bluuebunny/crossref_metadata_2025 huggingface dataset:
Sugar-sweetened beverage intake and long-term mortality in individuals with metabolic dysfunction-associated steatotic liver disease: a longitudinal analysis of the National Health and Nutrition Examination Survey database
Authors: Zhou Ji , Liu Chu , Liu Lili , Li Lei
Published: March 2024

Background

Consuming sugar-sweetened beverages (SSBs) has been linked to the development of various adverse health conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD). This study evaluated associations between SSB intake and long-term mortality among individuals with MASLD using a nationally representative database.

Methods

This population-based, longitudinal study extracted data of adults aged 20–79 years with MASLD from the USA (US) National Health and Nutrition Examination Survey database 2003–2014. Associations between the amount of SSB intake and all-cause, cancer and cardiovascular disease mortality until the end of 2019 were determined using Cox proportional hazards regression analyses.

Results

A total of 12 965 individuals aged 20–79 years who had MASLD were identified in the database. After exclusion, 5630 participants remained for the analyses. This cohort can be extrapolated to 43 420 321 individuals in the entire US after proper weighting. The mean age of the study cohort was 44.1 years. After adjusting for confounders, no significant association was observed between SSB intake (tertile 3 vs. tertile 1) and all-cause [adjusted hazard ratio (aHR): 1.03, 95% confidence interval (CI), 0.60–1.76) or cancer mortality (aHR, 0.41; 95% CI, 0.15–1.16). However, higher SSB intake (tertile 3 vs. tertile 1) was significantly associated with elevated cardiovascular disease mortality risk (aHR = 2.83; 95% CI, 1.01–7.91).

Conclusion

In US adults with MASLD, high SSB intake is associated with nearly three-fold increased cardiovascular disease mortality risk. The findings underscore the critical need for concerted action on the part of healthcare providers and policymakers.
Comparative maintenance performance of all biologic agents and small molecules in ulcerative colitis: a network meta-analysis
Authors: Rokkas Theodore , Gisbert Javier P. , Ekmektzoglou Konstantinos , Dassopoulos Themistocles , Niv Yaron , O’Morain Colm
Published: March 2024

Background and aims

Βiologic agents and small molecules have expanded the therapeutic armamentarium of moderate to severe ulcerative colitis (UC). However, their comparative efficacy and safety performance as maintenance treatments have not been sufficiently explored. We performed a systematic review and network meta-analysis (NWM) to assess the comparative efficacy and safety of all approved and emerging treatments for maintenance in moderate to severe UC.

Methods

We searched Pubmed/Medline, EMBASE, and Cochrane Library databases for relevant RCTs through April 2023. The primary endpoint was clinical remission at the end of the maintenance therapy. Data were analyzed by means of a Bayesian NWM. The ranking probability concerning efficacy and safety was evaluated by means of surfaces under cumulative ranking (SUCRA) values.

Results

There were 20 eligible RCTs with 7660 patients randomized to 20 treatments. RCTs were grouped into two study designs, that is, re-randomization of patients after an induction period and treat-through patients. Concerning efficacy, in re-randomized patients, upadacitinib 30 mg/day was ranked first (SUCRA 94.9%) whereas in treat-through patients etrasimod 2 mg/day was ranked first (SUCRA 91.1%). The integrated efficacy-safety hierarchical analysis, showed that tofacitinib 10 mg had the best efficacy-safety therapeutic profile in re-randomized patients, whereas in treat-through patients infliximab 3.5 mg/Kg Q8W showed the best efficacy-safety profile.

Conclusion

For maintenance treatment, in moderate to severe UC, this NWM showed that upadacitinib 30 mg/day and etrasimod 2 mg/day were ranked best for efficacy in re-randomized and treat-through patients respectively. Tofacitinib 10 mg/day and infliximab 3.5 mg/Kg Q8W showed the best efficacy-safety therapeutic profile in re-randomized and treat-through patients respectively.
Idiopathic chronic intestinal pseudo-obstruction syndrome is strongly associated with low serum levels of vitamin D
Authors: Panarese Alba , Dajti Elton , Eusebi Leonardo Henry , Vestito Amanda , Zagari Rocco Maurizio
Published: March 2024

Idiopathic chronic intestinal pseudo-obstruction (CIPO) is associated with intestinal inflammation and malabsorption and may cause serum vitamin D deficiency. We aimed to assess whether there is an association between idiopathic CIPO and serum levels of 25-hydroxy-vitamin D. Consecutive patients with confirmed diagnosis of idiopathic CIPO were prospectively enrolled and matched with healthy controls by gender, age, and BMI. Median serum level of 25-hydroxy-vitamin D of patients with CIPO was compared with that of healthy subjects using the Wilcoxon signed-rank test for matched samples. A total of 35 patients with CIPO and 35 matched healthy subjects were enrolled. All patients with CIPO had a 25-hydroxy-vitamin D deficiency with serum levels <12 ng/ml. The median serum level of vitamin D was significantly lower in patients with CIPO than in healthy controls (5.7 vs. 29.7 ng/ml, P < 0.0001). Serum level of vitamin D was not associated with gender (P = 0.27), age (P = 0.22), BMI (P = 0.95), high (>10 000 × ml) WBC count (P = 0.08), or high (>5 mg/l) C-reactive protein (P = 0.87) among patients with CIPO. CIPO seems to be strongly associated with low serum levels of 25-hydroxy-vitamin D.
Paraneoplastic gastrointestinal dysmotility due to non-Hodgkin diffuse large B cell lymphoma: a case report
Authors: Nash Emily , Chetwood John D. , Tamilarasan Aravind G. , Prakoso Emilia
Published: March 2024

Paraneoplastic gastrointestinal dysmotility is a rare entity which occurs in association with malignancy. We present the second case associated with lymphoma, characterised by generalised gastrointestinal dysmotility with constipation, malnutrition, weight loss, and capsule endoscope retention. This case highlights the importance of maintaining a high index of suspicion for malignancy in patients with unexplained gastrointestinal dysmotility.
Outcomes of Colectomy and Proctectomy According to Surgeon Training: General vs Colorectal Surgeons
Authors: Purdy Amanda C , Murphy Serena , Vilchez Valery , Shanmugan Skandan , Whealon Matthew , Mills Steven , Carmichael Joseph C , Stamos Michael J , Nguyen Ninh T
Published: March 2024

BACKGROUND:

Colectomies and proctectomies are commonly performed by both general surgeons (GS) and colorectal surgeons (CRS). The aim of our study was to examine the outcomes of elective colectomy, urgent colectomy, and elective proctectomy according to surgeon training.

STUDY DESIGN:

Data were obtained from the Vizient database for adults who underwent elective colectomy, urgent colectomy, and elective proctectomy from 2020 to 2022. Operations performed in the setting of trauma and patients within the database’s highest relative expected mortality risk group were excluded. Outcomes were compared according to surgeon’s specialty: GS vs CRS. The primary outcome was in-hospital mortality. The secondary outcome was in-hospital complication rate. Data were analyzed using multivariate logistic regression.

RESULTS:

Of 149,516 elective colectomies, 75,711 (50.6%) were performed by GS and 73,805 (49.4%) by CRS. Compared with elective colectomies performed by CRS, elective colectomies performed by GS had higher rates of complications (4.9% vs 3.9%, odds ratio [OR] 1.23, 95% CI 1.17 to 1.29, p < 0.01) and mortality (0.5% vs 0.2%, OR 2.06, 95% CI 1.72 to 2.47, p < 0.01). Of 71,718 urgent colectomies, 54,680 (76.2%) were performed by GS, whereas 17,038 (23.8%) were performed by CRS. Compared with urgent colectomies performed by CRS, urgent colectomies performed by GS were associated with higher rates of complications (12.1% vs 10.4%, OR 1.14, 95% CI 1.08 to 1.20, p < 0.01) and mortality (5.1% vs 2.3%, OR 2.08, 95% CI 1.93 to 2.23, p < 0.01). Of 43,749 elective proctectomies, 28,458 (65.0%) were performed by CRS and 15,291 (35.0%) by GS. Compared with proctectomies performed by CRS, those performed by GS were associated with higher rates of complications (5.3% vs 4.4%, OR 1.16, 95% CI 1.06 to 1.27, p < 0.01) and mortality (0.3% vs 0.2%, OR 1.49, 95% CI 1.02 to 2.20, p = 0.04).

CONCLUSIONS:

In this nationwide study, colectomies and proctectomies performed by CRS were associated with improved outcomes compared with GS. Hospitals without a CRS on staff should consider prioritizing recruiting CRS specialists.
Evolutionary change in flight-to-light response in urban moths comes with changes in wing morphology
Authors: Van de Schoot Evert , Merckx Thomas , Ebert Dieter , Wesselingh Renate A. , Altermatt Florian , Van Dyck Hans
Published: March 2024

Moths and other insects are attracted by artificial light sources. This flight-to-light behaviour disrupts their general activity focused on finding resources, such as mating partners, and increases predation risk. It thus has substantial fitness costs. In illuminated urban areas, spindle ermine moths
Yponomeuta cagnagella
were reported to have evolved a reduced flight-to-light response. Yet, the specific mechanism remained unknown, and was hypothesized to involve either changes in visual perception or general flight ability or overall mobility traits. Here, we test whether spindle ermine moths from urban and rural populations—with known differences in flight-to-light responses—differ in flight-related morphological traits. Urban individuals were found to have on average smaller wings than rural moths, which in turn correlated with a lower probability of being attracted to an artificial light source. Our finding supports the reduced mobility hypothesis, which states that reduced mobility in urban areas is associated with specific morphological changes in the flight apparatus.
John Roundell Palmer, fourth Earl of Selborne. 24 March 1940—12 February 2021
Authors: Goodman Dougal , Napper Simon
Published: March 2024

Occasionally, the Royal Society confers a fellowship on individuals not because of distinction in any one branch of science but rather for their contribution to science as a whole. Among that select group of Fellows was John Roundell Palmer, fourth Earl of Selborne GBE DL FRS, who was elected in 1991. A member of the House of Lords for nearly 50 years, a primary focus for his work was the interface between science and technology on the one hand, and policy and legislation on the other. He was elected Chair of the House of Lords Select Committee on Science and Technology twice, being involved in some of the defining issues in the science agenda over those times. His involvement in the horticultural and agriculture business of his family's estate in Hampshire made him aware of how science research could be of great benefit to the agricultural sector and society at large. His interest led to his becoming the chair of the Agricultural Research Council (ARC), where his ability to achieve a consensus between people with diverse views enabled complex projects to progress. He joined the House of Lords in 1971 as a hereditary peer. In addition, he used his skills and wide-ranging interests to engage with a range of bodies across different sectors. He was at different times: President of the Royal Geographical Society (with Institute of British Geographers (IBG)); Chair of the Advisory Board of the Centre for Ecology and Hydrology; Chancellor of the University of Southampton; Chair of Trustees, Royal Botanic Gardens, Kew; Master of the Mercers’ Company; member of the Board of Lloyds Bank plc; Chair of Living with Environmental Change; Chair of the Foundation for Science and Technology; and chair or adviser to many other organizations. His contribution to the dialogue between science policy and society was recognized by the award of KBE in 1987 and GBE in 2011.
Genomic analysis of Oceanotoga teriensis strain UFV_LIMV02, a multidrug-resistant thermophilic bacterium isolated from an offshore oil reservoir
Authors: Santos Adriele Jéssica do Carmo , Dias Roberto Sousa , Silva Carlos Henrique Martins da , Vidigal Pedro Marcus Pereira , Sousa Maira Paula de , Silva Cynthia Canedo da , Paula Sergio Oliveira de
Published: March 2024

Bacteria of the species Oceanotoga teriensis belong to the Family Petrotogaceae, are moderately thermophilic and are included in the group of thiosulfate-reducing bactéria (TRB), being able to accelerate corrosion in metallic structures significantly. The O. teriensis strain UFV_LIMV02 was isolated from water samples from the separator of an offshore oil extraction platform in the Campos basin in Rio de Janeiro (Brazil). In this work, we describe the man phenotypic and genotypic characteristics, mainly related to hydrogen sulfide production and antimicrobial resistance to different classes of antibiotics. We also systematically investigate the presence of CRISPR-Cas loci and prophages. Through H2S titration, it was possible to verify thexistence of 150 ppm of hydrogen sulfide in the solution. It presented a genome with 2,812,778 bp in size, with 26% of GC content, organized into 34 contigs 2,629 genes encoding candidate proteins, and identified 51 genes of different RNAs. The search for CRISPRs systems in the genome of the isolate allowed us to identify the presence of four CRISPRs arrays, classified as type I-B and III-B, with the presence of 272 different spacers, which could provide the strain with immunity to other mobile genetic elements and infection by bacteriophages. Genomic analysis using RAST revealed the presence of resistance genes for the class of beta-lactams and fluoroquinolones; however, when evaluating the antimicrobial resistance of the isolate using the disk diffusion technique, it was possible to confirm not only the resistance to B-lactams and fluoroquinolones, but also to four other classes of antibiotics: aminoglycoside, sulfonamide, lincosamide, and rifamycin, a total of 14 antibiotics, probably due to the presence of mechanisms capable of expelling the antibiotic from the cells, such as efflux pumps, allowing them to grow in the presence of these antimicrobials. The results found in this study provide indications that residues from offshore oil exploration may represent a risk for the dissemination of ARGs due to the presence of multidrug-resistant bacteria. More comprehensive studies are needed on the microbial community present in oil tailings to assess the risks to public health.
Construction, analysis and assessment of relevance of an algebraic model for a class of biochemical networks
Authors: Kundu Siddhartha
Published: March 2024

The intracellular milieu presents a complex physicochemical environment where molecular redundancy prevails and infra-threshold perturbations are integrated by biochemical networks. The pathways that result from these interactions are complex and will result in a plethora of signalling cascades. The stoichiometry number matrix for a biochemical network is a suitable way to represent the interactions between various molecular species under baseline conditions and in response to stimuli. Here, we model a class of biochemical networks with a set of constrained, reaction-centric, stoichiometry equivalent and degenerate matrices. The matrices exhibit a many-to-one surjection with the null space and form a semigroup with respect to addition. The parameters for these studies are the probable dissociation constants and will be used to derive several network- and reaction-specific metrics. These will describe the class of modelled biochemical networks both, at the level of a single network and as a unit. The model is extendible and can be used to perturb a biochemical network by introducing a finite number of extraneous reactions and then comparing pairs of like-reactions. The theoretical assertions presented are complemented by detailed computational analyses of the hexose monophosphate shunt, urea cycle and folate metabolism in humans. The model provides a theoretically sound basis to interrogate the effects of molecular redundancy and perturbations in the genesis and regulation of complex biochemical function. The model is theoretically sound, mathematically rigorous, readily testable, biochemically relevant, easily parameterizable and can be used to compare biochemical networks under differing intracellular conditions, both, between cells and across taxa.
Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to β-amyloid deposition and lysyl oxidase
Authors: Ventura-Antunes Lissa , Nackenoff Alex , Romero-Fernandez Wilber , Bosworth Allison M , Prusky Alex , Wang Emmeline , Carvajal-Tapia Cristian , Shostak Alena , Harmsen Hannah , Mobley Bret , Maldonado Jose , Solopova Elena , Snider J. Caleb , Merryman W. David , Lippmann Ethan S , Schrag Matthew
Published: March 2024

Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by vascular β-amyloid (Aβ) deposition on cerebral blood vessels. CAA is closely linked to Alzheimer’s disease (AD) and intracerebral hemorrhage. CAA is associated with the loss of autoregulation in the brain, vascular rupture, and cognitive decline. To assess morphological and molecular changes associated with the degeneration of penetrating arterioles in CAA, we analyzed post-mortem human brain tissue from 26 patients with mild, moderate, and severe CAA end neurological controls. The tissue was optically cleared for three-dimensional light sheet microscopy, and morphological features were quantified using surface volume rendering. We stained Aβ, vascular smooth muscle (VSM), lysyl oxidase (LOX), and vascular markers to visualize the relationship between degenerative morphological features, including vascular dilation, dolichoectasia (variability in lumenal diameter) and tortuosity, and the volumes of VSM, Aβ, and LOX in arterioles. Atomic force microscopy (AFM) was used to assess arteriolar wall stiffness, and we identified a pattern of morphological features associated with degenerating arterioles in the cortex. The volume of VSM associated with the arteriole was reduced by around 80% in arterioles with severe CAA and around 60% in cases with mild/moderate CAA. This loss of VSM correlated with increased arteriolar diameter and variability of diameter, suggesting VSM loss contributes to arteriolar laxity. These vascular morphological features correlated strongly with Aβ deposits. At sites of microhemorrhage, Aβ was consistently present, although the morphology of the deposits changed from the typical organized ring shape to sharply contoured shards with marked dilation of the vessel. AFM showed that arteriolar walls with CAA were more than 400% stiffer than those without CAA. Finally, we characterized the association of vascular degeneration with LOX, finding strong associations with VSM loss and vascular degeneration. These results show an association between vascular Aβ deposition, microvascular degeneration, and increased vascular stiffness, likely due to the combined effects of replacement of VSM by β-amyloid, cross-linking of extracellular matrices (ECM) by LOX, and possibly fibrosis. This advanced microscopic imaging study clarifies the association between Aβ deposition and vascular fragility. Restoration of physiologic ECM properties in penetrating arteries may yield a novel therapeutic strategy for CAA.
Preserved spontaneous mentalizing amid reduced intersubject variability in autism during a movie narrative
Authors: Mangnus Margot , Koch Saskia B. J. , Cai Kexin , Greidanus Romaneli Miriam , Hagoort Peter , Bašnáková Jana , Stolk Arjen
Published: March 2024

Individuals with autism may perform well in structured Theory of Mind (ToM) tasks that assess their ability to infer mental states, yet encounter challenges in everyday social interactions. Using fMRI and pupillometry, we investigated whether this discrepancy stems from reduced spontaneous mentalizing or broader difficulties in unstructured environments. Autistic adults and neurotypical controls viewed a nonverbal animated movie featuring events known to evoke mental state inferences. Both groups exhibited similar ToM network activations and pupil responses to these events, alongside comparable verbal accounts of the mental states portrayed. However, intersubject correlation analysis revealed a significant reduction in response variability among autistic participants throughout the movie’s complex visual narrative, affecting brain regions beyond the ToM network. We suggest that the primary challenge for individuals with autism may lie in the idiosyncratic exploration of narratives in unstructured settings, regardless of whether mental state inferences are involved.
CXCL8 secreted by immature granulocytes inhibits wildtype hematopoiesis in chronic myelomonocytic leukemia
Authors: Deschamps Paul , Wacheux Margaux , Gosseye Axel , Morabito Margot , Pagès Arnaud , Lyne Anne-Marie , Alfaro Alexia , Rameau Philippe , Imanci Aygun , Chelbie Rabie , Marchand Valentine , Renneville Aline , Patnaik Mrinal , Lapierre Valerie , Badaoui Bouchra , Wagner-Ballon Orianne , Berthon Céline , Braun Thorsten , Willekens Christophe , Itzykson Raphael , Fenaux Pierre , Thépot Sylvain , Etienne Gabriel , Porteu Francoise , Elvira-Matelot Emilie , Droin Nathalie , Perié Leïla , Laplane Lucie , Solary Eric , Selimoglu-Buet Dorothée
Published: March 2024

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrated early clonal dominance with few residual wildtype hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explores the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs can be detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation is a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behave as myeloid-derived suppressor cells. Bulk and single cell RNA sequencing revealed a pro-inflammatory status of iGRAN that secrete multiple cytokines of which CXCL8 at the highest level. This cytokine inhibits the proliferation of wildtype but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors are epigenetically downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restore wildtype HSPC proliferation, suggesting that relieving CXCL8 selective pressure on wildtype HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.
Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate BrainsIn Vivo
Authors: Aurup Christian , Bendig Jonas , Blackman Samuel G. , McCune Erica P. , Bae Sua , Jimenez-Gambin Sergio , Ji Robin , Konofagou Elisa E.
Published: March 2024

Focused ultrasound (FUS) is an emerging noinvasive technique for neuromodulation in the central nervous system (CNS). To evaluate the effects of FUS-induced neuromodulation, many studies used behavioral changes, functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). However, behavioral readouts are often not easily mapped to specific brain activity, EEG has low spatial resolution limited to the surface of the brain and fMRI requires a large importable scanner that limits additional readouts and manipulations. In this context, functional ultrasound imaging (fUSI) holds promise to directly monitor the effects of FUS neuromodulation with high spatiotemporal resolution in a large field of view, with a comparatively simple and flexible setup. fUSI uses ultrafast Power Doppler Imaging (PDI) to measure changes in cerebral blood volume, which correlates well with neuronal activity and local field potentials. We designed a setup that aligns a FUS transducer with a linear array to allow immediate subsequent monitoring of the hemodynamic response with fUSI during and after FUS neuromodulation. We established a positive correlation between FUS pressure and the size of the activated area, as well as changes in cerebral blood volume (CBV) and found that unilateral sonications produce bilateral hemodynamic changes with ipsilateral accentuation in mice. We further demonstrated the ability to perform fully noninvasive, transcranial FUS-fUSI in nonhuman primates for the first time by using a lower-frequency transducer configuration.
GFPrint™: A MACHINE LEARNING TOOL FOR TRANSFORMING GENETIC DATA INTO CLINICAL INSIGHTS
Authors: Sanz-Martín Guillermo , Migliore Daniela Paula , del Campo Pablo Gómez , del Castillo-Izquierdo José , Domínguez Juan Manuel
Published: March 2024

The increasing availability of massive genetic sequencing data in the clinical setting has triggered the need for appropriate tools to help fully exploit the wealth of information these data possess. GFPrint™is a proprietary streaming algorithm designed to meet that need. By extracting the most relevant functional features, GFPrint™transforms high-dimensional, noisy genetic sequencing data into an embedded representation, allowing unsupervised models to create data clusters that can be re-mapped to the original clinical information. Ultimately, this allows the identification of genes and pathways relevant to disease onset and progression. GFPrint™has been tested and validated using two cancer genomic datasets publicly available. Analysis of the TCGA dataset has identified panels of genes whose mutations appear to negatively influence survival in non-metastatic colorectal cancer (15 genes), epidermoid non-small cell lung cancer (167 genes) and pheochromocytoma (313 genes) patients. Likewise, analysis of the Broad Institute dataset has identified 75 genes involved in pathways related to extracellular matrix reorganization whose mutations appear to dictate a worse prognosis for breast cancer patients. GFPrint™is accessible through a secure web portal and can be used in any therapeutic area where the genetic profile of patients influences disease evolution.
Automated Identification of Germlinede novoMutations in Family Trios: A Consensus-Based Informatic Approach
Authors: Shadrina Mariya , Kalay Özem , Demirkaya-Budak Sinem , LeDuc Charles A. , Chung Wendy K. , Turgut Deniz , Budak Gungor , Arslan Elif , Semenyuk Vladimir , Davis-Dusenbery Brandi , Seidman Christine E. , Yost H. Joseph , Jain Amit , Gelb Bruce D.
Published: March 2024

Accurate identification of germlinede novovariants (DNVs) remains a challenging problem despite rapid advances in sequencing technologies as well as methods for the analysis of the data they generate, with putative solutions often involvingad hocfilters and visual inspection of identified variants. Here, we present a purely informatic method for the identification of DNVs by analyzing short-read genome sequencing data from proband-parent trios. Our method evaluates variant calls generated by three genome sequence analysis pipelines utilizing different algorithms—GATK HaplotypeCaller, DeepTrio and Velsera GRAF—exploring the assumption that a requirement of consensus can serve as an effective filter for high- quality DNVs. We assessed the efficacy of our method by testing DNVs identified using a previously established, highly accurate classification procedure that partially relied on manual inspection and used Sanger sequencing to validate a DNV subset comprising less confident calls. The results show that our method is highly precise and that applying a force-calling procedure to putative variants further removes false-positive calls, increasing precision of the workflow to 99.6%. Our method also identified novel DNVs, 87% of which were validated, indicating it offers a higher recall rate without compromising accuracy. We have implemented this method as an automated bioinformatics workflow suitable for large- scale analyses without need for manual intervention.
Evolutionary integration of the geography and pacing of the annual cycle in migratory birds
Authors: Winger Benjamin M. , La Sorte Frank A. , Hack Matthew D. , Pegan Teresa M.
Published: March 2024

In migratory species, the temporal phases of the annual cycle are intrinsically linked to seasonally shifting geographic ranges. Despite intense interest in the annual cycle ecology of migration, a synthetic understanding of the relationship between the biogeography and phenology of seasonal migration remains elusive. Here, we interrogate the spatiotemporal structure of the annual cycle in a novel phylogenetic comparative framework. We use eBird, a massive avian occurrence dataset, to demarcate and measure in a consistent manner among species the portions of the annual cycle when a geographic distribution is stationary versus dynamic due to migration. Through comparative analyses of the durations of annual cycle stages for 150 species of migratory birds breeding in North America, we show that the duration of the migratory periods is remarkably consistent among species and is unrelated to the distance between breeding and nonbreeding locations. In other words, the seasonal distributions of long-distance migrants shift between their geographically distant stationary phases in the same amount of time as short-distance migrants, suggesting that individuals of long-distance migratory species have more synchronous periods of migration and likely a faster individual migratory pace than short-distance migrants. Our results further show that the amount of time a species spends on the breeding grounds is strongly inversely related to time spent on the nonbreeding grounds, revealing the length of the breeding versus nonbreeding stationary period to be the primary source of species-level variation in the pacing of the annual cycle, as opposed to the time needed for the migratory period. Further, our study reveals that the amount of time spent annually on the breeding versus nonbreeding grounds predicts the distance between breeding and nonbreeding locations, demonstrating key linkages between the biogeography of the migratory cycle, its phenology, and the evolution of life history tradeoffs.
A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data
Authors: Samorodnitsky Sarah , Campbell Katie , Ribas Antoni , Wu Michael C.
Published: March 2024

Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley’s K or Besag’s L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian cancer study. An R package and tutorial is provided athttps://github.com/sarahsamorodnitsky/SPOT.
LINC complex alterations are a hallmark of sporadic and familial ALS/FTD
Authors: Sirtori Riccardo , Gregoire Michelle , Potts Emily , Collins Alicia , Donatelli Liviana , Fallini Claudia
Published: March 2024

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in theC9ORF72gene (C9). Importantly, we show that such alterations are presentin vivoin a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex biopsies. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.
Chromosome-scale genome assembly ofApocynum pictum, a drought-tolerant medicinal plant from the Tarim Basin
Authors: Xie Wenlong , Bai Baowei , Wang Yanqing
Published: March 2024

Apocynum pictumSchrenk is a semi-shrub of the Apocynaceae family with a wide distribution throughout the Tarim Basin that holds significant ecological, medicinal, and economic values. Here, we report the assembly of its chromosome-level reference genome using Nanopore long-read, Illumina HiSeq paired-end, and high-throughput chromosome conformation capture sequencing. The final assembly is 225.32 Mb in length with a scaffold N50 of 19.64 Mb. It contains 23,147 protein-coding genes across 11 chromosomes, 21,148 of which (91.36%) have protein functional annotations. Comparative genomics analysis revealed thatA. pictumdiverged from the closely related speciesApocynum venetumapproximately 2.2 million years ago and has not undergone additional polyploidizations after the core eudicot WGT-γ event. Karyotype evolution analysis was used to characterize interchromosomal rearrangements in representative Apocynaceae species and revealed that severalA. pictumchromosomes were derived entirely from single chromosomes of the ancestral eudicot karyotype. Finally, we identified 50 members of the well-known stress-responsive WRKY transcription factor family and used transcriptomic data to document changes in their expression at two stages of drought stress, identifying a number of promising candidate genes. Overall, this study provides high-quality genomic resources for evolutionary and comparative genomics of the Apocynaceae, as well as initial molecular insights into the drought adaptation of this valuable desert plant.
Spatially heterogeneous responses of planktonic foraminifera assemblages over 700,000 years of climate change
Authors: Mathes Gregor H. , Reddin Carl J. , Kiessling Wolfgang , Antell Gawain S. , Saupe Erin E. , Steinbauer Manuel J.
Published: March 2024

Aim

To determine the degree to which assemblages of planktonic foraminifera track thermal conditions.

Location

The world’s oceans.

Time period

The last 700,000 years of glacial-interglacial cycles.

Major taxa studied

Planktonic foraminifera.

Methods

We investigate assemblage dynamics in planktonic foraminifera in response to temperature changes using a global dataset of Quaternary planktonic foraminifera, together with a coupled Atmosphere–Ocean General Circulation Model (AOGCM) at 8,000-year resolution. We use ‘thermal deviance’ to assess assemblage responses to climate change, defined as the difference between the temperature at a given location and the bio-indicated temperature (i.e., the abundance-weighted average of estimated temperature optima for the species present).

Results

Assemblages generally tracked annual mean temperature changes through compositional turnover, but large thermal deviances are evident under certain conditions. The coldest-adapted species persisted in polar regions during warming but were not joined by additional immigrants, resulting in decreased assemblage turnover with warming. The warmest-adapted species persisted in equatorial regions during cooling. Assemblages at mid latitudes closely tracked temperature cooling and showed a modest increase in thermal deviance with warming.

Main conclusions

Planktonic foraminiferal assemblages were generally able to track or endure temperature changes: as climate warmed or cooled, bio-indicated temperature also became warmer or cooler, although to a variable degree. At polar sites under warming and at equatorial sites under cooling, the change in temperature predicted from assemblage composition was less than, or even opposite to, expectations based on estimated environmental change. Nevertheless, all species survived the accumulation of thermal deviance—a result that highlights the resilience and inertia of planktonic foraminifera on an assemblage level to the last 700,000 years of climate change, which might be facilitated by broad thermal tolerances or depth shifts.
Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study
Authors: Strohman Andrew , Isaac Gabriel , Payne Brighton , Verdonk Charles , Khalsa Sahib S. , Legon Wynn
Published: March 2024

Background

The heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing. The insula and dorsal anterior cingulate cortex (dACC) are brain regions that may be involved in generating the HEP. Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that can selectively target sub-regions of the insula and dACC to better understand their contributions to the HEP.

Objective

Proof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP.

Methods

In a within-subject, repeated-measures design, healthy human participants (n=16) received 10 minutes of stereotaxically targeted LIFU to the AI, PI, dACC or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was change in HEP amplitudes. Relationships between LIFU pressure and HEP changes were examined using linear mixed modelling. Peripheral indices of visceromotor output including heart rate and heart rate variability (HRV) were explored between conditions.

Results

Relative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; this was partially explained by increased LIFU pressure. LIFU did not affect time or frequency dependent measures of HRV.

Conclusions

These results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.
Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability
Authors: Ali al-Badri Mohamed , Cross William CH , Barnes Chris P
Published: March 2024

Abstract

Chromosomal instability (CIN) refers to an increased rate of chromosomal changes within cells. It is highly prevalent in cancer cells and leads to abnormalities in chromosome number (aneuploidy) and structure. CIN contributes to genetic diversity within a tumour, which facilitates tumour progression, drug resistance, and metastasis. Here, we present a deep learning method and an exploration of the chromosome copy aberrations (CNAs) resultant from CIN, across 7,500 high-depth, whole genome sequences, representing 13 cancer types. We found that the types of CNAs can act as a highly specific classifier for primary site. Using an explainable AI approach, we revealed both established and novel loci that contributed to cancer type, and focusing on highly significant chromosome loci within cancer types, we demonstrated prognostic relevance. We outline how the developed methodology can provide several applications for researchers, including drug target and biomarker discovery, as well as the identification of cancers of unknown primary site.
Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the frontal cortex
Authors: Stowell Rianne , Wang Kuan Hong
Published: March 2024

Adolescence is a sensitive period for frontal cortical development and cognitive maturation. The dopaminergic (DA) mesofrontal circuit is particularly malleable in response to changes in adolescent experience and DA activity. However, the cellular mechanisms engaged in this plasticity remain unexplored. Here, we report that microglia, the innate immune cells of the brain, are uniquely sensitive to adolescent mesofrontal DA signaling. Longitudinalin vivotwo-photon imaging in mice shows that frontal cortical microglia respond dynamically to plasticity-inducing behavioral or optogenetic DA axon stimulation with increased parenchymal and DA bouton surveillance. Microglial-axon contact precedes new bouton formation, and both D1 and D2-type DA receptors regulate microglial-bouton interactions and axonal plasticity. Moreover, D2 antagonism in adults reinstates adolescent plasticity, including increased microglial surveillance and new DA bouton formation. Our results reveal that DA signaling regulates microglial surveillance and axonal plasticity uniquely in the adolescent frontal cortex, presenting potential interventions for restoring plasticity in the adult brain.
Mechanisms of genomic instability dictate cytosolic DNA composition and dendritic cell mediated anti-tumor immunity
Authors: Mosley Shayla R. , Chen Angie , Doell David N.W. , Choi Siwon , Mowat Courtney , Meier-Stephenson Felix , Meier-Stephenson Vanessa , Baker Kristi
Published: March 2024

Patients with microsatellite instable (MSI) colorectal cancers (CRC) face better prognosis than those with the more common chromosomal instable (CIN) subtype due to improved anti-tumor immune responses characterized by high cytotoxic T cell infiltration. Previous investigation identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and induces improved cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates MSI cyDNA is enriched for microsatellites, which upon DC uptake induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. Radiation also modulates cyDNA stimulation capacity through larger cyDNA size and increased mitochondrial DNA content. Identifying highly stimulatory cyDNA arising from genomic instability such as in MSI CRCs allows for optimized development of DNA-based STING agonist therapies to improve responses of CIN CRC patients to immunotherapies.
Exploration of phosphoproteomic association during epimorphic regeneration
Authors: Banu Sarena , Anusha P V , Mandal Komal , Idris Mohammed M
Published: March 2024

Unravelling the intricate patterns of site-specific protein phosphorylation during Epimorphic regeneration holds the key to unlocking the secrets of tissue complexity. Understanding these precise modifications and their impact on protein function could shed light on the remarkable regenerative capacity of tissues, with potential implications for therapeutic interventions. In this study we have systematically mapped the global phosphorylation modifications within regenerating tissue of zebrafish caudal fins, elucidating the intricate landscape of signalling pathway associate with the regeneration process. A total of 74 and 440 proteins were found undergoing differentially phosphorylated during the process of regeneration from 12hpa to 7dpa against control based on TiO2 column enrichment and immuno precipitation using phosphoserine, phosphothreonine and phosphotyrosine antibodies respectively. Interestingly 95% of the proteins identified from TiO2 enrichment method were also found to be identified through the phosphoprotein antibody pull down method impacting the high accuracy and significance of the methods and greater association of the 70 proteins undergoing differential phosphorylation during the process of regeneration. Whole mount immunohistochemistry analysis reveals high association of phosphorylation at 1dpa, 2dpa and 3 dpa regeneration time points. Based on network pathway analysis it was evident that Fc Receptor-mediated Phagocytosis in Macrophages and Monocytes, Actin cytoskeleton signaling, HGF signaling and Insulin receptor signaling are the most highly associated network pathways for regeneration through differential phosphorylation. This research enhances our comprehension on protein post-translational modification in the context of zebrafish caudal fin tissue regeneration, shedding light on its prospective application in the field of regenerative medicine.
Transcriptomic analysis of TGFβ-mediated fibrosis in primary human Tenon’s fibroblasts
Authors: Pasvanis Zoe , Boynes Antony , Kong Roy C.K. , Chan Elsa C. , Wong Raymond C.B. , Gaskin Jennifer Fan
Published: March 2024

Glaucoma filtration surgery (GFS) is performed to slow down disease progression in glaucoma, a leading cause of irreversible blindness worldwide. Following surgery, pathological wound healing may lead to conjunctival fibrosis and filtering failure. Myofibroblasts are the key cells responsible for postoperative conjunctival scarring. This study aims to further understand the molecular mechanisms of conjunctival fibrosis following GFS. We utilised RNA-sequencing (RNA-seq) to delineate the TGFβ1 induced changes in the transcriptome of human Tenon’s fibroblasts (HTFs). RNA sequencing was performed on HTFs after 5 days of TGFβ1 treatment. Following quality control, 3,362 differentially expressed genes were identified, of which 1,532 were upregulated and 1,820 were downregulated. We identified signaling pathways associated with the pathogenesis of conjunctival fibrosis. The DEGs (differentially expressed genes) were enriched in pathways including myofibroblast differentiation, TGFβ-signaling, collagen and extracellular matrix organization, epithelial to mesenchymal transition, and cell cycle regulation. The results of this study identified the transition from HTF to myofibroblast is characterised by the upregulation of key genes includingLDLRAD4, CDKN2B, FZD8, MYOZ1, and the downregulation ofSOD3, LTBP4andRCAN2. This unprecedented insight into the transcriptional landscape of HTFs and myofibroblast differentiation is essential to understand the pathophysiology of conjunctival scarring and develop new therapeutic agents.