bluuebunny/crossref_metadata_2025 huggingface dataset:
Does a Preoperative Bowel Regimen Change Time to Bowel Movement? A Randomized Clinical Trial
Authors: Holubyeva Anastasiya , Goodwin Alexandra I. , O’Shaughnessy Danielle , Pillalamarri Nirmala , Demertzis Kristen , Rahbani Ana Centeno , Stefanov Dimitre G. , Finamore Peter S.
Published: March 2024

Importance

This study is important because it aimed to assess an intervention to decrease patient discomfort after a robotic sacral colpopexy.

Objective

Our primary outcome was to determine whether preoperative use of polyethylene glycol decreases time to first bowel movement postoperatively. Secondary outcomes include degree of pain with first bowel movement and stool consistency.

Study Design

This was a randomized controlled trial. The experimental group was assigned polyethylene glycol daily for 7 days before surgery and the control group was not. All patients received polyethylene glycol postoperatively.

Results

There was no statistically significant reduction in the time to first postoperative bowel movement when preoperative polyethylene glycol was used (mean [SD] in days for the control and experimental groups of 2.32 [0.99] and 1.96 [1.00],P= 0.21). There was a statistically significant reduction in pain levels with the first postoperative bowel movement in the experimental group (median [IQR] of 4 [2–5] vs 1 [0–2],P= 0.0007). Postoperative day 1 pain levels were also significantly lower in the experimental group (median [IQR] of 4 [3–6] vs 2 [0–4],P= 0.0484). In addition, patients had decreased average postoperative pain levels over 7 days with an estimated difference in the median pain levels of 1.88 units (95% confidence interval, 0.64–3.12;P= 0.0038).

Conclusions

Preoperative administration of polyethylene glycol did not decrease time to first postoperative bowel movement. Patients in the experimental group exhibited less pain with their first postoperative bowel movement and had improved pain levels on postoperative day 1.
Obesity is associated with improved early survival but increased late mortality in surgical patients with Sepsis: A propensity matched analysis
Authors: Jalilvand Anahita , Ireland Megan , Collins Courtney , Kellett Whitney , Strassel Scott , Tamer Robert , Wahl Wendy , Wisler Jon
Published: March 2024

BACKGROUND

While obesity is a risk factor for postoperative complications, its impact following sepsis is unclear. The primary objective of this study was to evaluate the association between obesity and mortality following admission to the surgical intensive care unit (SICU) with sepsis.

METHODS

We conducted a single center retrospective review of SICU patients grouped into obese (n = 766, body mass index ≥30 kg/m2) and nonobese (n = 574; body mass index, 18–29.9 kg/m2) cohorts. Applying 1:1 propensity matching for age, sex, comorbidities, sequential organ failure assessment, and transfer status, demographic data, comorbidities, and sepsis presentation were compared between groups. Primary outcomes included in-hospital and 90-day mortality, ICU length of stay, need for mechanical ventilation (IMV) and renal replacement therapy (RRT). p < 0.05 was considered significant.

RESULTS

Obesity associates with higher median ICU length of stay (8.2 vs. 5.6, p < 0.001), need for IMV (76% vs. 67%, p = 0.001), ventilator days (5 vs. 4, p < 0.004), and RRT (23% vs. 12%, p < 0.001). In-hospital (29% vs. 18%, p < 0.0001) and 90-day mortality (34% vs. 24%, p = 0.0006) was higher for obese compared with nonobese groups. Obesity independently predicted need for IMV (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2–2.1), RRT (OR, 2.2; 95% CI, 1.5–3.1), in-hospital (OR, 2.1; 95% CI, 1.5–2.8), and 90-day mortality (HR, 1.4; 95% CI, 1.1–1.8), after adjusting for sequential organ failure assessment, age, sex, and comorbidities. Comparative survival analyses demonstrate a paradoxical early survival benefit for obese patients followed by a rapid decline after 7 days (logrank p = 0.0009).

CONCLUSION

Obesity is an independent risk factor for 90-day mortality for surgical patients with sepsis, but its impact appeared later in hospitalization. Understanding differences in systemic responses between these cohorts may be important for optimizing critical care management.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes
Authors: Muñiz-Castrillo Sergio , Honnorat Jérôme
Published: March 2024

Purpose of review

We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications.

Recent findings

The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01, anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01, and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05. Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size.

Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.
Palliative care communication with stroke patients: a best practice implementation project
Authors: Schaefer Ashley Brook , Garbo Candon , Palokas Michelle
Published: March 2024

Introduction:

Stroke patients frequently experience debilitating deficits, and some receive a. terminal diagnosis. Palliative care services are introduced to prioritize care, with the goal of improving quality of life. However, palliative care communication (PCC) is often delayed or used inefficiently with stroke patients.

Objectives:

This project aimed to promote PCC evidence-based practices (EBPs) with stroke patients.

Methods:

This project used the JBI Evidence Implementation Framework to improve compliance with PCC EBPs with stroke patients in a medical center in Mississippi, USA. Four EBPs were identified from a JBI evidence summary and used as audit criteria. A baseline audit was conducted to measure compliance of current practice with best practice. Barriers to EBPs were identified, improvement strategies were implemented, and a follow-up audit was conducted to determine compliance changes.

Results:

The baseline audit revealed 53% to 80% compliance with the four EBPs. Barriers to EBPs included lack of health care professionals’ knowledge regarding EBPs; lack of PCC, miscommunication, or delayed PCC with patients regarding hospitalization timeline and quality of life; and no standardized documentation or location for PCC within the electronic health record. Improvement strategies included a PCC education program for health care professionals and a concise statement and validation checkbox to the “progress note” in the electronic health record to promote daily PCC with patients. The follow-up audit revealed 20% to 34% compliance rate improvement with EBPs.

Conclusions:

Annual PCC training should be conducted for health care professionals. Implementing PCC through a multidisciplinary approach can promote more meaningful discussion and efficient decision-making, prioritizing patients’ quality of life.

Spanish abstract:

http://links.lww.com/IJEBH/A174
Direct inhibitors of InhA with efficacy similar or superior to isoniazid in novel drug regimens for tuberculosis
Authors: Encinas Lourdes , Li Si-Yang , Rullas-Trincado Joaquin , Tasneen Rokeya , Tyagi Sandeep , Soni Heena , Garcia-Perez Adolfo , Lee Jin , Rubén González del Rio , Mercado Jaime De , Sousa Verónica , Sosič Izidor , Gobec Stanislav , Mendoza-Losana Alfonso , Converse Paul J. , Mdluli Khisi , Fotouhi Nader , Barros-Aguirre David , Nuermberger Eric L.
Published: March 2024

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involvingkatG, encoding the pro-drug activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). During the past five years, successful target engagement andin vivoefficacy have been demonstrated by diverse DIIs. In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results presented increase the understanding of DII mechanism of action and provide further impetus to continue exploiting InhA as a promising target for TB drug development.
Residual Partial Least Squares Learning: Brain Cortical Thickness Simultaneously Predicts Eight Non-pairwise-correlated Behavioural and Disease Outcomes in Alzheimer's Disease
Authors: Chen Oliver Y. , Vu Duy Thanh , Diaz Christelle Schneuwly , Bodelet Julien S. , Phan Huy , Allali Gilles , Nguyen Viet-Dung , Cao Hengyi , He Xingru , Muller Yannick , Zhi Bangdong , Shou Haochang , Zhang Haoyu , He Wei , Wang Xiaojun , Munafo Marcus , Trung Nguyen Linh , Nagels Guy , Ryvlin Philippe , Pantaleo Giuseppe
Published: March 2024

Alzheimer's Disease (AD) is the leading cause of dementia. It results in cortical thickness changes and is associated with a decline in cognition and behaviour. Such decline affects multiple important day-to-day functions, including memory, language, orientation, judgment and problem-solving. Recent research has made important progress in identifying brain regions associated with single outcomes, such as individual AD status and general cognitive decline. The complex projection from multiple brain areas to multiple AD outcomes, however, remains poorly understood. This makes the assessment and especially the prediction of multiple AD outcomes - each of which may unveil an integral yet different aspect of the disease - challenging, particularly when some are not strongly correlated. Here, uniting residual learning, partial least squares (PLS), and predictive modelling, we develop an explainable, generalisable, and reproducible method called the Residual Partial Least Squares Learning (the re-PLS Learning) to (1) chart the pathways between large-scale multivariate brain cortical thickness data (inputs) and multivariate disease and behaviour data (outcomes); (2) simultaneously predict multiple, non-pairwise-correlated outcomes; (3) control for confounding variables (e.g., age and gender) affecting both inputs and outcomes and the pathways in-between; (4) perform longitudinal AD disease status classification and disease severity prediction. We evaluate the performance of the proposed method against a variety of alternatives on data from AD patients, subjects with mild cognitive impairment (MCI), and cognitively normal individuals (n=1,196) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Our results unveil pockets of brain areas in the temporal, frontal, sensorimotor, and cingulate areas whose cortical thickness may be respectively associated with declines in different cognitive and behavioural subdomains in AD. Finally, we characterise re-PLS' geometric interpretation and mathematical support for delivering meaningful neurobiological insights and provide an open software package (re-PLS) available at https://github.com/thanhvd18/rePLS.
Genome-wide association studies in a diverse strawberry collection unveil loci controlling agronomic and fruit quality traits
Authors: Muñoz Pilar , Roldán-Guerra F. Javier , Verma Sujeet , Ruiz-Velázquez Mario , Torreblanca Rocío , Oiza Nicolás , Castillejo Cristina , Sánchez-Sevilla José F. , Amaya Iraida
Published: March 2024

Strawberries are cherished for their organoleptic properties and nutritional value. However, breeding new cultivars involves the simultaneous selection of many agronomical and fruit quality traits. The strawberry germplasm collection here studied exhibited extensive phenotypic variation in 26 agronomic and fruit quality traits across three consecutive seasons. Phenotypic correlations and Principal Component Analysis (PCA) revealed relationships among traits and accessions, emphasizing the impact of plant breeding. Genetic diversity analysis on 124 accessions using 44,408 markers denoted a population structure divided into six subpopulations that still retain considerable diversity. Genome-wide association studies (GWAS) for the 26 traits unveiled 121 significant marker-trait associations distributed across 95 quantitative traitloci(QTL). Multiple associations were detected for fruit firmness, a key breeding target, including a prominentlocuson chromosome 6A. The candidate geneFaPG1,controlling fruit softening, was identified within this QTL region. Differential expression ofFaPG1confirmed its role as the main contributor to natural variation in fruit firmness. A Kompetitive Allele-Specific PCR (KASP) assay based on SNP AX-184242253, associated with the 6A QTL, predicts a substantial increase in fruit firmness, validating its utility for Marker-Assisted Selection (MAS). In essence, this comprehensive study provides insights into the phenotypic and genetic landscape of the strawberry collection and lays a robust foundation for propelling the development of superior strawberry cultivars through precision breeding.

Highlight

Several QTL controlling agronomic and fruit quality traits detected by genome wide association studies. Natural variation onFaPG1expression is associated with a mayor and stable QTL for fruit firmness.
Seasonal structural stability promoted by forest diversity and composition explains overyielding
Authors: Guzmán Q J. Antonio , Park Maria H. , Williams Laura J. , Cavender-Bares Jeannine
Published: March 2024

The stability of forest productivity over time is a widely studied parameter often associated with benefits of forest diversity. Yet, the structural stability (SS) through the season of forest communities and its relationship to diversity, composition, and productivity remains poorly understood. Using a large-scale (10 ha) young tree diversity experiment, we evaluated how forest structure and multiple dimensions of diversity and composition affect remotely-sensed structural metrics and their stability through the growing season. We then studied the impact ofSSacross the season (April-October) on the net biodiversity effects of annual wood productivity (i.e., overyielding) of forest mixtures. We surveyed experimental tree communities eight times at regular intervals from before bud-break to after leaf senescence, using an UAV-LiDAR to derive metrics associated with canopy height heterogeneity, gap probability, and forest structural complexity (i.e., fractal geometry). The inverse coefficient of variation of these metrics through the season was used as descriptorsSS. These metrics along with theirSSwere then coupled with annual tree inventories to evaluate their relationships. Our findings indicate that plot wood volume and, to some extent, multiple dimensions of diversity and composition (i.e., taxonomic, phylogenetic, and functional) influence remotely-sensed metrics of forest structure and stability over time. We found that increases in plot wood volume as well as functional and phylogenetic diversity and variability (a measure of diversity independent of species richness), are linked to higher structural stability of forest complexity over time. We further found that higher stability of forest structural complexity and tree cover (i.e., 1 - gap probability) increases net biodiversity effects in forest mixtures through species complementarity. Structural equation models indicate that structural stability explains more the variation among plots in net biodiversity effects than multiple dimensions of diversity or variability, highlighting it as a measure that integrates several contributors to net biodiversity effects. Our results provide evidence that diversity and composition promote temporal stability of remotely-sensed forest structure and, in turn, enhanced productivity. The study highlights the potential to integrate remote sensing and ecology to disentangle the role of forest structural stability into ecological processes.
Expanding and enriching the LncRNA gene-disease landscape using the GeneCaRNA database
Authors: Aggarwal Shalini , Rosenblum Chana , Gould Marshall , Ziman Shahar , Barshir Ruth , Zelig Ofer , Guan-Golan Yaron , Iny-Stein Tsippi , Safran Marilyn , Pietrokovski Shmuel , Lancet Doron
Published: March 2024

The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ∼280,000 human non-coding RNA genes, identified algorithmically from ∼690,000 RNAcentral’s transcripts. This expands by ∼tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains ∼120,000 long non-coding RNAs (LncRNAs, >200 bases long), including ∼100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1,547 genes associated with 1 to 50 diseases. ∼15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of LncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 LncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for ∼110,000 LncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further LncRNA research in disease decipherment.
Elucidating the influence of RNA modifications and Magnesium ions on tRNAPheconformational dynamics inS. cerevisiae: Insights from Replica Exchange Molecular Dynamics simulations
Authors: Nowzari Zohreh R. , D’Esposito Rebecca J , Vangaveti Sweta , Chen Alan A.
Published: March 2024

Post-transcriptional modifications in RNA can significantly impact their structure and function. In particular, transfer RNAs (tRNAs) are heavily modified, with around 100 different naturally occurring nucleotide modifications contributing to codon bias and decoding efficiency. Here, we describe our efforts to investigate the impact of RNA modifications on the structure and stability of tRNA Phenylalanine (tRNAPhe) from S.cerevisiaeusing molecular dynamics (MD) simulations. Through temperature replica exchange MD (T-REMD) studies, we explored the unfolding pathway to understand how RNA modifications influence the conformational dynamics of tRNAPhe, both in the presence and absence of magnesium ions (Mg2+). We observe that modified nucleotides in key regions of the tRNA establish a complex network of hydrogen bonds and stacking interactions which is essential for tertiary structure stability of the tRNA. Furthermore, our simulations show that modifications facilitate the formation of ion binding sites on the tRNA. However, high concentrations of Mg2+ions can stabilize the tRNA tertiary structure in the absence of modifications. Our findings illuminate the intricate interactions between modifications, magnesium ions, and RNA structural stability.

Graphical Abstract
Wild lytic bacteriophages: a potential enhancer of disinfectants’ biofilm inhibition in bio-industrial settings for fruit fly production
Authors: Matute Torres Julio Roberto , Linares Fernández Mariandrée , Rendón Pedro , Pennington Pamela Marie
Published: March 2024

The pathogenic nature ofMorganella morganiito fruit flies has been described earlier; its biofilm prevents the larvae of mass reared fruit flies from proceeding to their next life stage by trapping them in their polymeric matrix. For the Mediterranean (Ceratitis capitata) fruit fly (“medfly”) mass rearing plants, this can be problem, due to losses generated in the production process. The presence of this bacteria is prevented by using different disinfectants, by themselves, or combined, which can act as selective pressure for the biofilm to resist the disinfectants. In this paper, we propose a method to isolate lytic bacteriophages and use them as quorum quenchers, to prevent microbial consortium from forming biofilms. When tried as viral cocktails, a very significant reduction of biofilm was found. However, when used with one of the two tried industrial disinfectants, the viral effect wasn’t as significant. When interpreted alongside the first experiments, this result opens the door to use bacteriophages to reduce the minimum inhibitory concentration necessary of the disinfectant. A reduction of said concentration would translate into less selective pressure for a resistance against it, and a reduction in costs for the mass rearing process at the time of implementation of the system.
A perfusion-independent high-throughput method to isolate liver sinusoidal endothelial cells
Authors: Babin-Ebell Gonçalves Anna , Mao Yifang , Baljkas Tinja , Wiedmann Felix , Pilz Franziska , Winkler Manuel , Kürschner-Zacharias Sina W. , Hoffarth Marlene , Schmidt Constanze , Goerdt Sergij , Reiners-Koch Philipp-Sebastian , Singhal Mahak
Published: March 2024

Liver sinusoidal endothelial cells (LSECs) critically regulate homeostatic liver function and liver pathogenesis. However, the isolation of LSECs remains a major technological bottleneck in studying molecular mechanisms governing LSEC functions. Current techniques to isolate LSECs, relying on perfusion-dependent liver digestion, are cumbersome with limited throughput. We here describe a perfusion-independent high-throughput procedure to isolate LSECs with high purity. Indifferently from previous perfusion-independent approaches, chopped liver tissue was incubated in the digestion mix for 30 minutes with intermittent mixing with a serological pipette. This led to the safeguarding of LSEC integrity and yielded 10 ± 1.0 million LSECs per adult mouse liver, which is far higher than previous perfusion-independent protocols and comparable yield to established perfusion-dependent protocols for isolating LSECs. Combining magnetic and fluorescence-activated cell sorting (FACS), LSECs from different zones of the hepatic sinusoid can now be isolated in high numbers in less than two hours for downstream applications including proteomics. Our protocol enabled the isolation of LSECs from fibrotic liver tissues from mice and healthy liver tissues from higher vertebrate species (pigs), where traditional perfusion-based digestion protocols have very limited application. In conclusion, these technical advancements reduce post-mortem changes in the LSEC state and aid in reliable investigation of LSEC functions.
Stiffness regulates dendritic cell and macrophage subtype development and increased stiffness induces a tumor-associated macrophage phenotype in cancer co-cultures
Authors: Guenther Carla
Published: March 2024

Mechanical properties of tissues including their stiffness change throughout our lives, during both healthy development but also during chronic diseases like cancer (1-4). How changes to stiffness, occurring during cancer progression, impact leukocytes is unknown. To address this, myeloid phenotypes resulting from mono- and cancer co-cultures of primary murine and human myeloid cells on 2D and 3D hydrogels with varying stiffnesses were analyzed. On soft hydrogels, conventional DCs (cDCs) developed, whereas on stiff hydrogels plasmacytoid DCs (pDCs) developed. Cell populations expressing macrophage markers CD14, Ly6C, and CD16 also increased on stiff hydrogels. In cancer co-cultures, CD86+populations decreased on higher stiffnesses across four different cancer types. High stiffness also led to increased vascular endothelial growth factor A (VEGFA), matrix metalloproteinases (MMP) and CD206 expression; ‘M2’ markers expressed by tumour-associated macrophages (TAMs) (5). Indeed, the majority of CD11c+cells expressed CD206 across human cancer models. Targeting the PI3K/Akt pathway led to a decrease in CD206+cells in murine cultures only, while human CD86+cells increased.

Increased stiffness in cancer could, thus, lead to the dysregulation of infiltrating myeloid cells and shift their phenotypes towards a M2-like TAM phenotype, thereby actively enabling tumor progression. Additionally, stiffness-dependent signaling appears species-dependent, potentially contributing to the high failure rate of clinical trials (6).
Subject-Agnostic Transformer-Based Neural Speech Decoding from Surface and Depth Electrode Signals
Authors: Chen Junbo , Chen Xupeng , Wang Ran , Le Chenqian , Khalilian-Gourtani Amirhossein , Jensen Erika , Dugan Patricia , Doyle Werner , Devinsky Orrin , Friedman Daniel , Flinker Adeen , Wang Yao
Published: March 2024

Objective

This study investigates speech decoding from neural signals captured by intracranial electrodes. Most prior works can only work with electrodes on a 2D grid (i.e., Electrocorticographic or ECoG array) and data from a single patient. We aim to design a deep-learning model architecture that can accommodate both surface (ECoG) and depth (stereotactic EEG or sEEG) electrodes. The architecture should allow training on data from multiple participants with large variability in electrode placements and the trained model should perform well on participants unseen during training.

Approach

We propose a novel transformer-based model architecture named SwinTW that can work with arbitrarily positioned electrodes by leveraging their 3D locations on the cortex rather than their positions on a 2D grid. We train subject-specific models using data from a single participant and multi-patient models exploiting data from multiple participants.

Main Results

The subject-specific models using only low-density 8×8 ECoG data achieved high decoding Pearson Correlation Coefficient with ground truth spectrogram (PCC=0.817), over N=43 participants, outperforming our prior convolutional ResNet model and the 3D Swin transformer model. Incorporating additional strip, depth, and grid electrodes available in each participant (N=39) led to further improvement (PCC=0.838). For participants with only sEEG electrodes (N=9), subject-specific models still enjoy comparable performance with an average PCC=0.798. The multi-subject models achieved high performance on unseen participants, with an average PCC=0.765 in leave-one-out cross-validation.

Significance

The proposed SwinTW decoder enables future speech neuropros-theses to utilize any electrode placement that is clinically optimal or feasible for a particular participant, including using only depth electrodes, which are more routinely implanted in chronic neurosurgical procedures. Importantly, the generalizability of the multi-patient models suggests that such a model can be applied to new patients that do not have paired acoustic and neural data, providing an advance in neuroprostheses for people with speech disability, where acoustic-neural training data is not feasible.
Treatment Outcomes of Doxycycline Use for Musculoskeletal Infections: A Systematic Review and Meta-Analysis
Authors: Aljadani Rawabi , Bravo Carolina Gonzalez , Bojang Matida , Carvour Martha L.
Published: March 2024

Doxycycline is among the most commonly used antibiotics for the treatment and long-term suppression of musculoskeletal infections such as osteomyelitis and periprosthetic joint infection. We systematically reviewed clinical trials and cohort studies that examined outcomes of musculoskeletal infections treated with doxycycline. Eligible studies were published in Medline or Embase in English before March 2, 2021. Eleven reports were included; eight addressed medical/non-dental infections, and three addressed dental infections.Brucellawas the most frequently studied organism in the non-dental studies. Random-effects meta-analyses showed no significant difference inBrucellarelapse risk after six weeks of treatment with 200 mg doxycycline compared to 400 mg ofloxacin daily (pool risk ratio: 0.94, 95% confidence interval: 0.2 - 4.45, I2=L0%). Despite a large number of case reports, case series, and cross- sectional studies on this topic, few studies investigated doxycycline treatment outcomes; and evidence was largely limited to rare infections such asBrucella.
SCAPE-APA: a package for estimating alternative polyadenylation events from scRNA-seq data
Authors: Cheng Guangzhao , Le Tien , Zhou Ran , Cheng Lu
Published: March 2024

SCAPE is a package we previously developed to estimate alternative polyadenylation events from single cell RNA-seq (scRNA-seq) data, which is composed of ad-hoc python scripts and has speed issues when handling large scRNA-seq data. To suit the needs of analyzing large scRNA-seq datasets, we present SCAPE-APA, which is a re-implementation of SCAPE with substantial changes. We made the following updates to the package (1) we binned similar reads together to accelerate the estimation (2) we re-derived the mixture model to tailor it for binned reads (3) we implemented the inference algorithm using Taichi language for acceleration (4) we re-implemented the untranslated region (UTR) annotation extraction script using the professional package gffutils for better maintenance (5) we wrote a script to detect spurious alternative polyadenylation sites generated due to junction reads and (6) we made a formal python package and uploaded it to the Python Package Index website (Pypi).

Availability and Implementation

Scape-apa is freely available athttps://github.com/chengl7-lab/scapeand can be easily installed using pip.

Contact

lu.cheng.ac@gmail.com
TheMycobacterium tuberculosiscomplex pangenome is small and driven by sub-lineage-specific regions of difference
Authors: Behruznia Mahboobeh , Marin Maximillian , Farhat Maha , Thomas Jonathan C , Domingo-Sananes Maria Rosa , Meehan Conor J
Published: March 2024

TheMycobacterium tuberculosiscomplex (MTBC) is a group of bacteria causing tuberculosis (TB) in humans and animals. Understanding MTBC genetic diversity is crucial for insights into its adaptation and traits related to survival, virulence, and antibiotic resistance. While it is known that within MTBC diversity is characterised by large lineage-specific deletions (regions of difference [RD]), a comprehensive pangenomic analysis incorporating both coding and non-coding regions remains unexplored. We utilised a curated dataset representing various MTBC genomes, including under-represented lineages to quantify the true diversity of the MTBC pangenome. The MTBC was found to have a small, closed pangenome with distinct genomic features and RDs both between lineages (as previously known) and between sub-lineages. The accessory genome was identified to be a product of genome reduction, showing both lineage-specific and independent deletions. This variation has implications for traits like virulence, drug resistance, and metabolism. The study provides a comprehensive understanding of the MTBC pangenome, highlighting the importance of genome reduction in its evolution and showing that within-lineage genome content diversity is present. The findings underline the significance of genomic variations in determining the pathogenic traits of different MTBC lineages.
Proteomic Analysis Reveals Trilaciclib-Induced Senescence
Authors: Hermosilla-Trespaderne Marina , Hu-Yang Mark Xinchen , Dannoura Abeer , Frey Andrew M. , George Amy L. , Trost Matthias , Marín-Rubio José Luis
Published: March 2024

Trilaciclib, a CDK4/6 inhibitor, was approved as a myeloprotective agent for protecting bone marrow from chemotherapy-induced damage in extensive-stage small cell lung cancer (ES-SCLC). This is achieved through the induction of a temporary halt in the cell cycle of bone marrow cells. While it has been studied in various cancer types, its potential in haematological cancers remains unexplored. This research aimed to investigate the efficacy of trilaciclib in haematological cancers. Utilizing mass spectrometry-based proteomics, we examined the alterations induced by trilaciclib in the chronic myeloid leukaemia (CML) cell line, K562. Interestingly, trilaciclib promoted senescence in these cells rather than cell death, as observed in acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), and myeloma cells. In K562 cells, trilaciclib hindered cell cycle progression and proliferation by stabilising CDK4/6 and downregulating cell cycle-related proteins, along with the concomitant activation of autophagy pathways. Additionally, trilaciclib-induced senescence was also observed in the non-small cell lung carcinoma cell line (NSCLC), A549. These findings highlight trilaciclib’s potential as a therapeutic option for haematological cancers and underscore the need to carefully balance senescence induction and autophagy modulation in CML treatment, as well as in NSCLC.

ABSTRACT GRAPHIC
The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay
Authors: Qiu Yi , Kang Yoon Mo , Korfmann Christopher , Pouyet Fanny , Eckford Andrew , Palazzo Alexander F.
Published: March 2024

In vertebrates, most protein-coding genes have a peak of GC-content near their 5’ transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation of mRNAs. Despite the importance of GC-content for RNA metabolism, its general features, origin, and maintenance remain mysterious. We investigated the evolutionary forces shaping GC-content at the transcriptional start site (TSS) of genes through both comparative genomic analysis of nucleotide substitution rates between different species and by examining humande novomutations. Our data suggests that GC-peaks at TSSs were present in the last vertebrate common ancestor and are largely dictated by recombination patterns. We observe that in primates and rodents, where recombination is directed away from TSSs by PRDM9, GC-content at protein-coding gene TSSs is currently undergoing mutational decay. In canids, which lack PRDM9 and perform recombination at TSSs, GC-content at protein-coding gene TSSs is increasing. These patterns extend into the open reading frame affecting protein-coding regions, and we show that changes in GC-content due to recombination affect synonymous codon position choices at the start of the open reading frame. Our results indicate that although high GC-content in protein-coding genes may be shaped by selective pressures to enhance expression, the dynamics of GC-content in mammals are largely shaped by patterns of recombination.
Reliability of brain metrics derived from a Time-Domain Functional Near-Infrared Spectroscopy System
Authors: Dubois Julien , Field Ryan M. , Jawhar Sami , Koch Erin M. , Aghajan Zahra M. , Miller Naomi , Perdue Katherine L. , Taylor Moriah
Published: March 2024

With the growing interest in establishing brain-based biomarkers for precision medicine, there is a need for noninvasive, scalable neuroimaging devices that yield valid and reliable metrics. Kernel’s second-generation Flow2 Time-Domain Functional Near-Infrared Spectroscopy (TD-fNIRS) system meets the requirements of noninvasive and scalable neuroimaging, and uses a validated modality to measure brain function. In this work, we investigate the test-retest reliability (TRR) of a set of metrics derived from the Flow2 recordings. We adopted a repeated-measures design with 49 healthy participants, and quantified TRR over multiple time points and different headsets—in different experimental conditions including a resting state, a sensory, and a cognitive task. Results demonstrated high reliability in resting state features including hemoglobin concentrations, head tissue light attenuation, amplitude of low frequency fluctuations, and functional connectivity. Additionally, passive auditory and Go/No-Go inhibitory control tasks each exhibited similar activation patterns across days. Notably, areas with the highest reliability were in auditory regions during the auditory task, and right prefrontal regions during the Go/No-Go task, consistent with prior literature. This study underscores the reliability of Flow2-derived metrics, supporting its potential to actualize the vision of using brain-based biomarkers for diagnosis, treatment selection and treatment monitoring of neuropsychiatric and neurocognitive disorders.
A longevity-specific bank of induced pluripotent stem cells from centenarians and their offspring
Authors: Dowrey Todd W. , Cranston Samuel F. , Skvir Nicholas , Lok Yvonne , Gould Brian , Petrowitz Bradley , Villar Daniel , Shan Jidong , James Marianne , Dodge Mark , Belkina Anna C. , Giadone Richard M. , Sebastiani Paola , Perls Thomas T. , Andersen Stacy L. , Murphy George J.
Published: March 2024

Centenarians provide a unique lens through which to study longevity, healthy aging, and resiliency. Moreover, models ofhumanaging and resilience to disease that allow for the testing of potential interventions are virtually non-existent. We obtained and characterized over 50 centenarian and offspring peripheral blood samples including those connected to functional independence data highlighting resistance to disability and cognitive impairment. Targeted methylation arrays were used in molecular aging clocks to compare and contrast differences between biological and chronological age in these specialized subjects. Isolated peripheral blood mononuclear cells (PBMCs) were then successfully reprogrammed into high-quality induced pluripotent stem cell (iPSC) lines which were functionally characterized for pluripotency, genomic stability, and the ability to undergo directed differentiation. The result of this work is a one-of-a-kind resource for studies of human longevity and resilience that can fuel the discovery and validation of novel therapeutics for aging-related disease.
Divergent marine anaerobic ciliates harbor closely relatedMethanocorpusculumendosymbionts
Authors: Schrecengost Anna , Rotterová Johana , Poláková Kateřina , Čepička Ivan , Beinart Roxanne
Published: March 2024

Ciliates are a diverse group of protists known for their ability to establish various partnerships and thrive in a wide variety of oxygen-depleted environments. Most anaerobic ciliates harbor methanogens, one of the few known archaea living intracellularly. These methanogens increase the metabolic efficiency of host fermentation via syntrophic use of host end-product in methanogenesis. Despite the ubiquity of these symbioses in anoxic habitats, patterns of symbiont specificity and fidelity are not well known. We surveyed two unrelated, commonly found groups of anaerobic ciliates, the Plagiopylea and Metopida, isolated from anoxic marine sediments. We sequenced host 18S rRNA and symbiont 16S rRNA marker genes as well as the symbiont ITS region from our cultured ciliates to identify hosts and their associated methanogenic symbionts. We found that marine ciliates from both of these co-occurring, divergent groups harbor closely related yet distinct intracellular archaea within theMethanocorpusculumgenus. The symbionts appear to be stable at the host species level, but at higher taxonomic levels, there is evidence that symbiont replacements have occurred. Gaining insight into this unique association will deepen our understanding of the complex transmission modes of marine microbial symbionts, and the mutualistic microbial interactions occurring across domains of life.
Computational screening of the effects of mutations on protein-protein off-rates and dissociation mechanisms by τRAMD
Authors: D'Arrigo Giulia , Kokh Daria B. , Nunes-Alves Ariane , Wade Rebecca C.
Published: March 2024

The dissociation rate, or its reciprocal, the residence time (τ), is a crucial parameter for understanding the duration and biological impact of biomolecular interactions. Accurate prediction of τ is essential for understanding protein-protein interactions (PPIs) and identifying potential drug targets or modulators for tackling diseases. Conventional molecular dynamics simulation techniques are inherently constrained by their limited timescales, making it challenging to estimate residence times, which typically range from minutes to hours. Building upon its successful application in protein-small molecule systems, τ-Random Acceleration Molecular Dynamics (τRAMD) is here investigated for estimating dissociation rates of protein-protein complexes. τRAMD enables the observation of unbinding events on the nanosecond timescale, facilitating rapid and efficient computation of relative residence times. We tested this methodology for three protein-protein complexes and their extensive mutant datasets, achieving good agreement between computed and experimental data. By combining τRAMD with MD-IFP (Interaction Fingerprint) analysis, dissociation mechanisms were characterized and their sensitivity to mutations investigated, enabling the identification of molecular hotspots for selective modulation of dissociation kinetics. In conclusion, our findings underscore the versatility of τRAMD as a simple and computationally efficient approach for computing relative protein-protein dissociation rates and investigating dissociation mechanisms, thereby aiding the design of PPI modulators.
Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis
Authors: Knight S.R. , Abbasova L. , Zeighami Y. , Hansen J.Y. , Martins D. , Zelaya F. , Dipasquale O. , Liu T. , Shin D. , Bossong M.G. , Azis M. , Antoniades M. , Howes O. , Bonoldi I. , Egerton A. , Allen P. , O’Daly O. , McGuire P. , Modinos G.
Published: March 2024

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain function that are associated with schizophrenia spectrum disorders (SSD) are already present in young adults at clinical high-risk for psychosis (CHR-P), yet the cellular and molecular determinants of these alterations are not well understood. Here, combining regional cerebral blood flow (rCBF) data with existing transcriptomic and neurotransmitter data, we show that cell-types involved in stress response and inflammation, as well as the dopamine, acetylcholine, GABAA and NMDA receptor systems, align as shared and distinct cellular and neurochemical signatures of rCBF phenotypes in people with SSD and those at CHR-P. Decoding the biological pathways involved in neuroimaging-based psychosis phenotypes may provide a basis for the development of novel interventions.
Stem rot affects the structure of rhizosphere microbiome in Berseem Clover (Trifolium alexandrinum)
Authors: Mukhtar Salma , Ahmad Zain , Khan Noor , John Michael , Aiysha Dalaq
Published: March 2024

Rhizosphere microbiome plays an essential role in maintaining plant health and productivity. Fungal and bacterial diseases may affect the rhizosphere-associated microbial communities and overall structure of plant microbiome. Here, we studied the effect of stem rot of berseem clover on the bacterial and fungal communities associated with the rhizosphere. We analyzed the rhizosphere-associated bacterial and fungal microbiome from healthy and infected berseem clover collected from three sampling sites by using 16S rRNA and ITS based Illumina sequencing metabarcoding approach. Microbiome analysis showed that healthy plants had higher bacterial and fungal diversity as compared to stem rot infected plants. At the genus level, bacterial generaRhizobiumandComamonaswere more abundant in healthy plants whilePantoeawas more abundant in infected plants and fungal generaSclerotinia,FusariumandCladorrhinumwere more abundant in infected plants whileMicrodochiumandCladosporiumwere distinctively abundant in healthy Berseem. Functional characterization of bacterial and fungal microbiomes revealed that bacterial communities from infected plants showed more abundance of bacteria with functions replication and repair, enzyme families and biosynthesis of other secondary metabolites as compared to healthy plant microbiome and decreased in fungal groups including arbuscular mycorrhiza and soil saprotrophs and an increase in plant saprotrophs and fungal parasite-plant pathogens. This study provides comprehensive information about the structure and composition of bacterial and fungal communities associated with the berseem clover rhizosphere that could be utilized for future research on the control of stem rot of berseem clover.
Early intermediates in bacterial RNA polymerase promoter melting visualized by time-resolved cryo-electron microscopy
Authors: Saecker Ruth M. , Mueller Andreas U. , Malone Brandon , Chen James , Budell William C. , Dandey Venkata P. , Maruthi Kashyap , Mendez Joshua H. , Molina Nina , Eng Edward T. , Yen Laura Y. , Potter Clinton S. , Carragher Bridget , Darst Seth A.
Published: March 2024

During formation of the transcription-competent open complex (RPo) by bacterial RNA polymerases (RNAP), transient intermediates pile up before overcoming a rate-limiting step. Structural descriptions of these interconversions in real time are unavailable. To address this gap, time-resolved cryo-electron microscopy (cryo-EM) was used to capture four intermediates populated 120 or 500 milliseconds (ms) after mixingEscherichia coliσ70-RNAP and the αPRpromoter. Cryo-EM snapshots revealed the upstream edge of the transcription bubble unpairs rapidly, followed by stepwise insertion of two conserved nontemplate strand (nt-strand) bases into RNAP pockets. As nt-strand “read-out” extends, the RNAP clamp closes, expelling an inhibitory σ70domain from the active-site cleft. The template strand is fully unpaired by 120 ms but remains dynamic, indicating yet unknown conformational changes load it in subsequent steps. Because these events likely describe DNA opening at many bacterial promoters, this study provides needed insights into how DNA sequence regulates steps of RPo formation.