bluuebunny/crossref_metadata_2025 huggingface dataset:
Postcesarean section abdominal wall endometriosis: a rare case report
Authors: Ibrahim Rana , Fadel Abbas , Dika Zakaria
Published: August 2024

Introduction and importance:

Abdominal wall endometriosis (AWE) is a rare but significant complication following cesarean sections. It manifests with recurring right lower quadrant pain, particularly during menstruation, and palpable masses at the cesarean scar site. Recognizing these symptoms is critical for timely diagnosis and effective management. This report discusses the clinical manifestations, diagnostic approach, surgical intervention, and postoperative outcomes of AWE in a specific patient.

Case presentation:

A 28-year-old female presented with recurrent right lower quadrant pain, exacerbated during menstruation, and a palpable mass at her previous cesarean scar. Imaging revealed a well-defined 3.6 ×3 cm mass infiltrating through all layers of the abdominal wall.

Clinical discussion:

This case highlights the challenges of diagnosing AWE, often presenting with vague symptoms like cyclic pain and palpable masses. The primary diagnostic tool was a CT scan, with histopathological examination confirming the diagnosis. Surgical excision was performed, resulting in significant symptom relief and a low recurrence rate.

Conclusion:

This case underscores the importance of vigilance for AWE symptoms in patients with prior cesarean sections. Early recognition and surgical intervention are paramount for effective management and symptom alleviation
A case report on incidentally detected pulmonary sclerosing pneumocytoma: a diagnostic challenge
Authors: Mursalin Golam , Sawon Mehede H. , Alam Md. Kamrul , Islam Salwa
Published: August 2024

Introduction and importance:

Pulmonary sclerosing pneumocytoma (PSP) is a rare non-cancerous lung tumor that is usually asymptomatic, but may cause respiratory distress if it becomes large. PSPs are often detected incidentally because of their slow growth, lack of symptoms, characteristic radiographic features, and increased use of imaging studies. Although it is not a malignant tumor, it can mimic malignancy on imaging and histology, leading to misdiagnosis and unnecessary surgery.

Case presentation:

A 23-year-old asymptomatic female was incidentally diagnosed with PSP during evaluation for a breast fibroadenoma. A chest CT revealed a 3 cm lobulated mass in the left upper lobe. Cytology showed malignant cells with necrotic debris. Immunohistochemistry was positive for TTF-1 and EMA, negative for p63 and AE1/AE3. Histopathology confirmed a well-circumscribed benign neoplasm, consistent with pulmonary sclerosing pneumocytoma. There was no mediastinal lymph node invasion, and the post-surgery prognosis was good.

Clinical discussion:

PSP is a slow-growing tumor that is often asymptomatic until it reaches a significant size. Owing to their well-circumscribed margins and the presence of calcifications, they are often detected incidentally during imaging studies, such as routine chest radiography or CT scans for unrelated conditions. Although these tumors are often incidental, it is important to diagnose and treat them appropriately to prevent potential complications and malignant transformation.

Conclusion:

The findings of this study contribute to the existing literature, increase awareness of this rare tumor, and provide insights into its diagnosis, treatment, and follow-up.
Comprehensive Characterization of Surface-Bound Proteins and Measurement of Fibrin Fiber Thickness on Extracorporeal Membrane Oxygenation Circuits Collected From Patients*
Authors: Cai Tengyi , Emery-Corbin Samantha J. , McCafferty Conor , Van Den Helm Suelyn , Letunica Natasha , Attard Chantal , Barton Rebecca , Horton Stephen , Bottrell Steve , Schultz Bradley , MacLaren Graeme , Chiletti Roberto , Best Derek , Johansen Amy , Newall Fiona , Butt Warwick , d’Udekem Yves , Dagley Laura F. , Yousef Jumana M. , Monagle Paul , Ignjatovic Vera
Published: August 2024

OBJECTIVE:

To characterize surface-bound proteins and to measure the thickness of fibrin fibers bound to extracorporeal membrane oxygenation (ECMO) circuits used in children.

DESIGN:

Single-center observational prospective study, April to November 2021.

SETTING:

PICU, Royal Children’s Hospital, Melbourne, Australia.

PATIENTS:

Patients aged less than 18 years on venoarterial ECMO and without preexisting disorder.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

ECMO circuits were collected from six patients. Circuit samples were collected from five different sites, and subsequently processed for proteomic and scanning electron microscopy (SEM) studies. The concentration of proteins bound to ECMO circuit samples was measured using a bicinchoninic acid protein assay, whereas characterization of the bound proteome was performed using data-independent acquisition mass spectrometry. The Reactome Over-representation Pathway Analyses tool was used to identify functional pathways related to bound proteins. For the SEM studies, ECMO circuit samples were prepared and imaged, and the thickness of bound fibrin fibers was measured using the Fiji ImageJ software, version 1.53c (https://imagej.net/software/fiji/). Protein binding to ECMO circuit samples and fibrin networks showed significant intra-circuit and interpatient variation. The median (range) total protein concentration was 19.0 (0–76.9) μg/mL, and the median total number of proteins was 2011 (1435–2777). A total of 933 proteins were commonly bound to ECMO circuit samples from all patients and were functionally involved in 212 pathways, with signal transduction, cell cycle, and metabolism of proteins being the top three pathway categories. The median intra-circuit fibrin fiber thickness was 0.20 (0.15–0.24) μm, whereas the median interpatient fibrin fiber thickness was 0.18 (0.15–0.21) μm.

CONCLUSIONS:

In this report, we have characterized proteins and fiber fibrin thickness bound to ECMO circuits in six children. The techniques and approaches may be useful for investigating interactions between blood, coagulation, and the ECMO circuit and have the potential for circuit design.
Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037)
Authors: Ho Ken , Hoesley Craig , Anderson Peter L. , Fernández-Romero Jose A. , Friedland Barbara A. , Kelly Clifton W. , Jiao Yuqing , Edick Stacey , Brand Rhonda , Kunjara Na Ayudhya Ratiya Pamela , Zyhowski Ashley , Hartman Douglas J. , Reddy Nipun B. , Al-Khouja Amer , Piper Jeanna , Bauermeister Jose A. , Teleshova Natalia , Melo Claudia , Cornejal Nadjet , Barnable Patrick , Singh Devika , Scheckter Rachel , McClure Tara , Hillier Sharon L. , Hendrix Craig W. ,   on behalf of the MTN-037 Study Team
Published: August 2024

Background:

On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005.

Methods:

HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours.

Results:

Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity.

Conclusions:

MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate.

Clinical Trials:

NCT03408899.
Exposure to calls before hatching affects the post-hatching behaviour of domestic chickens
Authors: Gall Gabriella E. C. , Letherbarrow Megan , Strandburg-Peshkin Ariana , Radford Andrew N. , Madden Joah R.
Published: August 2024

The soundscape experienced by animals early in life can affect their behaviour later in life. For birds, sounds experienced in the egg can influence how individuals learn to respond to specific calls post-hatching. However, how early acoustic experiences affect subsequent social behaviour remains unknown. Here, we investigate how exposure to maternal ‘cluck’ calls pre-hatching affects the behaviour of domestic chickens (
Gallus gallus domesticus
) at 3–5 days and 17–21 days old. We incubated eggs and played cluck calls to half of them. After hatching, we raised chicks in small groups occupying different enclosures. At 3–5 days old, we tested chicks’ responses to three stimuli: (i) background sound, (ii) chick calls and (iii) cluck calls. We found that the pre-hatching experience of cluck calls reduced the likelihood of moving in response to all three stimuli. At 17–21 days old, some chicks explored beyond their own enclosure and ‘visited’ other groups. Chicks exposed to cluck calls before hatching were three times more likely to enter another group’s enclosure than control chicks, and this was unaffected by the chicks’ social connectedness. Our results indicate age- and context-dependent responses of chicks to pre-hatching cluck-call playbacks, with potential long-term effects on individual social behaviour.
Was the steppe bison a grazing beast in Pleistocene landscapes?
Authors: Hofman-Kamińska Emilia , Merceron Gildas , Bocherens Hervé , Boeskorov Gennady G. , Krotova Oleksandra O. , Protopopov Albert V. , Shpansky Andrei V. , Kowalczyk Rafał
Published: August 2024

The history and palaeoecology of the steppe bison (
Bison priscus
) remain incompletely understood despite its widespread distribution. Using dental microwear textural analysis (DMTA) and vegetation modelling, we reconstructed the diet and assessed the habitat of steppe bison inhabiting Eurasia and Alaska since the Middle Pleistocene. During the Late Pleistocene, steppe bison occupied a variety of biome types: from the mosaic of temperate summergreen forest and steppe/temperate grassland (Serbia) to the tundra biomes (Siberia and Alaska). Despite the differences in the identified biome types, the diet of steppe bison did not differ significantly among populations in Eurasia. DMTA classified it as a mixed forager in all populations studied. The DMTA of Bb1 bison—a recently identified genetically extinct sister-clade of
Bison bonasus
—was typical of a highly grazing bovid species and differed from all
B. priscus
populations. The results of the study temper the common perception that steppe bison were grazers in steppe habitats. The dietary plasticity of the steppe bison was lower when compared with modern European bison and may have played an important role in its extinction, even in the stable tundra biome of eastern Siberia, where it has survived the longest in all of Eurasia.
Vagococcus jeotgali sp. nov., isolated from cutlassfish jeotgal, a traditional Korean fermented seafood
Authors: Joe Sung-Hong , Yang Ah-In , Kim Bora , Joe Hae-In , Hong Yeongjin , Shin Na-Ri
Published: August 2024

A novel, Gram-positive, facultatively anaerobic, and non-motile bacterial strain, designated B2T-5T, was isolated from jeotgal, a traditional Korean fermented seafood. Colonies grown on gifu anaerobic medium agar plates were cream-coloured, irregular, and umbonate with curled margins. Optimal growth of strain B2T-5T occurred at 20 °C, pH 8.0, and in the presence of 1% (w/v) NaCl. Strain B2T-5T was negative for oxidase and catalase activity. Hippurate was not hydrolysed and acetoin was not produced. The major cellular fatty acids were C18 : 1
 ω9c and C16 : 0. The cell-wall peptidoglycan was of the A4α type containing l-Lys–d-Asp. The predominant respiratory quinone was menaquinone 7. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylcholine. According to the phylogenetic analysis based on 16S rRNA gene sequences, strain B2T-5T was most closely related to Vagococcus teuberi DSM 21459T, showing 98.2% sequence similarity. Genome sequencing of strain B2T-5T revealed a genome size of 2.0 Mbp and a G+C content of 33.8 mol%. The average nucleotide identities of strain B2T-5T with Vagococcus teuberi DSM 21459T, Vagococcus bubulae SS1994T, and Vagococcus martis D7T301T were 75.0, 74.7, and 75.1%, respectively. Based on the phenotypic, chemotaxonomic, and genotypic data, strain B2T-5T represents a novel species of the genus Vagococcus, for which the name Vagococcus jeotgali sp. nov. is proposed. The type strain is B2T-5T (=KCTC 21223T=JCM 35937T).
Minutes of the closed plenary meeting of the International Committee on Systematics of Prokaryotes, 13 June 2024, via Zoom
Authors: Oren Aharon
Published: August 2024

A closed virtual plenary meeting of the International Committee on Systematics of Prokaryotes (ICSP) was held online on 13 June 2024. The meeting was open to full, co-opted and life members of the ICSP and to members of the Judicial Commission. To comply with Articles 4(d) and 5(d)(1) of the Statutes of the ICSP, the minutes of this meeting are published here.
High-coverage genome sequencing of Yayoi and Jomon individuals shed light on prehistoric human population history in East Eurasian
Authors: Ishiya Koji , Mizuno Fuzuki , Gojobori Jun , Kumagai Masahiko , Taniguchi Yasuhiro , Kondo Osamu , Matsushita Masami , Matsushita Takayuki , Wang Li , Kurosaki Kunihiko , Ueda Shintaroh
Published: August 2024

The migration of prehistoric humans led to intriguing interactions and changes in cultural and genetic heritage. In Eurasia, prehistoric migration and population replacement have affected present-day humans. The available high-quality genetic evidence for prehistoric migration in eastern Eurasia, particularly in the Far East, is still limited. We succeeded in obtaining low-contaminant, high-coverage genomes from middle-Yayoi (>46-fold coverage) and Initial Jomon (>67-fold coverage) individuals from mainland Japan. This study demonstrated that the Yayoi individual exhibited a genetic profile distinct from that of the indigenous Jomon population of the Japanese archipelago, suggesting that Yayoi ancestry was connected to the peopling of the Eurasian continent. Our high-coverage genome provides interesting insights into the evolution of copy number polymorphisms related to the dietary styles of ancient Japanese people. The copy number estimates of the amylase gene for the Yayoi individual were comparable to those of present-day East Asians who have diets high in starch. This suggests that the population in the middle Yayoi period may have already adapted to high-starch diets, which may have been related to paddy rice agriculture introduced from the continent. Furthermore, the individual from the initial Jomon period showed high amylase copy numbers comparable to those from modern East Eurasia, including modern Japanese. This suggests that some Jomon people may have consumed a high-starch diet then. The high-coverage whole-genome sequence also revealed differences in the demographic backgrounds of the two ancestral populations during the Yayoi and Jomon periods. Our results shed light on the prehistorical events and origins of related migrations from Eurasia at that time and their genetic background, cultural transformations, and links to modern Japanese people.
Genetic analysis of retinal cell types reveals synaptic pathology in schizophrenia
Authors: Boudriot Emanuel , Stephan Marius , Rabe Finn , Smigielski Lukasz , Schmitt Andrea , Falkai Peter , Ziller Michael J , Rossner Moritz J , Homan Philipp , Papiol Sergi , Raabe Florian J
Published: August 2024

Importance: As an accessible part of the central nervous system, the retina provides a unique window to study pathophysiological mechanisms of brain disorders in humans. Imaging and electrophysiological studies have revealed retinal alterations across several neuropsychiatric and neurological disorders. However, it remains largely unclear whether primary disease mechanisms within the retina contribute to the observed retinal alterations and which specific retinal cell types and biological mechanisms are involved. Objective: To determine whether specific retinal cell types are affected by genomic risk for neuropsychiatric and neurological disorders and to explore the mechanisms through which genomic risk converges in these cell types. Design, Setting, and Participants: In this study, we combined findings from genome-wide association studies in schizophrenia, bipolar disorder, major depressive disorder, multiple sclerosis, Parkinson disease, Alzheimer disease, and stroke with retinal single-cell transcriptomic data sets from humans, macaques, and mice. To identify susceptible cell types, we applied MAGMA cell type enrichment analyses and performed subsequent pathway analyses. Furthermore, we translated the cellular top hit to the structural level by using retinal optical coherence tomography and genotyping data in the large population-based UK Biobank cohort (n = 36,349). Main Outcomes and Measures: Cell type-specific enrichment of genetic risk loading for neuropsychiatric and neurological disorder traits in the gene expression profiles of retinal cells. Results: Amacrine cells (interneurons within the retina) were robustly enriched in schizophrenia genetic risk across mammalian species and in different developmental stages. This enrichment was primarily driven by genes involved in synapse biology. On the structural level, higher polygenic risk for schizophrenia was associated with thinning of the ganglion cell-inner plexiform layer, which contains dendrites and synaptic connections of amacrine cells. Moreover, retinal immune cell populations were enriched in multiple sclerosis genetic risk. No consistent cell type associations were found for bipolar disorder, major depressive disorder, Parkinson and Alzheimer disease, or stroke. Conclusions and Relevance: This study provides novel insights into the cellular underpinnings of retinal alterations in neuropsychiatric and neurological disorders and highlights the retina as a potential proxy to study synaptic pathology in schizophrenia.
Associations between oral microbiota pathogens and elevated depressive and anxiety symptoms in men
Authors: Kerff Fannie , Pasco Julie A , Williams Lana J , Jacka Felice N , Loughman Amy , Dawson Samantha L
Published: August 2024

Background

Systemic inflammation has been associated with depression. Certain oral bacterial species contribute to extra oral inflammation, however their potential association with mental disorders remains unclear. This study investigated the associations between oral microbiota pathogens and depressive and anxiety symptoms.

Methods

Data came from 436 men from the Geelong Osteoporosis Study. Using 16S rRNA gene sequencing, we characterized the oral microbiota composition and created a composite variable representing the prevalence of known oral pathogens,Porphyromonas gingivalis,Treponema denticola,Fusobacterium nucleatum, andPrevotella nigrescens. Binary variables were created representing elevated depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale. Associations between oral pathogens and elevated depressive/anxiety symptoms were analyzed using logistic regression adjusted for confounders (age, socio-economic status, diet, smoking, alcohol, exercise, obesity and hypertension).

Results

We found limited evidence for an association between the pathogen composite and elevated depressive (N = 39) but not anxiety (N = 66) symptoms. Moreover, some of the comprising species,P. nigrescens(OR 1.61 (95% CI 1.21, 2.13)) andF. nucleatum (subsp. animalis ATCC 51191(1.54 (1.13, 2.11)),subsp. animalis(1.47 (1.05, 2.08)) andsubsp. vincentii(1.47 (1.06, 2.04))) were associated with elevated depressive symptoms. Exploratory analyses revealed several other taxa associated with depression and anxiety.

Limitations

This study focuses on mental health symptoms and not diagnoses in men, and the results may not be generalizable to women.

Conclusions

We identified several taxa within the oral microbiota that were associated with depressive and anxiety symptoms. Further replication and mechanistic studies are needed.

Highlights

A composite of oral pathogens is associated with depressive symptoms in adult men

Associations betweenP. nigrescens and other species and elevated depressive symptoms

Associations remain following adjustment for confounders

Oral microbial diversity was not associated with depressive or anxiety symptoms

Fewer associations between oral microbial composition and anxiety than depression
Characteristics of human donor lungs utilized for research
Authors: Shankar Nishanth R , Garnica Lorena , Stahlschmidt Emily , Byers Derek , Kulkarni Hrishikesh
Published: August 2024

Introduction

Many fundamental discoveries have occurred using primary cells from deceased donor lungs. These cells respond differently to injury when there are underlying co-morbidities like diabetes mellitus, hypertension, aging and exposures to cigarette smoke, cocaine and chronic alcohol use. However, the prevalence of these characteristics in donor lungs utilized for research is currently unknown.

Methods

This retrospective cohort study procured data of lung transplant donors from Mid-America Transplant from January 2017 until July 2023. The donors were characterized based on lung utilization into three groups - lungs used for research, lungs used for transplant, and lungs not recovered from donors for either research or transplantation.

Results

The mean age of donors whose lungs were utilized for research was 41±18 years. 25% of them were expanded criteria donors (ECD) while 10% of the donors in the transplant cohort were ECD. 14% of the donors whose lungs were utilized for research had history of diabetes compared to 8% of donors whose lungs were transplanted. A quarter of the research donor population had positive history of cigarette use within the preceding 20 years. At least 40% of donors had a positive history of non-intravenous drug use, of whom a majority had a history of continued non-intravenous drug use.

Conclusions

No strict selection criteria or protocols exist when human donor lungs are obtained for ex-vivo research. There is a high prevalence of diabetes mellitus, history of smoking and non-intravenous drug use along with older age distribution in donors whose lungs used are for research.
Regulatory Roles of Long Non-Coding RNAs in Arterial Stiffness and Hypertension: Insights from Two African American Studies
Authors: Vargas Jose D. , Abbas Malak , Goodney Gabriel , Gaye Amadou
Published: August 2024

Background

Arterial stiffness, commonly assessed via pulse wave velocity (PWV), is marked by reduced arterial elasticity and serves as a significant risk factor for cardiovascular disease and an early indicator of hypertension. This study investigated the regulatory roles of long non-coding RNAs (lncRNAs) in modulating mRNAs associated with arterial stiffness and hypertension, with a particular focus on African Americans, a population disproportionately impacted by hypertension.

Methods

We utilized whole-blood transcriptome sequencing data from two African American (AA) cohorts with high hypertension prevalence: the GENE-FORECAST study (436 subjects) and the MH-GRID study (179 subjects). Our objectives were to: (1) identify lncRNAs and mRNAs differentially expressed (DE) between the upper and lower tertiles of PWV, (2) determine DE lncRNAs associated with the expression levels of each DE mRNA, and (3) link the lncRNA-modulated mRNAs to hypertension across both datasets.

Results

Differential expression analysis revealed 1,035 DE mRNAs and 31 DE lncRNAs between upper and lower PWV groups. Then lncRNA-mRNA pairs significantly associated were identified, involving 31 unique lncRNAs and 1,034 unique mRNAs. Finally, 22 of the lncRNA-modulated mRNAs initially linked to PWV were found associated with hypertension, in both datasets. Interestingly, 30 lncRNAs were linked to the expression of UCP2 (Uncoupling Protein 2), a gene implicated in oxidative stress and endothelial function.

Conclusions

Our findings underscore the significant roles of lncRNAs in regulating gene expression associated with arterial stiffness and hypertension. The differential expression of UCP2 in relation to PWV and hypertension, along with its potential regulation by lncRNAs, offers valuable insights into the molecular mechanisms underlying arterial stiffness and its connection with hypertension.
3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility
Authors: Trang Khanh B. , Sharma Prabhat , Cook Laura , Mount Zachary , Thomas Rajan M. , Kulkarni Nikhil N. , Pahl Matthew C. , Pippin James A. , Su Chun , Kaestner Klaus H. , O’Brien Joan M. , Wagley Yadav , Hankenson Kurt D. , Jermusyk Ashley , Hoskins Jason W. , Amundadottir Laufey T. , Xu Mai , Brown Kevin M. , Anderson Stewart A. , Yang Wenli , Titchenell Paul M. , Seale Patrick , Zemel Babette S. , Chesi Alessandra , Romberg Neil , Levings Megan K. , Grant Struan F.A. , Wells Andrew D.
Published: August 2024

A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of genecis-regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by thesecis-regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by theFDFT1gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of genecis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.
Estimating ECG Intervals from Lead-I Alone: External Validation of Supervised Models
Authors: Alam Ridwan , Stultz Collin M.
Published: August 2024

The diagnosis, prognosis, and treatment of a number of cardiovascular disorders rely on ECG interval measurements, including the PR, QRS, and QT intervals. These quantities are measured from the 12-lead ECG, either manually or using automated algorithms, which are readily available in clinical settings. A number of wearable devices, however, can acquire the lead-I ECG in an outpatient setting, thereby raising the potential for out-of-hospital monitoring for disorders that involve clinically significant changes in ECG intervals. In this work, we therefore developed a series of deep learning models for estimating the PR, QRS, and QT intervals using lead-I ECG. From a corpus of 4.2 million ECGs from patients at the Massachusetts General Hospital, we train and validate each of the models. At internal holdout validation, we achieve mean absolute errors (MAE) of 6.3 ms for QRS durations and 11.9 ms for QT intervals, and an MAE of 9.2 ms for estimating PR intervals. Moreover, as a well-defined P-wave does not always exist in ECG tracings – for example, when there is atrial fibrillation – we trained a model that can identify when there is a P-wave, and consequently, a measurable PR interval. We validate our models on three large external healthcare datasets without any finetuning or retraining - 3.2 million ECG from the Brigham and Women’s Hospital, 668 thousand from MIMIC-IV, and 20 thousand from PTB-XL - and achieve similar performance. Also, our models significantly outperform two publicly available baseline algorithms. This work demonstrates that ECG intervals can be tracked from only lead-I ECG using deep learning, and highlights the potential for out-of-hospital applications.
Cannabidiol for treatment of Irritability and Aggressive Behavior in Children and Adolescents with ASD: Background and Methods of the CAnnabidiol Study in Children with Autism Spectrum DisordEr (CASCADE) Study
Authors: Sannar Elise M. , Winter Joan R. , Franke Ronda K. , Werner Emily , Rochowiak Rebecca , Romani Patrick W. , Miller Owen S. , Bainbridge Jacquelyn L. , Enabulele Obehi , Thompson Talia , Natvig Crystal , Mikulich-Gilbertson Susan K. , Tartaglia Nicole R.
Published: August 2024

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder commonly associated with behavioral challenges. There are few evidence based pharmacological interventions available for the treatment of behavioral symptoms associated with ASD. Cannabidiol (CBD), the non-psychoactive component of cannabis, has potential neuroprotective, antiepileptic, anxiolytic, and antipsychotic effects and may be useful in treating the behavioral symptoms of ASD.

Methods

We describe the research methods of a 27-week double-blind placebo-controlled cross-over trial of cannabidiol for the treatment of irritability and aggression associated with ASD, utilizing the irritability subscale of the Aberrant Behavior Checklist-2nd edition (ABC-2) as the primary outcome measure. Adverse effects and safety monitoring protocols are included. Several secondary and exploratory outcomes measures also include anxiety, communication, repetitive behaviors, attention, hyperactivity, autism family experience, and telehealth functional behavior assessment.

Conclusion

There is a significant need for clinical research exploring alternative medications for the treatment of behavioral symptoms of ASD. Cannabidiol (CBD) is being studied for the management of irritability, aggression, and other problem behaviors associated with ASD.
Comparison of ChatGPT and Gemini as sources of references in otorhinolaryngology
Authors: Jędrzejczak W. Wiktor , Pastucha Małgorzata , Skarżyński Henryk , Kochanek Krzysztof
Published: August 2024

Introduction

An effective way of testing chatbots is to ask them for references since such items can be easily verified. The purpose of this study was to compare the ability of ChatGPT-4 and Gemini Advanced to select accurate references on common topics in otorhinolaryngology.

Methods

ChatGPT-4 and Gemini Advanced were asked to provide references on 25 topics within the otorhinolaryngology category of Web of Science. Within each topic, we set as target the most cited papers which had “guidelines” in the title. The chatbot responses were collected on three consecutive days to take into account possible variability. The accuracy and reliability of the provided references were evaluated.

Results

Across the three days, the accuracy of ChatGPT-4 was 29–45% while that of Gemini Advanced was 10–17%. Common errors included false author names, false DOI numbers, and incomplete information. Lower percentage errors were associated with higher number of citations.

Conclusions

Both chatbots performed poorly in finding references, although ChatGPT-4 provided higher accuracy than Gemini Advanced.
Urinary multi-omics reveal non-invasive diagnostic biomarkers in clear cell renal cell carcinoma
Authors: Jonsson Gustav , Hofmann Maura , Oliveira Tiago , Lemberger Ursula , Stejskal Karel , Krššáková Gabriela , Sakic Irma , Novatchkova Maria , Mereiter Stefan , Grabmann Gerlinde , Köcher Thomas , Kikic Zeljko , Rechberger Gerald N. , Züllig Thomas , Englinger Bernhard , Schmidinger Manuela , Penninger Josef M.
Published: August 2024

Clear cell renal cell carcinoma (ccRCC) is the kidney malignancy with the highest incidence and mortality rates. Despite the high patient burden, there are no biomarkers for rapid diagnosis and public health surveillance. Urine would be an ideal source of ccRCC biomarkers due to the low invasiveness, easy accessibility, and the kidney’s intrinsic role in filtering urine. In the present work, by combining proteomics, lipidomics and metabolomics, we detected urogenital metabolic dysregulation in ccRCC patients with increased lipid metabolism, altered mitochondrial respiration signatures and increased urinary lipid content. Importantly, we identify three early-stage diagnostic biomarkers for ccRCC in urine samples: Serum amyloid A1 (SAA1), Haptoglobin (HP) and Lipocalin 15 (LCN15). We further implemented a parallel reaction monitoring mass spectrometry protocol for rapid and sensitive detection of SAA1, HP and LCN15 and combined all three proteins into a diagnostic UrineScore. In our discovery cohort, this score had a performance accuracy of 96% in receiver operating characteristic curve (ROC) analysis for classification of ccRCC versus control cases. Our data identifies tractable and highly efficacious urinary biomarkers for ccRCC diagnosis and serve as a first step towards the development of more rapid and accessible urinary diagnostic platforms.
Genome-wide Association Study of Rice Vegetative Biomass under Different Inorganic Nitrogen Forms — Ammonium or Nitrate
Authors: Kasemsap Pornpipat , Cohen Itay , Bloom Arnold J.
Published: August 2024

Rice is the most important source of daily calories in human diets and second only to wheat as the most important protein source. Rice is generally exposed to high ammonium (NH4+) levels in the rhizosphere but may employ both NH4+and nitrification-derived nitrate (NO3-) as major sources of nitrogen. However, the genetic basis underlying rice adaptation to different nitrogen forms remains poorly characterized. Here, we assessed biomass under either NH4+or NO3-as a sole nitrogen source in 390 accessions from the USDA Rice Diversity Panel 1. Rice effectively used either form of nitrogen to support early growth. Tolerance to a high-NH4+exposure was correlated with biomass under NO3-and lower NH4+levels. Both genotype and nitrogen source strongly influenced biomass accumulation and partitioning between shoot and root. Root showed the greatest biomass variability and sensitivity to nitrogen source. Genome-wide analyses identified 176 single nucleotide polymorphism (SNP) markers associated with biomass across the full diversity panel and individual populations. The majority of the associations were unique to the individual nitrogen source. We compiled a list of candidate genes, including putative genes involved in nitrogen metabolism, located within 150 kb of 112 most significant SNPs, each with at least 3 adjacent markers detected under the same combination of population and nitrogen source. A flexible consumer, rice may employ distinct genetic mechanisms to use different nitrogen sources, making the species more resilient to fluctuations in soil nitrogen. These insights can guide matching rice genotypes with fertilizer management to improve nitrogen-use efficiency.
A conserved regulation of cell expansion underlies notochord mechanics, spine morphogenesis, and endochondral bone lengthening
Authors: Voigt Brittney , Frazier Katherine , Yazdi Donya , Gontarz Paul , Zhang Bo , Sepich Diane S. , Solnica-Krezel Lilianna , Gray Ryan S.
Published: August 2024

Cell size is a key contributor to tissue morphogenesis1. As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10-20 times in size to drive lengthening of endochondral bone2,3. Similarly, notochordal cells expand to one of the largest cell types in the developing embryo to drive axial extension4–6. In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion7. When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition resulting in adult spines with misshapen vertebral bones and scoliosis8. However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5’-inositol phosphatase gene,inppl1a, regulates notochord expansion, spine morphogenesis, and endochondral bone lengthening in zebrafish. Furthermore, we show thatinppl1aregulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate thatinppl1a-dependent notochord expansion is essential to establish normal mechanical properties of the notochord to facilitate the development of a straight spine. Finally, we find thatinppl1ais also important for endochondral bone lengthening in fish, as has been shown in the humanINPPL1-related endochondral bone disorder, Opsismodysplasia9. Overall, this work reveals a conserved mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.
Serotonin neuromodulation directs optic nerve regeneration
Authors: Saied-Santiago Kristian , Baxter Melissa , Mathiaparanam Jaffna , Granato Michael
Published: August 2024

Optic nerve (ON) regeneration in mammalian systems is limited by an overshadowing dominance of inhibitory factors. This has severely hampered the identification of pro- regenerative pathways. Here, we take advantage of the regenerative capacity of larval zebrafish to identify pathways that promote ON regeneration. From a small molecule screen, we identified modulators of serotonin (5-HT) signaling that inhibit ON regeneration. We find several serotonin type-1 receptor genes are expressed in RGC neurons during regeneration and that inhibiting 5- HT1 receptors or components of the 5-HT pathway selectively impedes ON regeneration. We show that 5-HT1 receptor signaling is dispensable during ON development yet is critical for regenerating axons to emerge from the injury site. Blocking 5-HT receptors once ON axons have crossed the chiasm does not inhibit regeneration, suggesting a selective role for 5-HT receptor signaling early during ON regeneration. Finally, we show that agonist-mediated activation of 5-HT1 receptors leads to enhanced and ectopic axonal regrowth. Combined, our results provide evidence for mechanisms through which serotonin-dependent neuromodulation directs ON regeneration in vivo.

Summary Statement

5-HT1 receptors selectively promote early optic nerve regrowth in zebrafish but are dispensable during development. Serotonin receptor-dependent modulation instructs regenerating optic nerve axons toward the brain in vivo.
Stochastic Character Mapping of Continuous Traits on Phylogenies
Authors: Martin B. S. , Weber M. G.
Published: August 2024

Abstract

Living and fossilized organisms represent only a tiny fraction of Earth’s evolutionary history, motivating “ancestral state reconstruction” techniques that aim to infer the unobserved phenotypes of evolving lineages based on measurements of their relatives. Stochastic character mapping (“simmapping”) methods perform ancestral state reconstruction by randomly sampling maps (“simmaps”) of probable phenotypic evolutionary histories along phylogenies, allowing researchers to conveniently and flexibly analyze macroevolutionary patterns and processes while accounting for the inherent uncertainty of ancestral state estimates. Here, we introduce a flexible and efficient algorithm for simmapping continuous phenotypes evolving under Brownian Motion models, which we term continuous simmaps or “contsimmaps”, thereby generalizing existing simmapping methods which only work with discrete phenotypes. To demonstrate potential applications of contsimmaps, we develop a pipeline that uses contsimmaps to test for associations between rates of continuous trait evolution and continuously-varying factors (e.g., generation time, climatic niche)–a difficult statistical problem for which few methods are currently available. Through an extensive simulation study, we show that this novel pipeline can accurately and robustly infer factor-rate relationships from phylogenetic comparative data, albeit with low power under certain conditions. Lastly, we apply this pipeline to an empirical dataset, showing that rates of leaf and flower trait evolution are highly variable yet unrelated to height in a clade of eucalyptus trees spanning roughly 1 to 100 meters in maximum height. Ultimately, contsimmaps provide a valuable new tool for macroevolutionary biology by allowing researchers to more flexibly analyze the evolutionary dynamics of continuous phenotypes and test complex evolutionary hypotheses involving continuous variables.
Real-time identification of carbapenemase-producingKlebsiella pneumoniaelineages and outbreak detection using FT-IR ATR
Authors: Gonçalves Ana Beatriz , Alves Valquíria , Neves Isabel , Read Maria Antónia , Pinheiro Natália , Henius Anna Emilie , Hasman Henrik , Peixe Luísa , Novais Ângela
Published: August 2024

Expansion of carbapenemase-producingKlebsiella pneumoniae(CP-Kp) is driven by nosocomial dissemination, and effective infection control depends on timely and reliable typing data. Here, we evaluated our previously developed Fourier-transform infrared spectroscopy (FT-IR) with attenuated total reflectance (ATR) workflow for real-time typing ofKpcapsular (KL)-types and lineages to support infection control. FT-IR spectra were acquired from Columbia agar with 5% sheep blood cultures of all CP-Kpinfection isolates (n=136) from hospitalized patients at a northern Portugal hospital (April 2022 – March 2023), and analyzed using automated machine-learning (ML) classification models. Typing results were confirmed bywzisequencing, MLST and/or WGS. FT-IR typing on Columbia agar plates showed 73% sensitivity, 79% specificity and 74% accuracy. Our method correctly typed 94% of typeable isolates (78/83), from which 87% were comunicated in <24h. Sixty percent of non-typeable isolates were considered false negatives, but the majority (66%) was correctly predicted when re-tested in Mueller-Hinton agar, improving sensitivity (92%), specificity (76%) and accuracy (89%) ofKptyping. ThreeKplineages (ST147-KL64, ST15-KL19, ST268-KL20) represented 74% of the sample, with ST268-KL20 causing an outbreak in Neonatal Intensive Care unit, quickly recognized by FT-IR enabling immediate infection control measures. Epidemiological links between patiens were mostly found on medical, surgical and urology units, using EpiLinx software. Most isolates (98%) produced KPC-3. Our FT-IR ATR ML-based typing workflow demonstrated high performance standards in real-time and high adaptability to clonal dynamics. The unprecedent time-to-response (same day of species identification) represents an opportunity to implement timely and effective infection control measures.

Importance

This study represents the first prospective and real-time evaluation of FT-IR spectroscopy to type multidrug resistantKlebsiella pneumoniaeto support surveillance and infection control. We demonstrate a high sensitivity, specificity and accuracy of a previously developed workflow that allows precise identification ofK. pneumoniaelineages. The adaptability to changes in clonal dynamics and bacterial typing in <24h offer significant advantages in both high- and low-income countries for a timely infection control and improvement of antimicrobial resistance management.
Bovine highly pathogenic avian influenza virus stability and inactivation in the milk byproduct lactose
Authors: Kwon Taeyong , Gebhardt Jordan T. , Lyoo Eu Lim , Nooruzzaman Mohammed , Gaudreault Natasha N. , Morozov Igor , Diel Diego G. , Richt Juergen A.
Published: August 2024

A bovine isolate of highly pathogenic avian influenza H5N1 virus was stable for 14 days in a concentrated lactose solution at under refrigerated conditions. Heat or citric acid treatments successfully inactivated viruses in lactose. This study highlights the persistence of HPAIV in lactose and its efficient inactivation under industrial standards.
Arp2/3 iso-complexes limit t-tubule overgrowth to ensure myofiber formation and synchronous contraction
Authors: Pereira Ana Raquel , Soares Ana da Rosa , Liu Tianyang , Ferreira Josie Liane , Leal Graciano , Faleiro Inês , Kogata Naoko , Way Michael , Moores Carolyn A. , Gomes Edgar R.
Published: August 2024

T-tubules are long plasma membrane invaginations that form contact sites with two adjacent endoplasmic reticulum compartments to generate a skeletal muscle triad. Although the importance of t-tubules is well established, and abnormalities are found in multiple muscle disorders, the mechanisms of t-tubule growth are currently unknown. We found that the branched actin nucleator Arp2/3 regulates t-tubule organisation in myofibers. Cortical actin limits t-tubule growth, suggesting that it must be locally disassembled to allow the t-tubule to grow. T-tubule overgrowth is limited by Arpc5-containing Arp2/3 iso-complexes, but not those containing Arpc5L. Loss of Arpc5 results in malformed t-tubule clusters, impaired triads, and asynchronous muscle contraction, as found in multiple muscle disorders. Therefore, limiting t-tubule overgrowth has a role in triad formation and myofiber contraction, providing a possible pathophysiological mechanism for these muscle disorders.

Graphical abstract
Pharmacological GCase Activity Enhancement Inhibits Tau Accumulation
Authors: Ciccaldo Matteo , Pérez-Carmona Natàlia , Piovesana Ester , Cano-Crespo Sara , Ruano Ana , Delgado Aida , Fregno Ilaria , Guzmán Beatriz Calvo-Flores , Bellotto Manolo , Molinari Maurizio , Taylor Joanne , Papin Stéphanie , García-Collazo Ana María , Paganetti Paolo
Published: August 2024

A slow decline in the autophagy-lysosomal pathway is a hallmark of the normal aging brain. Yet, an acceleration of this cellular function may propel neurodegenerative events. In fact, mutations in genes associated with the autophagy-lysosomal pathway can lead to Parkinson’s disease. Also, amyloidogenic protein deposition is observed in lysosomal storage disorders, which are caused by genetic mutations representing risk factors for Parkinson’s disease. For example, Gaucher’s diseaseGBA1mutations leading to defects in lysosomal sphingolipid metabolism cause α-synuclein accumulation. We observed that increased lysosomal Tau accumulation is found in human dermal fibroblasts engineered for inducible Tau expression. Inhibition of theGBA1product GCase augmented Tau-dependent lysosomal stress and Tau accumulation. Here, we show increased Tau seed-induced Tau accumulation in Gaucher’s fibroblasts carryingGBA1mutations when compared to normal fibroblasts. Pharmacological enhancement of GCase reversed this effect, notably, also in normal fibroblasts. This suggests that boosting GCase activity may represent a therapeutic strategy to slow down aging-dependent lysosomal deficits and brain protein deposition.