume and thickness, perivascular spaces (PVS) and water diffusion-based fractional anisotropy of main white matter tracts.

Results

We found that all neuroimaging markers of brain aging, except for PVS, were highly correlated with the XAI-based relevance maps. Overall, the strongest correlation was found between ventricular volume and relevance (r= 0.69), and by feature, temporal-parietal cortical thickness and volume, cerebellar gray matter volume and frontal-occipital white matter tracts showed the strongest correlations with XAI-based relevance.

Conclusion

Our ensembles of 3D-CNNs took into account a plethora of known aging processes in the brain to perform age prediction. Some age-associated features like PVS were not consistently considered by the models, and the cerebellum was more important than expected. Taken together, we highlight the ability of end-to-end deep learning models combined with XAI to reveal biologically relevant, multi-feature relationships in the brain.
Effect of differential protection regimes on the diversity and composition of woody plants in the Western Ghats
Authors: Shigwan Bhushan K. , Kulkarni Aboli , Smirthy Vijayan , Page Navendu V. , Shetti Rohan , Datar Mandar N.
Published: September 2024

Human interference in forests is inevitable, and despite significant conservation efforts, many forest areas continue to suffer from anthropogenic pressures. The forests of the Northern Western Ghats (NWG) exhibit varying degrees of protection, including private, community, and legal frameworks. However, the tree diversity within these protection regimes remains underexplored. This study aims to assess tree diversity, composition, and structure across four protection regimes using a transect-cum-quadrat method, with four quadrats (20×20 m) along a single transect line. Data collected included species richness, individual counts, girth at breast height (GBH), basal area, and a combined disturbance index (CDI). Approximately 50% commonality was observed among sites across the four protection regimes. Protected Areas (PA) and Reserved Forests (RF) exhibited higher tree densities compared to Sacred Groves (SG) and Private Forests (PV). Notably, Sacred Groves, despite experiencing high disturbance levels, displayed a similar tree variety to PAs and RFs. While species composition across the four regimes was comparable, structural elements such as tree density and basal area varied significantly. Sacred Groves were predominantly characterized by older trees, whereas RFs and PAs were primarily populated by younger trees. These findings underscore the critical need for targeted conservation strategies that address the unique challenges faced by each protection regime. Enhanced conservation planning is essential to mitigate the impacts of disturbances, such as climate change and land use changes, which threaten the biodiversity of these forests. The study highlights the importance of preserving Sacred Groves and emphasizes the role of community involvement in conservation efforts to safeguard endemic species and maintain ecological balance in the NWG.
Positive and Negative Retinotopic Codes in the Human Hippocampus
Authors: Angeli Peter A. , Steel Adam , Silson Edward H. , Robertson Caroline E.
Published: September 2024

The hippocampus is thought to coordinate sensory-mnemonic information streams in the brain, representing both the apex of the visual processing hierarchy and the central hub of mnemonic processing. Yet, the mechanisms underlying sensory-mnemonic interactions in the hippocampus are poorly understood. Recent work in cortex suggests that a retinotopic code – typically thought to be exclusive to visual areas – may help organize internal and external information at the cortical apex via opponent interactions. Here, we leverage high-resolution 7T functional MRI to test whether a bivalent retinotopic code structures activity within the human hippocampus and mediates hippocampal-cortical interactions. In seven densely-sampled individuals, we defined the retinotopic preferences of individual voxels within the hippocampus and cortex during a visual mapping task, as well as their functional connectivity during independent runs of resting-state fixation. Our findings reveal a robust retinotopic code in the hippocampus, characterized by stable population receptive fields (pRFs) with consistent preferred visual field locations across experimental runs. Notably, this retinotopic code is comprised of roughly equal proportions of positive and negative pRFs, aligning with the hypothesized role of negative pRFs in mnemonic processing. Finally, the signed amplitude of hippocampal pRFs predicts functional connectivity between retinotopic hippocampal and cortical voxels. Taken together, these results suggest that retinotopic coding may scaffold internal mnemonic and external sensory information processing within the hippocampus, and across hippocampal-cortical interactions.