bluuebunny/crossref_metadata_2025 huggingface dataset:
A NICU Postoperative Pain Management Improvement Project to Reduce Uncontrolled Pain and Improve Staff Satisfaction
Authors: Sprecher Alicia , Roeloffs Kimberly , Czarnecki Michelle L. , Labovsky Kristen , Kissell Anna , Hornung Genesee , Uhing Michael
Published: December 2024

Background:

Postoperative pain management in the neonatal period is an area of high variability and a source of staff dissatisfaction. Pain management is a key component of high-quality care; however, pain assessment in infants is difficult and analgesics can negatively impact the developing brain.

Purpose:

We aimed to improve postoperative pain control for infants in our neonatal intensive care unit (NICU), limit variability in the approach to pain management, and increase staff satisfaction.

Methods:

This project was completed between April 2019 and March 2022 with sustainment tracked through December 2023. Interventions took place in a 70-bed level IV NICU using quality improvement methodology. Interventions included efforts aimed at improving pain assessment as well as development and implementation of a pain management guideline. Outcome measures included frequency of uncontrolled postoperative pain and measures of staff satisfaction. Process measures included compliance with pain assessment cadence and guideline recommendations. Opioid exposure within 24 hours of surgery was included as a balancing measure.

Results:

Pain management was assessed in 811 infants: 392 prior to guideline implementation, 273 during implementation, and 146 during sustainment period. Uncontrolled postoperative pain decreased from 26% pre-implementation to 18% post implementation and into the sustainment period. Staff satisfaction improved from 67% to 83%. These improvements were associated with decreased variability in postoperative pain management and a decrease in postoperative opioid exposure.

Implications for Practice and Research:

The use of a postoperative pain management guideline can improve pain control, decrease drug regimen variability, decrease opioid exposure, and increase staff satisfaction.
A Case of Leukemia Cutis (Acute Myeloid Leukemia) With Epidermotropism
Authors: Aran Brenna M. , Duran Juanita , Gru Alejandro A.
Published: December 2024

Acute myeloid leukemia is a cancer involving uncontrolled proliferation of hematopoietic cells. Cutaneous involvement is referred to as leukemia cutis (LC). The histopathologic presentation of LC is variable, and may present with perivascular, periadnexal, dermal, or subcutaneous infiltrate. Epidermotropism is notably absent. We report an unusual case of acute myeloid LC with epidermotropism in a 68-year-old man. A punch biopsy revealed a mononuclear myeloblast infiltrate involving the dermis and subcutaneous tissue. The epidermis was focally acanthotic, with several vesicles and atypical epidermotropic cells. Mitotic figures and apoptotic cells were present. Immunohistochemistry showed the blasts to be positive for CD56, CD123, and lysozyme, and weakly positive for CD4 and CD163. Negative immunostaining included CD3, CD20, CD34, TdT, and CD117. Epstein–Barr virus in situ hybridization was negative. A bone marrow biopsy revealed the same myeloblast population with identical phenotype to the skin. The blasts were negative for CD34, CD117, CD3, CD19, CD163, CD68, CD61, myeloperoxidase, pankeratin, E-cadherin, CD4, and transcription factor 4. A diagnosis of acute myeloid leukemia with monocytic differentiation and leukemia cutis was established. These findings suggest that the differential diagnosis for conditions with epidermotropism may be even broader than previously thought.
A review of validated techniques and tools for tumor intensity-modulated radiation therapy
Authors: Yao Xiao , Chuan Chen
Published: December 2024

Intensity-modulated radiation therapy (IMRT) is an advanced tumor treatment technique that enables precise three-dimensional dose distribution. However, factors such as field design, data algorithms, and machine errors may lead to deviations between the actual dose and the planned dose, potentially resulting in irradiation errors.

Common dose verification methods include point dose verification, two-dimensional dose verification, and three-dimensional dose verification. This paper reviews various verification methods and focuses on the errors and limitations of each method to improve the safety and effectiveness of IMRT treatment.
Pediatric T-lymphoblastic Leukemia With an Entirely Mature Immunophenotype: A Prompt and Challenging Diagnosis
Authors: Cheng Jinjun , Wang Yannan , Gong Shunyou , Wistinghausen Birte , Jacobs Shana , Schore Reuven J. , Toner Keri
Published: December 2024

Children with T-ALL/LBL require prompt diagnosis and treatment. Flow cytometric analysis of T-lineage and immaturity markers usually leads to a straightforward diagnosis. However, rare cases of T-ALL expressing bright CD45 and lacking expression of immature markers can be a diagnostic conundrum and difficult to differentiate from mature T-cell lymphomas lacking surface CD3 expression or aberrantly expressing immature markers, which affects treatment decisions and prognosis. Here, we summarize the clinical, pathologic, and genetic features of 3 pediatric T-ALL cases with an entirely mature immunophenotype.
Accuracy of ICD-10 Codes for Suicidal Ideation and Action in Pediatric Emergency Department Encounters
Authors: Xu Rena , Bode Louisa , Geva Alon , Mandl Kenneth D. , McMurry Andrew J.
Published: December 2024

Objectives

According to the ideation-to-action framework of suicidality, suicidal ideation and suicidal action arise via distinct trajectories. Studying suicidality under this framework requires accurate identification of both ideation and action. We sought to assess the accuracy of International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes for suicidal ideation and action in emergency department encounters.

Methods

Accuracy of ICD-10-CM coding for suicidality was assessed through chart review of clinical notes for 205 emergency department encounters among patients 6–18 years old at a large academic pediatric hospital between June 1, 2016 and June 1, 2022. Physician notes were reviewed for documentation of past or present suicidal ideation, suicidal action, or both. The study cohort consisted of 103 randomly selected “cases,” or encounters assigned at least 1 ICD-10-CM code for suicidality, and 102 propensity-matched “noncases” lacking ICD-10-CM codes. Accuracy of ICD-10-CM codes was assessed using sensitivity, specificity, positive predictive value, and negative predictive value.

Results

Against a gold standard chart review, the positive predictive value for ICD-10-CM suicidality codes was 86.9% (95% confidence interval [CI]: 84.5%–89.3%), and the negative predictive value was 76.2% (95% CI: 73.2%–79.2%). Nearly half of encounters involving suicidality were not captured by ICD-10-CM coding (sensitivity = 53.4%; 95% CI: 49.9%–56.9%). Sensitivity was higher for ideation-present (82.4%, 95% CI: 77.7%–87.1%) than for action-present (33.7%, 95% CI: 27.9%–39.5%) or action-past (20.4%, 95% CI: 15.5%–25.3%).

Conclusions

Many cases of suicidality may be missed by relying on only ICD-10-CM codes. Accuracy of ICD-10-CM codes is high for suicidal ideation but low for action. To scale the ideation-to-action model for use in large populations, better data sources are needed to identify cases of suicidal action.
Immediate Implant Placement in a Hypothyroid Geriatric Patient: Aesthetic Excellence, Secondary Stability, and Successful Outcome—A Case Report
Authors: Srinivas Sowmya , Aradya Anupama , Somashekarachar Ganesh , Doddawad Vidya G.
Published: December 2024

Placing an implant immediately into extraction sockets provides a distinct advantage over delayed placement, eliminating the need for a 4 to 6 months waiting period for bone formation. However, when patients present with hypothyroidism, the feasibility of immediate placement of dental implants becomes uncertain. This case involved a hypothyroid woman in her late 60s with loose lower anterior teeth. We performed atraumatic extractions. Immediately after extraction, we implanted tilted implants into her lower posterior arch, which is an area with limited vertical bone height. In the anterior arch, which is characterized by thick, soft tissue, we implanted vertical implants. We used multiunit abutments in the anterior region to address hygiene and angulation issues. The final prosthesis comprised a porcelain-fused-to-metal screw-retained bridge with group function occlusion. These prostheses offer advantages compared with cement-retained prostheses, particularly with multiunit abutments that allow passive prosthetic fitting despite implant axis deviation. This approach strengthens the hemidesmosomal connection, reduces the need for repeated screwing and unscrewing, and promotes stability in the peri-implant tissues. This case underscores the clinical benefits of immediate implant placement and the advantages of using screw-retained prostheses in patients with hypothyroidism. Although extensive research has been conducted to analyze factors influencing the success of dental implants in individuals with hypothyroidism, ongoing debates persist in the literature. This case demonstrates successful implantation of dental implants in a patient with hypothyroidism.
Chest Feminization and Masculinization Surgery: Part Two of the Plastic Surgeon’s Perspective of Gender-Affirming Surgery
Authors: Hale Eva S. , Gibstein Alexander R. , Smartz Taylor , Boghosian Tanya , Jabori Sinan K. , Danker Sara
Published: December 2024

Transgender individuals commonly feel significant distress and discomfort, termed gender dysphoria, as a result of the discrepancy between their gender assigned at birth and their gender identity. A major source of gender dysphoria stems from distinct anatomical differences between the male and female chest. Gender-affirming mastectomy of transmasculine patients and breast augmentation for chest feminization of transfeminine patients, also referred to as top surgery, are often the first surgical interventions and most commonly pursued physical modifications for the treatment of gender dysphoria among this patient population. Surgical modification of the chest improves psychological functioning, relieves distress from gender dysphoria symptoms, and has low rates of postoperative regret. This article aims to explicate the various top surgery options available to clinicians to aid their transgender patients’ goal of achieving an outward appearance more closely aligning with their gender identity.
99mTc-Labeled Blood Pool Scintigraphy and SPECT/CT Findings in a Rare Case of Blue Rubber Bleb Nevus Syndrome
Authors: Wakankar Ritwik , Dharmashaktu Yamini , Kumar Rakesh
Published: December 2024

Blue rubber bleb nevus syndrome or Bean syndrome is a rare genetic disorder characterized by the presence of multiple venous hemangiomas, most commonly involving the skin and gastrointestinal tract, but which can also involve other organs as well. We present an interesting case of a 21-year-old woman with blue rubber bleb nevus syndrome and describe the findings of her 99mTc-labeled whole-body blood pool scintigraphy and SPECT/CT.
Rising to the Ultrasensitive Rapid Diagnostic Challenge with Buoyant-Analyte-Magnetic (BAM) Assays
Authors: Wang Chuanlei , Satterfield Emory , Livi Carolina B. , Dean Delphine , Anker Jeffrey N.
Published: December 2024

Ultrasensitive, inexpensive, rapid, and portable assays are needed to detect infectious diseases at early stages to improve treatment and prevent transmission, especially to vulnerable patients. Unfortunately, most ultrasensitive assays require rinsing and development steps which increase their complexity, cost, and read time. We address these issues in a novel assay that uses a combination of buoyant microbubbles and magnetic microspheres to doubly label an analyte (SARS-CoV-2 N-protein from surfactant-lysed viruses) and form buoyant-analyte-magnetic (BAM) sandwich complexes. A permanent magnet pulls down the BAM complexes, while unbound microbubbles float towards the surface and separate without rinsing. Removing the magnet releases the buoyant BAM complexes allowing them to float upwards. Under flashlight illumination, they appear as bright rising dots. A simple digital camera (or even cell phone camera) counts the BAM complexes. Remarkably, the analytical detection limit is ∼50 N-protein molecules in 5 µL of saliva. The assay gave positive results for all PCR-positive saliva specimens tested, with concentrations ranging from 0.7 to 2.51×105RNA copies/µL. We also discuss assay limitations and ways to address them in the future.
Detecting SARS-CoV-2 Cryptic Lineages using Publicly Available Whole Genome Wastewater Sequencing Data
Authors: Suarez Reinier , Gregory Devon A. , Baker David A. , Rushford Clayton , Hunter Torin , Minor Nicholas R. , Russ Clayton , Copen Emma , O’Connor David H. , Johnson Marc C.
Published: December 2024

Beginning in early 2021, unique and highly divergent lineages of SARS-CoV-2 were sporadically found in wastewater sewersheds using a sequencing strategy focused on the most mutagenic region of SARS-CoV-2, the receptor binding domain (RBD). Because these RBD sequences did not match known circulating strains and their source was not known, we termed them “cryptic lineages”. To date, more than 20 cryptic lineages have been identified using the RBD-focused sequencing strategy. Here, we identified and characterized additional cryptic lineages from SARS-CoV-2 wastewater sequences submitted to NCBI’s Sequence Read Archives (SRA). Wastewater sequence datasets were screened for individual sequence reads that contained combinations of mutations frequently found in cryptic lineages but not contemporary circulating lineages. Using this method, we identified 18 cryptic lineages that appeared in multiple samples from the same sewershed, including 12 that were not previously reported. Partial consensus sequences were generated for each cryptic lineage by extracting and mapping sequences containing cryptic-specific mutations. Surprisingly, seven of the mutations that appeared convergently in cryptic lineages were reversions to sequences that were highly conserved in SARS- CoV-2-related bat Sarbecoviruses. The apparent reversion to bat Sarbecovirus sequences suggests that SARS- CoV-2 adaptation to replicate efficiently in respiratory tissues preceded the COVID-19 pandemic.

Author Summary

Wastewater surveillance has been used during the SARS-CoV-2 pandemic to monitor viral activity and the spread of viral lineages. Occasionally, SARS-CoV-2 sequences from wastewater reveal unique evolutionary advanced lineages of SARS-CoV-2 from an unknown source, which are termed cryptic lineages. Many groups nationwide also use wastewater surveillance to track the virus and upload that information to NCBI’s SRA database. That sequence data was screened to identify 18 cryptic lineages worldwide and identify convergent mutations throughout the genome of multiple cryptic lineages that suggest reversion to residues common in SARS-CoV-2-related Sarbecoviruses.
TMS-induced modulation of brain networks and its associations to rTMS treatment for depression: a concurrent fMRI-EEG-TMS study
Authors: He Hengda , Sun Xiaoxiao , Doose Jayce , Faller Josef , McIntosh James R , Saber Golbarg T , Huffman Sarah , Hong Linbi , Pantazatos Spiro , Yuan Han , McTeague Lisa M , Goldman Robin I , Brown Truman R , George Mark S , Sajda Paul
Published: December 2024

Transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is an established intervention for treatment-resistant depression (TRD), yet the underlying therapeutic mechanisms remain not fully understood. This study employs an integrative approach that combines TMS with concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), aimed at assessing the acute/immediate effects of TMS on brain network dynamics and their correlation with clinical outcomes. Our study demonstrates that TMS acutely modulates connectivity within vital brain circuits, particularly the cognitive control and default mode networks. We found that the baseline TMS-evoked responses in the cognitive control and limbic networks significantly predicted clinical improvement in patients receiving a novel EEG-synchronized repetitive TMS treatment. Furthermore, this study explored the brain-state dependent effects of TMS, as the brain-state indexed by the phase of EEG prefrontal alpha oscillation. We found that clinical outcomes in this novel treatment are linked to state-specific TMS-modulated functional connectivity within a pivotal brain circuit of the L-DLPFC and the posterior subgenual anterior cingulate cortex within the limbic system. These findings contribute to our understanding of the therapeutic effects underlying TMS treatment in depression and support the potential of assessing state-dependent TMS effects in TMS timing target selection. This study emphasizes the importance of personalized timing of TMS for optimizing target engagement of specific clinically relevant brain circuits. Our results are crucial for future research into the development of personalized neuromodulation therapies for TRD patients.
Advantages to interspace-level analyses over person-level analyses when studying relationships between lumbar spinal degeneration findings : a cross-sectional study
Authors: Suri Pradeep , Elgaeva Elizaveta E. , Jarvik Jeffrey G. , Rundell Sean D. , Tsepilov Yakov A. , Williams Frances M.K. , Heagerty Patrick J.
Published: December 2024

Purpose

To examine associations between lumbar intervertebral disc degeneration (LDD) and type II Modic changes (MC) when retaining information at each interspace (“interspace-level analysis”), as compared to aggregating information across interspaces as is typically done in spine research (“person-level analysis”). The study compared results from (1) interspace-level analyses assuming a common relationship across interspaces (the “interspace-level, common-relationship” approach), (2) interspace-level analyses allowing for interspace-specific associations (an “interspace-level, interspace-specific” approach), and (3) a conventional person-level analytic approach.

Methods

Adults in primary care (n=147) received lumbar spine magnetic resonance imaging (MRI) and neuroradiologist-evaluated assessments of prevalent disc height narrowing (DHN), type II MC, and other LDD parameters. Analyses examined associations between DHN and type II MC in interspace-level, commonrelationship analyses, interspace-level, interspace-specific analyses, and conventional person-level analyses.

Results

Cross-sectional, interspace-level, common-relationship analyses found large-magnitude DHN-type II MC associations (adjusted OR [aOR]=6.5, 95% confidence intervals (CIs) 3.3-13; p<0.001). The magnitude of this association was larger and more precise than that yielded by person-level analyses (aOR=2.9 [95% CI 1.2-7]), and substantially more precise than interspace-level, interspace-specific analyses which allowed the association between DHN and type II MC to vary across levels. Across exploratory analyses of disc signal intensity and other MC types, interspace-level, common-relationship analyses produced larger-magnitude and more precise associations than person-level analyses in most situations, and were more precise than interspace-level, interspace-specific analyses.

Conclusions

Interspace-level analytic approaches offer some advantages to person-level analyses that may be useful in understanding relationships between spinal degeneration findings.
Lysosomal reduced thiols are essential for mouse embryonic development
Authors: Adelmann Charles H. , Venkatachalam Avanthika , Huang Lingjuan , Liu Michelle , Germana Sharon , Sabatini David M. , Fisher David E.
Published: December 2024

While it has been appreciated for decades that lysosomes can import cysteine, its for organismal physiology is unclear. Recently, the MFSD12 transmembrane protein was shown to be necessary to import cysteine into lysosomes (and melanosomes), enabling the study of these processes using genetic tools. Here, we find that mice lackingMfsd12die between embryonic days 10.5-12.5, suggesting that MFSD12 is essential for organogenesis. Within lysosomes, it is well known that a significant fraction of the cysteine is converted into cystine (oxidized cysteine), which accumulates and can be released into the cytosol via the CTNS (cystinosin) transporter. However, in contrast toMfsd12, loss ofCtnsresults in live animals, indicating that it is not an essential gene. This suggests that the essential function of MFSD12 is not to enable cystine storage for use in the cytosol but rather to supply reduced cysteine to the lysosomal lumen itself. Consistent with this idea, the treatment of breeding heterozygous mice with cysteamine, a lysosome-penetrant thiol, rescued the development ofMfsd12knockout mice and resulted in live births. Our work implicates lysosomal thiol import as an essential metabolic pathway and provides tools for deciphering its complex genetic and metabolic interactions.
The Efficacy and Safety of Sodium-Glucose Cotransporter Protein 2 Inhibitors (SGLT2Is) in Liver Cirrhosis: A Systematic Review and Meta-Analysis
Authors: Dhoop Sudheer , Shehada Mohammed , Sawaf Bisher , Patel Manthan , Roberts Luke , Smith Wade-Lee , Hart Benjamin
Published: December 2024

Background

Sodium-Glucose Cotransporter Protein 2 Inhibitors (SGLT2Is) are known for their cardiovascular and renoprotective benefits and are efficacious in managing Metabolic-Associated Steatotic Liver Disease (MASLD). However, limited data exist on their use in advanced liver disease, particularly liver cirrhosis.

Aims

To synthesize existing evidence on the efficacy and safety of SGLT2Is in patients with liver cirrhosis and to provide clinical guidance.

Methods

A systematic review and meta-analysis were conducted following the PRISMA 2020 Statement. Searches in major health databases identified studies where SGLT2Is were used in patients with cirrhosis. The analysis focused on prospective trials in decompensated cirrhosis and retrospective studies in compensated cirrhosis. Primary outcomes included the need for large-volume paracentesis (LVP) and mortality. Secondary outcomes assessed weight loss, loop diuretic dose reduction, residual ascites, acute kidney injury (AKI), hyponatremia, hepatic encephalopathy (HE), and urinary tract infections (UTIs).

Results

Ten studies (8 peer-reviewed) from 2020-2024 were included: 2 randomized controlled trials, 4 single-arm prospective trials, and 4 retrospective studies. SGLT2I use was associated with reduced LVP (RR 0.45, CI 0.31-0.66, p<0.001) and mortality (aHR 0.46, CI 0.38-0.55, p<0.001). Benefits included a 39 mg reduction in loop diuretic dose, 7 kg weight loss, and no significant increase in residual ascites, AKI, hyponatremia, HE, or UTIs.

Conclusions

SGLT2Is show promise in managing diuretic-resistant ascites and reducing mortality in liver cirrhosis without causing significant adverse events. Larger, randomized controlled trials are needed to validate these findings.
3D Structure-based Generative Small Molecule Drug Design: Are We There Yet?
Authors: Yang Bo , Xiang Chijian , Li Jianing
Published: December 2024

Structure-based drug design (SBDD) plays a crucial role in pre-clinical drug discovery. Recently developed structure-based 3D generative algorithms have the potential to streamline the SBDD process by enabling the generation of novel, druglike molecules based on the structure of a target protein’s binding pocket. However, no effective metric currently exists to assess the chemical plausibility of molecules generated by these algorithms, which hampers further advancements in their development. In this study, we propose two novel metrics for evaluating the chemical plausibility of generated molecules. Combined with additional analyses, we demonstrate that existing algorithms could generate chemically implausible structures with some property distributions that deviate from those of known drug-like molecules. The metrics and analytical methods presented here offer model developers and user valuable tools to quantify the chemical plausibility of molecules they generate, ultimately facilitating the application of these algorithms in drug discovery.
Epigenetic restoration of differentiation competency via reversal of epiblast regionalisation
Authors: Sutcliffe Magdalena A. , Wingett Steven W. , Morris Charles A.J. , Wong Eugenia , Schoenfelder Stefan , Lancaster Madeline A.
Published: December 2024

Although the epiblast in the embryo has the capacity to generate all tissues of the body, itsin vitrocounterparts often exhibit differentiation biases, posing significant challenges for both basic research and translational applications involving pluripotent stem cells (PSCs). The origins of these biases remain incompletely understood. In this study, we identify PSC differentiation biases as arising from fluctuations in repressive and activating histone posttranslational modifications, leading to the acquisition of a caudal epiblast-like phenotype.

We present a novel approach to overcome this bias using a chemical chromatin restoration (CHR) treatment. This method restores transcriptional programs, chromatin accessibility, histone modification profiles, and differentiation potential, effectively recapitulating the competent anterior epiblast-like state. Furthermore, we propose that a high bivalency state is a defining feature of the anterior human epiblast. We suggest that fluctuations in histone modification marks drive epiblast regionalization, ultimately shaping cellular responses to differentiation cues.
Virological and antigenic characteristics of SARS-CoV-2 variants LF.7.2.1, NP.1, and LP.8.1
Authors: Liu Jingyi , Yu Yuanling , Yang Sijie , Jian Fanchong , Song Weiliang , Yu Lingling , Shao Fei , Cao Yunlong
Published: December 2024

XEC and KP.3.1.1 have surpassed KP.3 to become the globally dominant lineages due to their unique NTD mutations. However, several emerging JN.1 sublineages, such as LF.7.2.1, MC.10.1, NP.1, and, especially, LP.8.1, have demonstrated superior growth advantages compared to XEC. It is critical to access the virological and antigenic characteristics of these emerging SARS-CoV-2 variants. Here, we found that LF.7.2.1 is significantly more immune invasive than XEC, primarily due to the A475V mutation, which enabled the evasion of Class 1 neutralizing antibodies. However, LF.7.2.1’s weak ACE2 binding affinity substantially impaired its fitness. Likewise, MC.10.1 and NP.1 exhibited strong antibody immune evasion due to the A435S mutation, but their limited ACE2 engagement efficiency restricted their growth advantage, suggesting that A435S may regulate the Spike conformation, similar to the NTD glycosylation mutations found in KP.3.1.1 and XEC. Most importantly, we found that LP.8.1 showed comparable humoral immune evasion to XEC but demonstrated much increased ACE2 engagement efficiency, supporting its rapid growth. These findings highlight the trade-off between immune evasion and ACE2 engagement efficiency in SARS-CoV-2 evolution, and underscore the importance of monitoring LP.8.1 and its descend lineages.
Sequence-based coevolutionary prediction of species-specific interactomes
Authors: Fernandez-Martin Miguel , Pontes Camila , Ruiz-Serra Victoria , Valencia Alfonso
Published: December 2024

Evolutionarily conserved protein-protein interactions (PPIs) reveal fundamental biological processes. However, predicting protein function solely from these interactions provides an incomplete picture of biological systems. Computational methods for predicting PPIs often struggle due to limited functional annotations in databases, making it difficult to fully understand unique biological systems.. This study introduces ContextMirror2.0 (CM2.0), a coevolution-based method designed to address these limitations. Coevolutionary approaches, unlike supervised machine learning methods, do not rely on labelled datasets, proving valuable in addressing the scarcity of data for species-specific PPIs. While around 40% of CM2.0’s top-1000 predicted PPIs forE. coli, S. enterica, andS. aureusare present in experimental PPI databases, a comparative analysis of predicted functional communities revealed highly conserved interaction patterns and species-specific interactions. CM2.0 leverages coevolutionary information to explore protein interaction dynamics and understand the functional consequences of species-specific variations. This information can inform further studies on the emergence of novel functions, adaptation to specific environments, and the development of targeted therapies.
Species rich but data poor: leveraging distribution modelling techniques to map cetacean occurrence in South Asian waters
Authors: Samad Imran , Sutaria Dipani , Shanker Kartik
Published: December 2024

Cetaceans play important ecosystem roles but are challenging to study since they are highly mobile and spend their entire life at sea. More than a third of all cetaceans occur in South Asian waters where they overlap with several key threats including fisheries, pollution, and high vessel traffic. However, baseline information on their occurrence at the sub-continental scale is lacking even for relatively well studied species. To address this gap, we collated sighting information on cetaceans from the North Indian Ocean region (5-25˚N, 65-95˚E) and used species-tuned distribution models and ensemble modelling approaches with physiographic and oceanographic predictors to map habitat suitability and species richness. We used Multivariate Environmental Similarity Surfaces (MESS) indices and expert reviews to validate our predictions and better infer species distribution. We collated 2329 sighting records for 31 species and modelled the distribution of 18 species. Areas of high species richness, defined by high slope and bathymetric complexity, occurred along the east coast of India, in south Sri Lanka, and around the Lakshadweep and Andaman and Nicobar archipelagos. Species richness patterns were generally consistent with the six identified ecoregions in the area. Most of our predictions were given high scores by the expert reviewers. Our maps underpredicted the occurrence of a few oceanic species, highlighting the need for focused offshore surveys, and overpredicted areas with high MESS indices for all species. We discuss the occurrence patterns and their drivers for these cetacean species while highlighting knowledge gaps and the importance of fine-scale distribution data for conservation planning, especially during the development of regional management plans for cetaceans.
Boundary flow induced membrane tubulation under turgor pressures
Authors: Xue Hao , MA RUI
Published: December 2024

During clathrin-mediated endocytosis in yeast cells, a small patch of flat membrane is deformed into a tubular shape. It is generally believed that the tubulation is powered by actin polymerization. However, studies based on quantitative measurement of the actin molecules suggest that they are not sufficient to produce the forces to overcome the high turgor pressure inside of the cell. In this paper, we model the membrane as a viscous 2D fluid with elasticity and study the dynamic membrane deformation powered by a boundary lipid flow under osmotic pressure. We find that in the absence pressure, the lipid flow drives the membrane into a spherical shape or a parachute shape. The shapes over time exhibit self-similarity. The presence of pressure transforms the membrane into a tubular shape that elongates almost linearly with time and the self-similarity between shapes at different times is lost. Furthermore, the width of the tube is found to scale inversely to the cubic root of the pressure, and the tension across the membrane is negative and scales to the cubic root squared of the pressure. Our results provide a new mechanism to explain the deformation of membrane during endocytosis in addition to the actin polymerization.
SLC35A2 loss of function variants affect glycomic signatures, neuronal fate, and network dynamics
Authors: Lai Dulcie , Sosicka Paulina , Williams Damian J , Bowyer MaryAnn E , Ressler Andrew K , Kohrt Sarah E , Muron Savannah J , Crino Peter B , Freeze Hudson H , Boland Michael J , Heinzen Erin L
Published: December 2024

SLC35A2encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline geneticSLC35A2variants have been identified in congenital disorders of glycosylation and somaticSLC35A2variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain elusive.

In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants inSLC35A2through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology.

We show that loss of function variants inSLC35A2result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation ofSLC35A2loss of function variants towards the GABAergic fate. Additionally, electrophysiological recordings of synaptic activity reveal a shift in excitatory/inhibitory balance towards increased inhibitory drive, indicating changes occurring specifically at the pre-synaptic terminal.

Our study is the first to provide mechanistic insight regarding the early development and functional connectivity ofSLC35A2loss of function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.
Cellular cartography reveals mouse prostate organization and determinants of castration resistance
Authors: Cho Hanbyul , Zhang Yuping , Tien Jean C. , Mannan Rahul , Luo Jie , Narayanan Sathiya Pandi , Mahapatra Somnath , Hu Jing , Shelley Greg , Cruz Gabriel , Shahine Miriam , Wang Lisha , Su Fengyun , Wang Rui , Cao Xuhong , Dhanasekaran Saravana Mohan , Keller Evan T. , Pitchiaya Sethuramasundaram , Chinnaiyan Arul M.
Published: December 2024

Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer, we identified cellular orthologs and key determinants of ADT response and resistance. Our findings reveal that mouse prostates harbor lobe-specific luminal epithelial cell types distinguished by unique gene regulatory modules and anatomically defined androgen-responsive transcriptional programs, indicative of divergent developmental origins. Androgen-insensitive, stem-like epithelial populations - resembling human club and hillock cells - are notably enriched in the urethra and ventral prostate but are rare in other lobes. Within the ventral prostate, we also uncovered two additional androgen-responsive luminal epithelial cell types, marked by Pbsn or Spink1 expression, which align with human luminal subsets and may define the origin of distinct prostate cancer subtypes. Castration profoundly reshaped luminal epithelial transcriptomes, with castration-resistant luminal epithelial cells activating stress-responsive and stemness programs. These transcriptional signatures are enriched in tumor cells from ADT-treated and castration-resistant prostate cancer patients, underscoring their likely role in driving treatment resistance. Collectively, our comprehensive cellular atlas of the mouse prostate illuminates the importance of lobe-specific contexts for prostate cancer modeling and reveals potential therapeutic targets to counter castration resistance.

Significance Statement

Androgen deprivation therapy is a mainstay in prostate cancer treatment, yet many patients eventually develop castration-resistant disease—a lethal progression driven by poorly understood cellular mechanisms. Our study provides a comprehensive cellular map of the prostate, identifying key determinants of normal organization and castration-induced remodeling. By pinpointing the cell types and molecular programs that confer ADT responsiveness or resistance, our findings offer new directions for prostate cancer modeling and pave the way toward novel therapeutic strategies aimed at enhancing ADT efficacy and preventing the emergence of castration-resistant prostate cancer.
Direct and indirect effects of spliceosome disruption compromise gene regulation by Nonsense-Mediated mRNA Decay
Authors: Embree Caleb M. , Stephanou Andreas , Singh Guramrit
Published: December 2024

Pre-mRNA splicing, carried out in the nucleus by a large ribonucleoprotein machine known as the spliceosome, is functionally and physically coupled to the mRNA surveillance pathway in the cytoplasm called nonsense mediated mRNA decay (NMD). The NMD pathway monitors for premature translation termination signals, which can result from alternative splicing, by relying on the exon junction complex (EJC) deposited on exon-exon junctions by the spliceosome. Recently, multiple genetic screens in human cell lines have identified numerous spliceosome components as putative NMD factors. Using publicly available RNA-seq datasets from K562 and HepG2 cells depleted of 18 different spliceosome components, we find that natural NMD targeted mRNA isoforms are upregulated when members of the catalytic spliceosome are reduced. While some of this increase could be due to widespread pleiotropic effects of spliceosome dysfunction (e.g., reduced expression of NMD factors due to mis-splicing of their mRNAs), we identify that AQR, SF3B1, SF3B4 and CDC40 may have a more direct role in NMD. We also test the hypothesis that increased production of novel NMD substrates may overwhelm the pathway to find a direct correlation between the amount of novel NMD substrates detected and the degree of NMD inhibition observed. Finally, similar transcriptome alterations and NMD substrate upregulation are also observed in cells treated with spliceosome inhibitors and in cells derived from retinitis pigmentosa patients with mutations inPRPF8andPRPF31. Overall, our results show that regardless of the cause, spliceosome disruption upregulates a broad set of NMD targets, which could contribute to cellular dysfunction in spliceosomopathies.

AUTHOR SUMMARY

During gene expression, a complex cellular machine known as spliceosome removes extraneous non-coding sequences from precursor RNAs to produce messenger RNA (mRNA) with a contiguous code for protein sequence. To guard against splicing errors that may interrupt protein coding sequence, splicing is linked to a mRNA surveillance pathway known as nonsense mediated mRNA decay (NMD). In this work, we follow up on recent findings from multiple genetic screens that several spliceosome components are necessary for efficient NMD. Our analysis of transcriptomes of lymphoblast K562 cells depleted of 18 spliceosome factors show that NMD based regulation is compromised in cells lacking catalytic spliceosome proteins. Four of these spliceosome proteins may have a direct effect on NMD even though spliceosome disruption in general also causes other changes in gene expression that indirectly affect NMD. Our results suggest that defective NMD based regulation contributes to cellular dysfunction in spliceosomopathies, a collection of human genetic disorders caused by mutations in spliceosome factors.
The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia
Authors: Arneson-Wissink Paige C. , Pelz Katherine , Worley Beth , Mendez Heike , Pham Peter , McCarthy Grace , Chitsazan Alex , Brody Jonathan R. , Grossberg Aaron J.
Published: December 2024

Background

Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.

Methods

Adult C57BL/6J mice received orthotopic PDAC cell (KrasG12D; p53R172H/+; Pdx1-cre) (OT-PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24h, or fasted 24h and refed 24h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analyzed body mass, gross fat pad mass, and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytesin vitro, and gonadal fat pads (gWAT)ex vivo.

Results

3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) liberated less triglyceride into the culture media than control-treated adipocytes (−28.1%) and had lower expression of lipolysis and lipogenesis genes than control cells. PDAC gWAT culturedex vivodisplayed decreased lipolysis compared to sham gWAT (−54.7%). PDAC and sham mice lost equivalent fat mass after a 24h fast, however, PDAC mice could not restore inguinal fat pads (iWAT) (−40.5%) or gWAT (−31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n=126) were associated with adipogenesis (adj p=0.05), and expression of adipogenesis master regulatorsPpargandCebpawere reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%) and genes regulating adipogenesis (Pparγ,Cebpa,Retn,Adipoq,Fasn).

Conclusions

Our work highlights deficient adipose anabolism as a driver of wasting in 3T3-L1 adipocytes treated with PDAC conditioned media and OT-PDAC mice. The small molecule KH3, which disrupts HuR binding, was sufficient to restore adipogenic and lipogenic gene expression and prevent adipose wasting. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.
Community Engagement in Dengue Interventions in Conflict-affected Aden, Yemen: An Implementation Research Using CFIR Framework 2.0.
Authors: Dhaiban Mustafa Mohammed , Basaleem Huda , Purohit Neetu
Published: December 2024

Dengue fever is described by the World Health Organization (WHO) as “the most important mosquito-borne viral disease in the world.” In Yemen, dengue cases have consistently increased, with Aden Governorate reporting 12% of total cases and over 45% of dengue-related deaths, making it a leading public health challenge. Conflict has exacerbated health system weaknesses, limiting resources and energy for prevention efforts. Community engagement (CE) emerges as a critical approach to address these challenges.

This study aimedto identify barriers and facilitators to CE in dengue interventions within conflict-affected contexts and recommend evidence-based strategies for improved implementation. A cross-sectional qualitative study was conducted between February and July 2024 in Aden Governorate, involving 15 in-depth interviews (IDIs) and four focus group discussions (FGDs) with key stakeholders.

Findingsrevealed that while stakeholders perceived CE interventions positively, challenges included systemic issues such as lack of community trust, resource shortages, and health system politicization. Conflict intensified these barriers, reflected in security concerns, inadequate training, and fragmented institutional work. Financial constraints also limited implementers’ capacities. Facilitators included moral incentives, personal recognition, and community support from business owners. However, the dominance of policymakers and influencers due to systemic weaknesses negatively impacted the implementation process, particularly in participant selection and coordination strategies.

In conclusion,addressing systemic fragmentation, enhancing political support, and defining clear coordination plans are critical to adapting CE interventions effectively in conflict

Author Summary

Dengue fever is considered a major health problem for many low-and middle-income countries, leading to high numbers of mortality and morbidity rates with a significant economic burden. Our study highlights the intersection of public health challenges and conflict dynamics, providing unique insights into how community engagement strategies for vector-borne diseases can be adapted to conflict settings. Using the implementation research tool CFIR Framework 2.0, we identified critical barriers, including systemic fragmentation, lack of trust, resource shortages, and weak coordination mechanisms. Conversely, facilitators such as moral incentives, personal recognition, and community-driven support offer actionable strategies for improving implementation outcomes.
Multi-omic Biomarkers Distinguish Rheumatoid Arthritis in Discordant Monozygotic Twins
Authors: Blank Rebecca B. , Bu Kevin , Chen Weixi , Cunningham Ian , Sokolove Jeremy , Lahey Lauren , Heguy Adriana , Medina Rhina , Ubeda Carles , Nayak Renuka R. , Hu Jiyuan , Cantor Adam , Lee Jakleen , Clemente Jose C. , Scher Jose U.
Published: December 2024

Background

Although genetic factors have been identified in the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other features contribute to disease development. Further, the relative contribution of such non-genetic elements in identical twins have not been characterized. Here, we aimed to measure differentiating host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multi-omics approach.

Methods

Eight pairs of MZ twins discordant for RA (n=16) were enrolled. Gut microbiome was assessed using shotgun metagenomic sequencing. Autoantibodies, cytokines, and other plasma proteins were measured in both plasma and feces. Levels of short and medium-chain fatty acids from serum and feces were quantified using gas chromatography mass spectrometry (GC-MS).

Results

While overall microbiome diversity and composition did not significantly differ between twins, we observed a decrease inBlautia faecisin affected twins. Affected twins had higher concentrations of both fecal and plasma citrullinated and non-citrullinated autoantibodies, as well as significantly lower concentrations of fecal butyrate and propionate.

Conclusion

Multi-omics biomarkers differentiate MZ twins discordant for RA.Blautia faecis, which is associated with reduced inflammatory cytokine expression, was decreased in RA twins. Similarly, short-chain fatty acids, known to have immune modulatory effects, were decreased in affected twins, suggesting further bi-directional interactions between inflammation at the gut barrier and disease state. If confirmed in other cohorts, exhaustive multi-omics approaches may improve our understanding of RA pathogenesis and potentially contribute to novel diagnostics and co-adjuvant therapies.