bluuebunny/crossref_metadata_2025 huggingface dataset:
Epithelioid and Spindle Cell Hemangioma
Authors: Papke David J. , Jagannathan Jyothi , Dong Fei , Dickson Brendan C. , Mertens Fredrik , Hornick Jason L. , Fletcher Christopher D.M.
Published: October 2022

Epithelioid and spindle cell hemangioma was initially described in 1999 in a series of primary bone tumors and was subsequently suggested by some to represent a variant of epithelioid hemangioma. Here, we studied 18 epithelioid and spindle cell hemangiomas. Nine patients (50%) were male. Age at presentation ranged from 12 to 78 years (median: 38.5 y). Nine patients (50%) had tumor(s) limited to bone, 5 (28%) had tumor(s) limited to soft tissue, and 4 (22%) had tumor(s) involving bone and soft tissue. Nine patients (50%) had multiple tumors, all in a unilateral anatomic region involving the wrist, hand, ankle, or foot. Seventeen tumors (94%) occurred in an extremity, including 12 (67%) in the hands and feet, and 1 occurred in a vertebra. In imaging studies, primary bone tumors were lobulated, expansile, and lytic, and 7 bone tumors with available imaging (58%) showed cortical breakthrough. Tumor sizes were 0.8 to 7.2 cm (median: 2.2 cm). Epithelioid and spindle cell hemangioma is composed of lobules of epithelioid and spindled endothelial cells with bland, vesicular nuclei. Neoplastic cells show orderly vasoformative growth, with hemorrhagic stroma and no endothelial atypia or multilayering. Immunohistochemistry demonstrated uniform positivity for CD31 and ERG. Where positive, SMA highlighted pericytes (11/13 tumors). FOSB was strongly positive in 4 of 16 tumors (25%), and FOS was strongly positive in 5 of 10 stained tumors (50%). Break-apart fluorescence in situ hybridization confirmed the presence of FOS split signals in 4 tumors positive for FOS by immunohistochemistry and FOSB split signals in 2 FOSB-positive tumors. DNA sequencing demonstrated a GATA6::FOXO1 fusion in 1 of 3 sequenced tumors. Clinical follow-up was available for 15 patients (83%; range: 5 mo to 11 y; median: 3.5 y). Seven patients (47%) had no evidence of disease at most recent follow-up. Seven of 13 patients (54%) who underwent surgery experienced local recurrence at the primary tumor site: 5 patients within a year, 1 at 2.4 years, and 1 thrice at 2, 3, and 5 years. Six patients were alive with multifocal disease (median: 3.5 y; range: 5 mo to 6 y). No tumors gave rise to distant metastases. The clinicopathologic and genetic findings in this study support the notion that epithelioid and spindle cell hemangioma is a morphologic variant of epithelioid hemangioma that can occur in soft tissue as well as bone and that shows a striking predilection for the extremities. Given that most recurrences and primary tumors behaved indolently, watchful waiting would be reasonable for patients with multicentric disease that is not readily amenable to surgery.
Estimated changes in price discounts for tenofovir-inclusive HIV treatments following introduction of tenofovir alafenamide
Authors: Dickson Sean , Gabriel Nico , Hernandez Inmaculada
Published: October 2022

We estimated list and net prices for tenofovir disoproxil fumarate (TDF) products Truvada, Complera, and Stribild, and their tenofovir alafenamide (TAF) versions Descovy, Odefsey, and Genvoya. Gilead offered discounts for Descovy that resulted into lower net prices compared to Truvada. This strategy encouraged patients switching from Truvada to Descovy before the availability of generic Truvada. Conversely, Gilead offered lower discounts for Odefsey and Genvoya, which resulted into higher net prices compared to Complera and Stribild.
Novel agents in development for multidrug-resistant Gram-negative infections: potential new options facing multiple challenges
Authors: Arya Radhika , Goldner Breanna S. , Shorr Andrew F.
Published: October 2022

Purpose of review

To review novel antiinfective agents in development for multidrug-resistant (MDR) Gram-negative bacterial infections.

Recent findings

Four novel agents are in various phases of development (tebipenem, durlobactam-sulbactam, cefepime-taniborbactam, and xeruborbactam). Tebpipenem is an oral carbapenem with a recently completed phase III trial for complicated urinary tract infections while durlobactam-sulbactam represents a potential alternative for drug-resistant Acinetobacter baumannii. Cefepime-taniborbactam possesses in-vitro potency against a range of troubling pathogens and we await further information on a recently completed study on complicated urinary tract infection. Finally, xeruborbactam is an ultrabroad beta-lactamase inhibitor that can be paired with a range of intravenous and oral agents. It exhibits enhanced in-vitro activity against many MDR pathogens, including those resistant to newer, broader spectrum options. Data in humans with xeruborbactam are limited.

Each of the newer options reviewed possesses a unique range of in-vitro activity against select, challenging pathogens with some narrowly tailored and other broader in activity. Several have both oral and intravenous formulations. Two agents have presented data from recent phase III trials, whereas two are not as advanced in their clinical programs.
DCD Liver Grafts Can Safely Be Used for Recipients With Grade I–II Portal Vein Thrombosis: A Multicenter Analysis
Authors: Mercado Lydia A. , Bhangu Harpreet K. , Calderon Esteban , Mathur Amit K. , Aqel Bashar , Musto Kaitlyn R. , Watt Kymberly D. , Rosen Charles B. , Bolan Candice , LeGout Jordan D. , Taner C. Burcin , Harnois Denise M. , Croome Kristopher P.
Published: October 2022

Background.

With donation after circulatory death (DCD) liver transplantation (LT), the goal of the recipient implantation procedure is to minimize surgical complexity to avoid a tenuous environment for an already marginal graft. The presence of portal vein thrombosis (PVT) at the time of LT adds surgical complexity, yet‚ to date, no studies have investigated the utilization of DCD liver grafts for patients with PVT.

Methods.

All DCD LT performed at Mayo Clinic-Florida, Mayo Clinic-Arizona, and Mayo Clinic-Rochester from 2006 to 2020 were reviewed (N = 771). Patients with PVT at the time of transplant were graded using Yerdel classification. A 1:3 propensity match between patients with PVT and those without PVT was performed.

Results.

A total of 91 (11.8%) patients with PVT undergoing DCD LT were identified. Grade I PVT was present in 62.6% of patients, grade II PVT in 27.5%, grade III in 8.8%, and grade 4 in 1.1%. At the time of LT, thromboendovenectomy was performed in 89 cases (97.8%). There was no difference in the rates of early allograft dysfunction (43.2% versus 52.4%; P = 0.13) or primary nonfunction (1.1% versus 1.1%; P = 0.41) between the DCD PVT and DCD without PVT groups, respectively. The rate of ischemic cholangiopathy was not significantly different between the DCD PVT (11.0%) and DCD without PVT groups (10.6%; P = 0.92). Graft (P = 0.58) and patient survival (P = 0.08) were similar between the 2 groups. Graft survival at 1-, 3-, and 5-y was 89.9%, 84.5%, and 79.3% in the DCD PVT group.

Conclusions.

In appropriately selected recipients with grades I–II PVT, DCD liver grafts can be utilized safely with excellent outcomes.
Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients
Authors: Frölke Sophie C. , Bouwmans Pim , Messchendorp A. Lianne , Geerlings Suzanne E. , Hemmelder Marc H. , Gansevoort Ron T. , Hilbrands Luuk B. , Reinders Marlies E.J. , Sanders Jan-Stephan F. , Bemelman Frederike J. , Peters-Sengers Hessel ,   RECOVAC Collaborators
Published: October 2022

Background.

Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response.

Methods.

Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome.

Results.

The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA); chronic lung disease, heart failure, and diabetes; increased age; shorter time after transplantation; lower body mass index; lower kidney function; no alcohol consumption; ≥2 transplantations; and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations.

Conclusions.

In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies.
Omental Flap Wrapping Around the Esophagogastric Anastomosis and Association with Anastomotic Leak in Esophagectomy for Esophageal Cancer: A Propensity Score-Matching Analysis
Authors: Yoshida Naoya , Eto Kojiro , Matsumoto Takashi , Kosumi Keisuke , Imamura Yu , Iwatsuki Masaaki , Baba Yoshifumi , Miyamoto Yuji , Watanabe Masayuki , Baba Hideo
Published: October 2022

BACKGROUND:

Anastomotic leakage after esophagectomy remains frequent and can cause surgery-related mortality. Wrapping the esophageal conduit anastomosis with a greater omental flap is a proposed method to reduce leakage. However, the usefulness of omental wrapping (OW) has not been elucidated.

STUDY DESIGN:

This study included 338 patients with esophageal cancer who underwent McKeown esophagectomy and reconstruction using a gastric conduit between April 2005 and August 2021. The study participants were divided into 2 groups: reconstructions with and without OW. We performed propensity score matching between the reconstructions with and without OW. The propensity score was calculated according to baseline characteristics, performance and physical statuses, presence of comorbidities, and types and details of the treatment procedures undergone.

RESULTS:

We included 338 patients (169 with OW and 169 without OW) in this study. After matching, all clinical and surgical features were statistically equivalent between the groups. Reconstruction and anastomosis with OW were significantly associated with decreased leakage (p = 0.016) and surgical site infection (p = 0.041). Reconstruction and anastomosis with OW also exhibited a trend toward more frequent stricture, although this was not statistically significant (p = 0.051). Independent risk factors for leakage were reconstruction without OW (odds ratio, 2.55; 95% CI, 1.234 to 5.285; p = 0.0088) and younger age (odds ratio, 1.06; 95% CI, 1.012 to 1.102; p = 0.011).

CONCLUSIONS:

OW can reduce leakage in the esophagogastric anastomosis. OW can be performed conveniently and may be recommended to reinforce the anastomotic site, which can improve short-term outcomes after esophagectomy for esophageal cancer.
Analysis of the genome of grapevine red blotch virus and related grabloviruses indicates diversification prior to the arrival of Vitis vinifera in North America
Authors: Thompson Jeremy R.
Published: October 2022

In this study 163 complete whole-genome sequences of the emerging pathogen grapevine red blotch virus (GRBV; genus Grablovirus, family Geminiviridae) were used to reconstruct phylogenies using Bayesian analyses on time-tipped (heterochronous) data. Using different combinations of priors, Bayes factors identified heterochronous datasets (3×200 million chains) generated from strict clock and exponential tree priors as being the most robust. Substitution rates of 3.2×10−5 subsitutions per site per year (95% HPD 4.3–2.1×10−5) across the whole of the GRBV genome were estimated, suggesting ancestral GRBV diverged from ancestral wild Vitis latent virus 1 around 9 000 years ago, well before the first documented arrival of Vitis vinifera in North America. Whole-genome analysis of GRBV isolates in a single infected field-grown grapevine across 12 years identified 12 single nucleotide polymorphisms none of which were fixed substitutions: an observation not discordant with the in silico estimate. The substitution rate estimated here is lower than those estimated for other geminiviruses and is the first for a woody-host-infecting geminivirus.
Captive rearing effects on the methylome of Atlantic salmon after oceanic migration: sex-specificity and intergenerational stability
Authors: Venney Clare J. , Bouchard Raphaël , April Julien , Normandeau Eric , Lecomte Laurie , Côté Guillaume , Bernatchez Louis
Published: October 2022

Captive rearing in salmon hatcheries can have considerable impacts on both fish phenotype and fitness within a single generation, even in the absence of genetic change. Evidence for hatchery-induced changes in DNA methylation is becoming abundant, though questions remain on the sex-specificity of these effects, their persistence until spawning, and potential for transmission to future generations. Here we performed whole genome methylation sequencing of fin tissue for 16 hatchery and 16 wild Atlantic salmon (Salmo salar) returning to spawn in the Rimouski River, Québec. We identified two cohorts of hatchery-reared salmon through methylation analysis, one of which was epigenetically similar to wild fish, suggesting that supplementation efforts may be able to minimize the epigenetic effects of hatchery rearing. We found considerable sex-specific effects of hatchery rearing, with few genomic regions being affected in both males and females. We also analysed the methylome of 32 F1 offspring from four groups (pure wild, pure hatchery origin, and reciprocal hybrids). We found that few epigenetic changes due to parental hatchery rearing persisted in the F1 offspring though the patterns of inheritance appear to be complex, involving nonadditive effects. Our results suggest that the epigenetic effects of hatchery rearing can be minimal in F0. There may also be minimal epigenetic inheritance and rapid loss of epigenetic changes associated with hatchery rearing. However, due to sex-specificity and nonadditive patterns of inheritance, methylation changes due to captive rearing are rather complex and the field would benefit from further research on minimizing the epigenetic effects of captive rearing in conservation efforts.
PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy
Authors: Yoshida Teruhiko , Latt Khun Zaw , Rosenberg Avi Z. , Santo Briana A. , Myakala Komuraiah , Ishimoto Yu , Zhao Yongmei , Shrivastav Shashi , Jones Bryce A. , Yang Xiaoping , Wang Xiaoxin X. , Tutino Vincent M. , Sarder Pinaki , Levi Moshe , Okamoto Koji , Winkler Cheryl A. , Kopp Jeffrey B.
Published: October 2022

HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes; and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the profibrogenic PKR-STAT3-platelet derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.

Translational Statement

This work identified mitochondrial dysfunction in transgenic mice manifesting HIV-associated nephropathy mice kidney, using combination of single-nuclear and bulk RNA-seq analysis. Kidney damage was ameliorated by the PKR inhibitor C16, and mitochondrial rescue was shown by transcriptomic profiling and functional assay. These findings suggest that PKR inhibition and mitochondrial rescue are potential therapeutic approaches for HIV-associated nephropathy.
Environmental filtering of life-history trait diversity in urban populations ofArabidopsis thaliana
Authors: Schmitz Gregor , Linstädter Anja , Frank Anke S. K. , Dittberner Hannes , Thome Jessica , Schrader Andrea , Linne von Berg Karl-Heinz , Fulgione Andrea , Coupland George , de Meaux Juliette
Published: October 2022

The challenges to which plants are exposed in urban environments represent, in miniature, the challenges plants face as a result of global environmental change. Hence, urban habitats provide a unique opportunity to assess whether processes of local adaptation are taking place despite the short temporal and geographical scales that characterize the Anthropocene.

We quantified the ecological diversity of urban habitats hostingA. thalianapopulations. Using plant community indicators, we show that these patches differ in their levels of soil nutrient content and disturbance. Accordingly, plants in each patch displayed a range of flowering time, size and fitness.

Using a deep sampling approach coupled with reduced genome-sequencing, we demonstrate that most individuals can be assigned to a limited set of clonal lineages; the genetic diversity of these lineages is a sample of the diversity observed in western European populations of the species, indicating that established urban populations originate from a broad regional pool of lineages.

We assessed the genetic and phenotypic diversity of these lineages in a set of common garden experiments. We report marked genetic differences in life-history traits, including time of primary and secondary dormancy as well as of flowering. These genetic differences in life-history traits are not randomly distributed but sorted out by ecological differences among sites of origin.

Synthesis:Our study shows that the genetically diverse phenology of a regionalA. thalianagene pool is not randomly distributed but filtered by heterogeneity in the urban environment. To out knowledge, this report is the first to show a pattern indicative of environmental filtering enhancing local genetic adaptation within urban environments. We conclude that environmental filtering helps maintain functional diversity within species.
Inferring time of infection from field data using dynamic models of antibody decay
Authors: Borremans Benny , Mummah Riley O , Guglielmino Angela H , Galloway Renee L , Hens Niel , Prager K C , Lloyd-Smith James O
Published: October 2022

Studies of infectious disease ecology often rely heavily on knowing when individuals were infected, but estimating this time of infection can be challenging, especially in wildlife. Time of infection can be estimated from various types of data, with antibody level data being one of the most promising sources of information. The use of antibody levels to back-calculate infection time requires the development of a host-pathogen system-specific model of antibody dynamics, and a leading challenge in such quantitative serology approaches is how to model antibody dynamics in the absence of experimental infection data. Here, we present a way to do this in a Bayesian framework that facilitates the incorporation of all available information about potential infection times. We apply the model to estimate infection times of Channel Island foxes infected withLeptospira interrogans, leading to reductions of 51-92% in the window of possible infection times. Using simulated data, we show that the approach works well across a broad range of parameter settings and can lead to major improvements of infection time estimates that depend on system characteristics such as antibody decay rate and variation in peak antibody levels after exposure. The method substantially simplifies the challenge of modeling antibody dynamics in the absence of individuals with known infection times, opens up new opportunities in wildlife disease ecology, and can even be applied to cross-sectional data once the model is trained.
Improved RNA homology detection and alignment by automatic iterative search in an expanded database
Authors: Singh Jaswinder , Paliwal Kuldip , Singh Jaspreet , Litfin Thomas , Zhou Yaoqi
Published: October 2022

Unlike 20-letter-coded proteins, RNA homologous sequences are notoriously difficult to detect because their 4-letter-coded sequences can quickly lose their sequence identity. As a result, employing secondary structures has been found necessary to improve the sensitivity and the accuracy of homolog search. However, exact secondary structures often are not known. As a result, Rfam, the de facto gold-standard of RNA homologous families, has to rely on manual curation and experimental secondary structure if available. Here, we showed that using a combination of BLAST and iterative INFERNAL searches along with an expanded sequence database leads multiple sequence alignments (MSA) that are comparable to those provided by Rfam MSAs, according to secondary structure extracted from mutational coupling analysis and alignment accuracy when compared to structure alignment. The fully automatic tool (RNAcmap2) allows making homolog search, multiple sequence alignment, and mutational coupling analysis for any non-Rfam RNA sequences with Rfam-like performance.
EGIDExpress: An Interactive Shiny Web App to Visualize and Share Large Biological Datasets
Authors: Besse John A. , Osswald Garrett A. , Ballaban Adina Y. , Caldwell Julie M. , Rothenberg Marc E.
Published: October 2022

Biomedical research on rare diseases faces challenges such as low availability of biological specimens to study and limited funding. Eosinophilic gastrointestinal diseases (EGIDs) are rare conditions associated with inappropriate inflammation and the accumulation of eosinophils in various segments of the gastrointestinal tract. We aimed to build a repository of large datasets related to EGIDs that would be easily browsable, interpretable, and accessible in order to facilitate data sharing and hypothesis generation. Using the R-code based package Shiny, we built a website that allows visualization of multiple types of datasets including microarray, RNAseq, protein array, single-cell RNAseq, and ChIPseq. Users can access EGIDExpress (https://egidexpress.research.cchmc.org/) to browse data on a per-gene basis and to generate graphic representation of the data. Additionally, users can download the processed data to initiate their own analyses. Within 34 months of launching EGIDExpress, over 2400 users from 37 countries and 37 states within the United States accessed the site. Overall, EGIDExpress is accelerating research on EGIDs and provides a prototypic platform for broad research data sharing.
Engineering human spinal microphysiological systems to model opioid-induced tolerance
Authors: Cai Hongwei , Ao Zheng , Tian Chunhui , Wu Zhuhao , Kaurich Connor , Chen Zi , Gu Mingxia , Hohmann Andrea G. , Mackie Ken , Guo Feng
Published: October 2022

Opioids are commonly used for treating chronic pain. However, with continued use, they may induce tolerance and/or hyperalgesia, which limits therapeutic efficacy. The human mechanisms of opioid-induced hyperalgesia are significantly understudied, in part, because current models cannot fully recapitulate human pathology. Here, we engineered novel human spinal microphysiological systems (MPSs) integrated with plug-and-play neural activity sensing for modeling human nociception and opioid-induced tolerance. Each spinal MPS consists of a flattened human spinal cord organoid derived from human stem cells and a 3D printed organoid holder device for plug-and-play neural activity measurement. We found that the flattened organoid design of MPSs not only reduces hypoxia and necrosis in the organoids, but also promotes their neuron maturation, neural activity, and functional development. We further demonstrated that prolonged opioid exposure resulted in neurochemical correlates of opioid tolerance and hyperalgesia, as measured by altered neural activity, reduced densities of glutamate transporter levels and downregulation of μ-opioid receptor expression of human spinal MPSs. The MPSs are scalable, cost-effective, easy-to-use, and compatible with commonly-used well-plates, thus allowing plug-and-play measurements of neural activity. We believe the MPSs hold a promising translational potential for studying human pain etiology, screening new treatments, and validating novel therapeutics for human pain medicine.
The complete genome sequence of Pseudomonas syringae pv. actinidifoliorum ICMP 18803
Authors: Templeton Matthew D. , Arshed Saadiah , Andersen Mark T. , Jayaraman Jay
Published: October 2022

The complete genome of Pseudomonas syringae pv. actinidifoliorum ICMP18803 (Pfm) was sequenced using the Oxford Nanopore minION platform to an average read depth of 123. The genome assembled into a single chromosome of 6,353,853 bp after error-correction with Illumina short reads using Pilon. The complement of effector genes from a P. syringae pathovar plays the predominant role in defining its pathogenicity. Automatic gene annotation pipelines often poorly identify and name effector genes, however. Despite Pfm being a relatively weak pathogen of kiwifruit, a set of 31 effectors, 26 of which were full length, was identified by mapping the comprehensive effector library generated by Dillon et al. (2019). The Pfm genome with the effector complement, correctly named and annotated was resubmitted to Genbank (CP081457).
Dysregulated Expression of Circadian Genes in Lymphoblastoid Cells of Patients with ASD
Authors: Ding Hui , Kuang Shuzhen , Chen Chin-Fu
Published: October 2022

Patients with Autism Spectrum Disorder (ASD) often exhibit disturbances in sleep, metabolism, and immune system. The molecular mechanisms for these clinical features in ASD are currently unknown. We demonstrated that circadian genes in the cells of patients with ASD often are dysregulated compared to controls. The dysregulation of circadian genes was reflected in two different ways: (1) abnormal levels of expression; and (2) a change of gene-gene association pattern in the co-expression network. We also observed a link between abnormal expression of circadian genes in lymphoblastoid cells with sleep phenotypes in patients with ASD. Our results suggest that circadian genes and circadian rhythms might play critical roles in the pathogenesis of ASD.
Experimental validation of the free-energy principle with in vitro neural networks
Authors: Isomura Takuya , Kotani Kiyoshi , Jimbo Yasuhiko , Friston Karl J.
Published: October 2022

Empirical applications of the free-energy principle are not straightforward because they entail a commitment to a particular process theory, especially at the cellular and synaptic levels. Using a recently established reverse engineering technique, we confirm the quantitative predictions of the free-energy principle using in vitro networks of rat cortical neurons that perform causal inference. Upon receiving electrical stimuli—generated by mixing two hidden sources—neurons self-organised to selectively encode the two sources. Pharmacological up- and downregulation of network excitability disrupted the ensuing inference, consistent with changes in prior beliefs about hidden sources. As predicted, changes in effective synaptic connectivity reduced variational free energy, where the connection strengths encoded parameters of the generative model. In short, we show that variational free energy minimisation can quantitatively predict the self-organisation of neuronal networks, in terms of their responses and plasticity. These results demonstrate the applicability of the free-energy principle to in vitro neural networks and establish its predictive validity in this setting.
An in-silico approach for novel molecular glue design by rationalizing known molecular glue mediated ternary complex formation
Authors: Geoffrey A S Ben , Kulkarni Nagaraj M , Agrawal Deepak , Bharti Nivedita , Vetrivel Rajappan , Gurram Kishan
Published: October 2022

Protein function modulation using small molecule binding is an important therapeutic strategy for many diseases. However, many proteins remain undruggable due to lack of suitable binding pockets for small molecule binding. Proximity induced protein degradation using molecular glues has recently been identified as in important strategy to target the undruggable proteins. Molecular glues were discovered serendipitously and as such currently lack an established approach for in-silico design rationale. In this work, we attempt to establish the rationale for a known case and having inferred the rationale, we discuss how the rationale can be applied in-silico to design novel molecular glue through AI powered techniques. We believe the establishing of in-silico rationale for molecular glue design would be a valuable and welcome addition to the literature to further accelerate the discovery of molecular glues to drug undruggable targets.
Single-cell analysis of myeloid cells in HPV+tonsillar cancer
Authors: Jimenez David Gomez , Altunbulakli Can , Swoboda Sabine , Sobti Aastha , Askmyr David , Ali Ashfaq , Greiff Lennart , Lindstedt Malin
Published: October 2022

The incidence of Human Papillomavirus positive (HPV+) tonsillar cancer has been sharply rising during the last two decades. Myeloid cells represent an appropriate therapeutic target due to their ability to orchestrate antigen-specific immunity within the tonsil, the availability of viral antigens, and the proximity of the tumor and the underlying lymphoid tissue. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+tonsillar cancer. Our analysis unveiled the existence of four dendritic cell lineages, two macrophage polarization processes, and their sequential maturation profiles. We observed an expansion of the myeloid compartment in HPV+tonsillar cancer, accompanied by interferon-induced cellular responses both in DCs and monocyte-macrophages. Within the DC lineages, we describe a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s, in HPV+lesions. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC profile. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which gave raise to inflammatory-activated, and chemokine-producing macrophages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1, activated DCs and macrophages in patient survival using signature scoring. The current study contributes towards the understanding of myeloid ontogeny and dynamics in human papilloma driven tonsillar cancer, and details myeloid biomarkers that can be used to predict therapy effects and assess patient prognosis.
Patterns of siderophore production and utilization at Station ALOHA from the surface to mesopelagic waters
Authors: Bundy Randelle M. , Manck Lauren E. , Repeta Daniel J. , Church Matthew J. , Hawco Nicholas J. , Boiteau Rene M. , Park Jiwoon , DeLong Edward F. , Saito Mak A.
Published: October 2022

The North Pacific subtropical gyre is a globally important contributor to carbon uptake and an oligotrophic ecosystem primarily limited by nitrogen. The microbial community is also seasonally exposed to low iron due to biological consumption and seasonally variable iron delivery. In this study, we examined changes in iron uptake rates, dissolved siderophore concentrations, and siderophore biosynthesis at Station ALOHA across time (2013-2016) and depth (surface to 500 m) to observe changes in iron acquisition and internal cycling by the microbial community. The genetic potential for siderophore biosynthesis was widespread throughout the upper water column, and biosynthetic gene clusters peaked in spring and summer along with siderophore concentrations, suggesting changes in nutrient delivery, primary production, and carbon export impact iron acquisition over the seasonal cycle. Dissolved iron turnover times, calculated from iron-amended experiments conducted using surface (15 m) and mesopelagic (300 m) waters, ranged from 9-252 days. The shortest average turnover times at both depths were associated with inorganic iron additions (14±9 days) and the longest with iron bound to strong siderophores (148±225 days). Uptake rates of siderophore-bound iron were faster in the mesopelagic waters than in the surface, leading to high Fe:C uptake ratios of heterotrophic bacteria in the upper mesopelagic. The rapid cycling and high demand for Fe at 300 m suggests differences in microbial metabolism and iron acquisition in the mesopelagic compared to surface waters. Together, changes in siderophore production and consumption over the seasonal cycle suggest organic carbon availability impacts iron cycling at Station ALOHA.

Scientific Significance Statement

Microbial community production in the subtropical oligotrophic North Pacific is limited by macronutrients such as nitrogen. However, dissolved iron is another important micronutrient that has seasonal inputs from dust and passing eddies, keeping the availability of iron low and episodic. Little attention has been paid to the microbial strategies for dealing with low iron to support primary production in the oligotrophic ocean, or how limited iron availability impacts the processing of sinking particulate organic carbon in this region. In this study, we explore iron cycling including siderophore production and uptake by the microbial community throughout the water column at Station ALOHA to examine how the microbial community adapts and responds to changing iron and carbon availability on seasonal timescales.
Predicting Pacific cod spawning habitat in a changing climate
Authors: Bigman Jennifer S. , Laurel Benjamin J. , Kearney Kelly , Hermann Albert J. , Cheng Wei , Holsman Kirstin K. , Rogers Lauren A.
Published: October 2022

Warming temperatures elicit shifts in habitat use and geographic distributions of fishes, with uneven effects across life stages. Spawners and embryos are particularly sensitive to environmental conditions, with direct impacts of temperature on spawning habitat, as well as indirect connections between their population dynamics and fisheries effort, productivity, and management. Here, we ask how changing environmental conditions and thermal sensitivities of developing embryos confer spatiotemporal variability of thermally-suitable spawning habitat for Pacific cod in the eastern Bering Sea. Specifically, we use bottom temperature values from regionally downscaled global climate models coupled with an experimentally-derived relationship between hatch success and temperature to predict how the extent, mean latitude, and consistency of suitable spawning habitat has changed in the past and may change into the future. We then validate our predictions of suitable spawning habitat with distributions of adults and larvae and examine whether thermal habitat availability relates to recruitment success into the adult cod into the population. We find that the extent and mean latitude of suitable spawning habitat increase over time, particularly if no climate change mitigation occurs in the future. Hotspots of suitable spawning habitat are consistent across shorter time periods but do shift across the Bering Sea shelf by the end of the century. Finally, we find no correlation between the availability of suitable spawning habitat and annual estimates of recruitment. Collectively, our results suggest that as temperatures warm, the availability of suitable spawning habitat will increase and expand spatially and, thus, is not likely to limit recruitment. This work highlights the importance of coupling experimental data with climate models to identify the complex and mechanistic dynamics among temperature, life histories, and ecology, and offers a pathway for examining life stage-specific changes in habitat use and distribution with continued climate change.
Mechanical Stimuli such as Shear Stress and Piezo1 Stimulation Generate Red Blood Cell Extracellular Vesicles
Authors: Sangha Gurneet S. , Weber Callie M. , Sapp Ryan M. , Setua Saini , Thangaraju Kiruphagaran , Pettebone Morgan , Doctor Allan , Buehler Paul W. , Clyne Alisa M.
Published: October 2022

Circulating red blood cell extracellular vesicles (RBC-EVs) are a promising biomarker for vascular health. However, generating, isolating, and characterizing physiologically relevant RBC-EVs with sufficient yield and purity for biological studies is non-trivial. Here, we present and rigorously characterize an in vitro model to mimic RBC-EV production during shear stress via mechanosensitive piezo1 ion channel stimulation. We optimize our RBC-EV isolation protocol to minimize hemolysis, maximize RBC-EV yield and purity, and improve the ease of EV characterization. RBC-EV purity was measured by quantifying protein (e.g., particles/μg), large particle (e.g., protein aggregates), and platelet EV contamination. This study compared RBC-EV isolation performance using membrane-based affinity (e.g., exoEasy), ultrafiltration (e.g., Amicon Ultra-15), and ultracentrifugation, with and without size exclusion chromatography purification. We found that treating 6% hematocrit with 10 μM piezo1-agonist yoda1 for 30 minutes and isolating RBC-EVs using ultracentrifugation minimized RBC hemolysis and maximized RBC-EV yield (~1012 particles/mL) and purity, provided the most consistent RBC-EV preparations, and improved ease of RBC-EV characterization. Our pressure myography experiments suggest that co-isolated protein contaminants, but not piezo1 RBC-EVs, induce rapid mouse carotid artery vasodilation. These results underscore the importance of characterizing EV purity for biological experiments. The standardized methods outlined here enable mechanistic studies of how RBC-EVs generated in physiological flow affect vascular response.
Factors affecting trust in clinical trials conduct: Views of stakeholders from a qualitative study in Ghana
Authors: Chatio Samuel Tamti , Ganle John Kuumuori , Adongo Philip Baba , Beisel Ulrike
Published: October 2022

Introduction

Globally, there are signs of declining public trust in science, especially in biomedical research. In Ghana, there are equally signs of public distrust in the conduct of biomedical research in Ghana. Typical examples are the unsuccessful conduct of the Ebola vaccine trial and the initial refusal of parents to allow their children to receive the recently piloted malaria vaccine in Ghana. Therefore, this study explored stakeholders’ views on factors affecting trust in clinical trials conduct in Ghana.

Methods

This was a cross-sectional exploratory study using qualitative research approach. Forty-eight in-depth interviews and Key informant interviews were conducted with stakeholders. Purposive sampling technique was used to select participants. All the interviews were recorded, transcribed and coded into main and sub-themes using QSR Nvivo 12 software to aid thematic analysis.

Results

Overall, participants saw the need for the conduct of clinical trials in Ghana because clinical trial studies enable scientists to come out with effective medicines for the management of diseases. Pre-implementation factors such as inadequate stakeholder engagement, rumours and negative influence affected trust. Implementation factors such as perceived risks about clinical trials medicines, apprehensions on drawing and use of blood samples, poor informed consent administration and perceived no illness all negatively affected trust in clinical trials conduct.

Conclusion

Trust is a fundamental factor affecting a successful conduct of clinical trials. Thus, there is need for collective efforts by all stakeholders including research institutions and clinical trial regulatory bodies to take the issue of trust in clinical trials conduct seriously.
Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia
Authors: Traschütz Andreas , Adarmes-Gomez Astrid D. , Anheim Mathieu , Baets Jonathan , Brais Bernard , Gagnon Cynthia , Gburek-Augustat Janina , Doss Sarah , Hanagasi Hasmet A. , Kamm Christoph , Klivenyi Peter , Klockgether Thomas , Klopstock Thomas , Minnerop Martina , Münchau Alexander , Renaud Mathilde , Santorelli Filippo M. , Schöls Ludger , Thieme Andreas , Vielhaber Stefan , van de Warrenburg Bart P. , Zanni Ginevra , Hilgers Ralf-Dieter ,   PREPARE consortium, Synofzik Matthis
Published: October 2022

Objective

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.

Methods

Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes.

Results

While SARA subitem responsiveness varied between ataxia severities,gait/stanceshowed a robust granular linear scaling across the broadest range (SARA<25). Responsiveness was diminished by incomplete sub-scale use at intermediate or upper levels, non-transitions (“static periods”), and fluctuating decreases/increases. All subitems -exceptnose-finger-showed moderate-to-strong correlations to activities of daily living, indicating that metric properties -not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes, e.g., SYNE1-ataxia: 0.55 points/year, AOA2: 1.14, POLG-ataxia: 1.56; but no change in others (ARSACS, COQ8A-ataxia). While sensitivity to change was optimal in mild ataxia (SARA≤10), it substantially deteriorated in advanced ataxia (SARA>25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitemsfinger-chaseandnose-fingerreduces sample sizes by 20-25%.

Interpretation

This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design.
Applying Transcriptomics for an Enhanced Clinical Research Framework, Implications for an Improved Research Strategy based on an Omics Approach: A Scoping Review
Authors: Rashid Asrar , Al-Obeida Feras , Krishnan Hari , Benakatti Govind , Hafez Wael , Brierley Joe , Hanisch Benjamin , Khilnani Praveen , Koutentis Christos , Brusletto Berit S , Toufiq Mohammed , Hussain Zain , Vyas Harish , Malik Zainab , Schumacher Maike , Malik Rayaz , Deshpande Shriprasad , Quraishi Nasir , Kadwa Raziya , Sarpal Amrita , Shaikh M. Guftar , Sharief Javed , Zaki Syed Ahmed , Phatak Rajesh , Deep Akash , Al-Dubai Ahmed , Hussain Amir
Published: October 2022

Sepsis remains a major global health issue in pediatric and adult populations, largely due to a lack of understanding of its complex pathophysiology. Despite its high mortality rate, there have been few advancements in sepsis-specific therapies over recent decades. The study aimed to investigate the potential benefits of a genome-wide transcriptomic approach to sepsis in pediatric and adult populations in reducing sepsis-related mortality and enhancing sepsis guidelines. The scoping review explored gene expression data pertinent to developing sepsis guidelines related to its definition, classification, disease severity, molecular biomarking, and benchmarking. A system-biology approach using transcriptomics was adopted to enhance the understanding of sepsis at the mRNA gene expression level. The study involved a search of the PubMed database for original research or systematic reviews that involved transcriptomic application in the context of clinical sepsis published over a ten-year period, from 2012-2022. Of the 14,048 studies retrieved, a full-text analysis was performed. Five main concepts emerged: case definition, classification, quantifying severity of sepsis, transcriptomic biomarkers, and benchmarking. Studies were categorized according to these five categories. The results showed evidence of a connection between the transcript and clinical sepsis, demonstrating that transcript-driven sepsis categorization is possible. Integrating transcriptomic data with clinical endpoints holds promise for more precise sepsis treatment. Although further exploration is needed, the methodology shows potential for disease modification.