bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebellar contribution to emotion regulation and its association with medial frontal GABA level
Authors: Oboshi Yumi , Iwabuchi Toshiki , Takata Yohei , Bunai Tomoyasu , Ouchi Yasuomi
Published: December 2024

As a tactic to regulate emotions, distancing involves changing perspectives to alter the psychological distance from stimuli that elicit emotional reactions. Using magnetic resonance spectroscopy and functional magnetic resonance imaging, this study aimed to examine (i) whether the neural correlates of emotion upregulation via distancing differ across emotional valence (i.e. emotional responses toward positive and negative pictures), and (ii) whether the gamma-aminobutyric acid (GABA) concentration in the medial prefrontal cortex (MPFC), one of the crucial areas of emotion regulation, is correlated with brain activity related to either negative or positive emotion upregulation. Thirty-four healthy Japanese adults participated in this study. Compared to the condition involving positive emotion upregulation, negative emotion upregulation induced increased activation in the MPFC, left temporoparietal junction, bilateral anterior insula, pre-supplementary motor area, and bilateral cerebellum. In contrast, when comparing positive emotion upregulation with negative emotion upregulation, no significant activation was found. Right cerebellar activity during negative emotion upregulation was positively correlated with GABA concentration in the MPFC. These findings provide evidence of cerebellar involvement in the upregulation of negative emotion via distancing and its association with the prefrontal GABA concentration.
A Single Tube RPA/Cas12a Based Diagnostic Assay for Early, Rapid and Efficient Detection of Botrytis cinerea in Sweet Cherry
Authors: Hussain Rafakat , Zhao Bingyu , Aarti Aarti , Yin Weixiao , Luo Chaoxi
Published: December 2024

The fungus Botrytis cinerea is a devastating plant pathogen that causes gray mold rot in many fruits and vegetables, leading to substantial losses globally. The pathogen induces a broad range of symptoms, making it challenging to differentiate from other pathogens, especially when plants exhibit no symptoms during visual inspection. Therefore, an efficient early warning and rapid detection system is crucial for surveillance and monitoring plant health, as well as for quantitative pathogen risk assessment to reduce microbial risks. In this study, we developed a single-tube detection method for B. cinerea based on RPA/Cas12a (Bc-RPA/Cas12a), which can be performed under field conditions and visualized using mini-UV light and ordinary mobile phone light within 45 minutes at a constant temperature. The Bc-RPA/Cas12a assay can detect B. cinerea without cross-reactivity with other pathogens and without compromising sensitivity. The universality of the Bc-RPA/Cas12a assay was demonstrated through its adaptability across different geographical regions of China. Furthermore, field simulation assays revealed that fruits inoculated with the target pathogen showed fluorescence, while fruits inoculated with non-targeted pathogens and double-distilled water (ddH2O) did not exhibit fluorescence. The findings suggest that this assay can be applied directly in field conditions for rapid and accurate detection of B. cinerea without the need for specialized equipment.
Temporomandibular joint in patients with rheumatoid arthritis
Authors: Khalayli Naram , Hajali Diaa , Ataya Jawdat , Kudsi Mayssoun , Alkhouri Issam M.
Published: December 2024

Introduction:

Our study aimed to evaluate temporomandibular joint involvement in rheumatoid arthritis (RA) patients and healthy individuals

Methods:

142 participants were recruited in two groups: 72 patients with RA and 70 healthy controls. All participants were tested for seropositivity of rheumatoid factor and anticitrullinated protein antibodies. TMD diagnosis was determined according to the standardized and validated diagnostic criteria for TMD (DC/TMD): myalgia, arthralgia, articular disc, displacement, degenerative joint disease, and headache attributed to TMD. Bruxism, a probable sleep and/or awake bruxism diagnosis was determined based on self-report and several clinical findings.

Results:

The prevalence of TMD was 44.44% in RA patients and 34.28% in the control group (P < 0.005). TMD-pain diagnosis presented either as myalgia, arthralgia, or both and for those who are having a degenerative joint disease. Within the RA group, seronegative patients had a TMD-pain diagnosis significantly more often than seropositive patients (P = 0.048).75% of participants used analgesics, especially paracetamol, during the last 24 h, without differences between participants with TMD-pain diagnosis or without (P = 0.759). No difference was found between the groups in maximum mouth opening, protrusion, and laterotrusion. There was reported no difference in probable sleep bruxism diagnosis between participants with TMD diagnosis and those without (P = 0.223).

Conclusion:

The prevalence of TMD pain is increased in seronegative RA patients and is associated with bruxism signs and symptoms. Health professionals should be alert to TMD pain in RA patients.
Robotic surgery: augmenting surgeons’ skills or replacing them?
Authors: Imran Hamza , Shuja Muhammad Hamza , Abid Mishal , Khemane Zoya , Haque Md Ariful , Abbasi Abeera Farooq
Published: December 2024

As a cutting-edge medical innovation, robotic surgery combines sophisticated robotics and engineering with minimally invasive techniques. Systems like the da Vinci Surgical System resulted from substantial advancements since NASA and defense agencies began investigating remote surgical systems. Robotic surgery improves surgical precision in complicated procedures and addresses problems like hand tremors. It is well-known for its accuracy, efficiency, and better patient outcomes. Intuitive Surgical’s da Vinci system has emerged as the industry leader in robotic-assisted surgery with its advancements in imaging quality, number of arms, and interfaces. The application of robotic surgery is growing across a range of specializations despite obstacles, including high costs and lengthy training programs. Artificial intelligence and haptic feedback systems will probably lead to further improvements in this field. Future developments, particularly in AI integration and haptic feedback, promise to enhance surgical precision and efficiency further, making procedures safer and less invasive.
Incarcerated at Birth
Authors: Martin Bailey E. , Bates Randi , Kelleher Kelly , Boch Samantha
Published: December 2024

Purpose: To conduct an integrative review of extant literature on prison nursery programs in the United States. Background: About 4-10% of U.S. women entering prison are pregnant. In response, several state prisons have developed nurseries to promote maternal-infant outcomes and reduce recidivism. Unfortunately, little is known about the current state of the science related to prison nurseries. Methods: Guided by Whittemore and Knafl’s methodology, a literature search was conducted in June 2023 for peer-reviewed articles using PubMed, CINAHL, MedLINE, SCOPUS, PsycINFO, socINDEX, and Academic Search Complete. Broad keywords were used (“prison” or “incarceration” or “inmate”) and (“nursery” or “nursery residential center”). Included articles were U.S.-based, peer-reviewed, and specific to prison nurseries. Results: The search yielded 216 articles, 10 of which were included for final review and synthesis. Using the Johns Hopkins Evidence Level and Quality Guide, the level of evidence ranged from low to moderate. Themes include (1) benefits to maternal-child attachment and bonding, (2) institutional barriers and challenges to maternal-child attachment and bonding and (3) beneficial maternal justice and custodial outcomes. Conclusions: Prison nurseries are a promising intervention to promote mother-infant outcomes. These programs promote positive maternal-infant attachment and bonding, help mothers maintain custody of their children, and reduce recidivism. Implications for Practice: There is a need to standardize nursery program characteristics to maximize benefits and promote equity. Better investment in longitudinal, quasi-experimental, and qualitative research is needed.
Transition to Practice
Authors: Tan Vicki , Lavoie-Tremblay Mélanie
Published: December 2024

Throughout existing transition programs for new nurses, few appear to include the participation of nurse managers in its activities. This qualitative study explores the perceptions of newly graduated nurses (N = 7) toward the participation of their nurse manager in a transition program through dedicated group discussion periods. Four interconnected themes emerged from the interviews. Our findings support the inclusion of this participation in transition programs by nurse leaders to improve the transition experience of new nurses.
Area Deprivation and Patient Complexity Predict Low-Value Health Care Utilization in Persons With Heart Failure
Authors: Ledwin Kathryn M. , Casucci Sabrina , Sullivan Suzanne S. , Hewner Sharon
Published: December 2024

Background

Heart failure is a debilitating condition affecting over 6.7 million adults in the United States. Social risks and complexity, or personal, social, and clinical aspects of persons’ experiences, have been found to influence health care utilization and hospitalizations in persons with HF. Low-value utilization, or irregular outpatient visits with frequent emergency room use, or hospitalization is common among persons with complex conditions and social risk and requires further investigation in the heart failure population.

Objective

The purpose of this research was to assess the influence of complexity and social risk on low-value utilization in persons with heart failure using machine learning approaches.

Methods

Supervised machine learning, tree-based predictive modeling was conducted on an existing data set of adults with heart failure in the eight-county region of Western New York for the year 2022. Decision tree and random forest models were validated using a 70/30 training/testing data set and k-fold cross-validation. The models were compared for accuracy and interpretability using the area under the curve, Matthew’s correlation coefficient, sensitivity, specificity, precision, and negative predictive value.

Results

Area deprivation index, a proxy for social risk, number of chronic conditions, age, and substance use disorders were predictors of low-value utilization in both the decision tree and random forest models. The decision tree model performed moderately, while the random forest model performed excellently and added hardship as an additional important variable.

Discussion

This is the first known study to look at the outcome of low-value utilization, targeting individuals who are underutilizing outpatient services. The random forest model performed better than the decision tree; however, features were similar in both models, with area deprivation index as the key variable in predicting low-value utilization. The decision tree was able to produce specific cutoff points, making it more interpretable and useful for clinical application. Both models can be used to create clinical tools for identifying and targeting individuals for intervention and follow-up.
Nuclear Medicine Cerebral Perfusion Studies as an Ancillary Test to Support Evaluation of Brain Death/Death by Neurologic Criteria: Single-Center Experience in Infants, 2005–2022*
Authors: Bach Ashley M. , McKinnon Nicole K. , Zhuang Hongming , Kaufman Elizabeth , Kirschen Matthew P.
Published: December 2024

OBJECTIVE:

To describe the use of nuclear medicine cerebral perfusion studies as an ancillary test for brain death/death by neurologic criteria (BD/DNC) in infants aged under 1 year.

DESIGN:

Retrospective case series.

SETTING:

Single-center, quaternary, academic children’s hospital in the United States.

PATIENTS:

Patients younger than 1 year of age whose evaluation for BD/DNC included a nuclear medicine cerebral perfusion study as an ancillary test, 2005–2022.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Ten infants were identified from local databases. Mechanisms of brain injury included hypoxic-ischemic injury (8/10), traumatic brain injury (1/10), and intracranial hemorrhage (1/10). Testable components of the first BD/DNC examination were consistent with BD/DNC in all patients. Apnea testing was consistent with BD/DNC in 5 of 10 patients and deferred or terminated prematurely in 5 of 10 patients. All patients underwent ancillary testing with a nuclear medicine scan to assess cerebral perfusion using 99mTc-ethyl cysteinate dimer (99mTc-ECD). Indications were inability to complete the apnea test (5/10), presence of a confounder to the clinical examination (3/10), and clinician discretion (2/10). Nine studies were consistent with BD/DNC. The patient whose ancillary test was inconsistent with BD/DNC had their examination limited by the inability to assess the pupillary reflex and subsequently underwent withdrawal of life-sustaining technology.

CONCLUSIONS:

Radionuclide cerebral perfusion studies using 99mTc-ECD were used in our setting to support the determination of BD/DNC in infants aged younger than 1 year of age.
Secretor status is a modifier of vaginal microbiota-associated preterm birth risk
Authors: Kundu Samit , dos Santos Correia Gonçalo , Lee Yun S. , Ng Sherrianne , Sykes Lynne , Chan Denise , Lewis Holly , Brown Richard G. , Kindinger Lindsay , Dell Anne , Feizi Ten , Haslam Stuart M. , Liu Yan , Marchesi Julian R. , MacIntyre David A. , Bennett Phillip R.
Published: December 2024

Mutations in the FUT2 gene that result in a lack of expression of histo-blood group antigens on secreted glycoproteins may shape the vaginal microbiota with consequences for birth outcome. To test this, we analysed the relationship between secretor status, vaginal microbiota and gestational length in an ethnically diverse cohort of 302 pregnant women, including 82 who delivered preterm. Lactobacillus gasseri and L. jensenii were found to have distinct co-occurrence patterns with other microbial taxa in non-secretors. Moreover, non-secretors with Lactobacillus spp. depleted high diversity vaginal microbiota in early pregnancy had significantly shorter gestational length than Lactobacillus spp. dominated non-secretors (mean of 241.54 days (sd=47.14) versus 266.21 (23.61); P-value=0.0251). Similar gestational length differences were observed between non-secretors with high vaginal diversity and secretors with Lactobacillus spp. dominance (mean of 262.52 days (SD=27.73); p-value=0.0439) or depletion (mean of 266.05 days (SD=20.81); p-value=0.0312). Our data highlight secretor status and blood-group antigen expression as being important mediators of vaginal microbiota–host interactions in the context of preterm birth risk.
Personalized Medicine for Meningiomas: Drug Screening on Tumor Organoids Exposes Therapeutic Vulnerabilities to HDAC1/2i Panobinostat
Authors: Jungwirth Gerhard , Cao Junguo , Lotsch Catharina , Warta Rolf , Moustafa Mahmoud , Knoll Maximilian , Yu Tao , Braun Viktor , Jassowicz Lena , Dao Trong Philip , Younsi Alexander , Scherer Moritz , Bendszus Martin , Krieg Sandro M. , von Deimling Andreas , Debus Juergen , Sahm Felix , Abdollahi Amir , Unterberg Andreas , Herold-Mende Christel
Published: December 2024

Managing aggressive meningiomas remains challenging due to limited treatment options besides surgical tumor removal and radiotherapy. To identify novel therapies for aggressive meningiomas, we established a multi-step drug screening workflow, focusing on targetable genes obtained from transcriptome data of highly aggressive grade 3 meningiomas.In vitroscreening of 107 targeted drugs identified nine effective inhibitors. To study these drugs in a more natural environment, we established a standardized patient-derived tumor organoid (TO) model preserving accurately the original tissue’s genotype and phenotype. Individual drug responses were assessed in TOs from 60 molecularly characterized meningioma cases. Especially the FDA-approved epigenetic drug panobinostat demonstrated high antimeningioma efficacy in 70% of TOs, mediated through HDAC1/2 inhibition. In addition, treatment in an orthotopicin vivomodel revealed a significantly improved survival. In a heavily pretreated patient suffering from an anaplastic meningioma, oral panobinostat treatment could delay the tumor growth rate. In search of the molecular mechanism underlying a potential intrinsic panobinostat resistance, we identified upregulation of the HDAC8-TGFβ-EMT axis in the TO model and subsequent HDAC8 depletion substantially increased the sensitivity to panobinostat. These data highlight the utility of personalized drug screenings on TOs to identify suitable drug targets and inhibitors for a more effective treatment of clinically aggressive meningiomas and help to advance our understanding of counteracting resistance mechanisms.

One Sentence Summary

This study provides strongin vitro,in vivo,ex vivo, and patient evidence for the efficacy of the HDACi panobinostat to treat clinically aggressive meningiomas and uncovered a potential intrinsic resistance mechanism by activation of the HDAC8-TGFβ-EMT axis.
DGKα and ζ Deficiency Causes Regulatory T-Cell Dysregulation, Destabilization, and Conversion to Pathogenic T-Follicular Helper Cells to Trigger IgG1-Predominant Autoimmunity
Authors: Li Lei , Huang Hongxiang , Wang Hongxia , Pan Yun , Tao Huishan , Zhang Shimeng , Karmaus Peer W.F. , Fessler Michael B. , Sleasman John W. , Zhong Xiao-Ping
Published: December 2024

Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases but also inhibit anti-tumor immunity. Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol (DAG) kinases (DGK) ( and ( are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGK( and ( derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center (GC) B-cell responses and IgG1/IgE predominant antibodies/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.
Research opportunities in precision oncology: Perspectives on biospecimen and genomic data sharing from adults with cancer in Ireland
Authors: O’Grady Shane , Ralston Jessica C. , McKiernan Eadaoin , Drummond Frances J. , Rynne Jan , Mitchell Derick , Gallagher William M. , Drury Amanda , Kolch Walter
Published: December 2024

Although surveys of people living with cancer in other nations have generally found a high degree of willingness to donate to research services such as genomic databases and biobanks, these results can vary from country to country. Additional questions also remain surrounding issues such as preferred model of consent, reporting of findings and concerns surrounding potential commercial application of health data. To address some of these gaps in our current knowledge, we collected responses from 176 people living with and beyond cancer in Ireland over a 16-month period. Twenty-eight percent of our survey respondents had previously donated a biological sample to research, with the majority indicating that they did so for altruistic reasons. We found that the vast majority of those who had not previously donated samples would do so if given the opportunity, suggesting that there is a significant untapped pool of potential sample donors, and increased efforts by researchers and clinicians to recruit these individuals, in an ethically acceptable way, could yield a substantial improvement in the availability of biological samples and data for research. There was also a strong preference among respondents for total transparency with personal health data, with the vast majority wanting to know of any risk factors identified in their genome, even if these risks were not medically actionable. A strong level of trust in both the clinical and scientific community was also observed in the responses, with most indicating that this played a major role in influencing their decision to donate. Finally, we found that although most respondents did not have issues with the involvement of a commercial entity in the donation process, there was still a sizeable percentage (26%) who did have some reservations.
Assessing an ICD-10 Code Approach for Tracking Xylazine-Involved Overdose Deaths in the United States
Authors: Friedman Joseph R.
Published: December 2024

Introduction

The national prevalence of the veterinary sedative xylazine in US overdose deaths rose between 2018 and 2021. More updated estimates are limited, partially due to the lack of a dedicated ICD-10 code—a primary mechanism used to specify drugs implicated in overdose deaths in the US, including in the CDC WONDER system, which provides public data requests with a 6-month lag. For other emerging substances lacking dedicated codes, over time umbrella codes have come tode factorepresent them, yet this has not yet been demonstrated for xylazine.

Methods

Overdose deaths in CDC WONDER involving T42.7 (“Antiepileptic and sedative-hypnotic drugs, unspecified”) or T46.5 (“Other antihypertensive drugs, not elsewhere classified”) were compared to two more specific, albeit delayed, sources: NVSS describing national trends in 2018-2021 and SUDORS describing state-level trends in 2020-2022. The CDC WONDER approach was also used to visualize trends in xylazine-involved deaths through Q1 2024 by geography, race/ethnicity, substance co-involvement, and demographic categories.

Results

At the national level, concordance between CDC WONDER records and previous NVSS estimates improved after 2019 and became highly similar in 2021 (3,480 vs 3,468 deaths). Concordance was also high for estimates stratified by race, age, and region. At the state-level, across 49 state-year pairs, correlation between CDC WONDER and SUDORS was 0.97. Xylazine-involved deaths doubled between 2021 and 2024 Q1, and racial inequalities widened.

Discussion

T42.7 or T46.5, together, may have become thede-factocoding scheme representing xylazine-involved deaths. This approach provides more up-to-date results, showing increasing prevalence and worsening racial inequalities in xylazine-involved deaths into 2024.
Household Vulnerability and Coping Amid the COVID-19 Pandemic in Bamako, Mali: Assessing Sociodemographic Factors Associated with Household Hardships
Authors: Muir Jonathan A. , Onwuchekwa Uduma U. , Madewell Zachary J. , Traore Moussa O. , Kourouma Moussa , Keiri Fatima , Cunningham Solveig A. , Kotloff Karen L , Tapia Milagritos D. , Sow Samba O
Published: December 2024

Background

COVID-19 resulted in vast disruption to life in the 21stcentury as governments implemented containment measures to quell disease spread. We assessed knowledge of local interventions and household coping strategies used to attenuate the impact of household hardships. We further examined associations between household and community characteristics with household hardships.

Methods

We conducted a cross-sectional household survey between August and September 2022 through a retrospective questionnaire fielded in the Health and Demographic Surveillance System (HDSS) operating in Bamako, Mali. Logistic regression was used to analyze associations between household characteristics, government interventions, and household hardships during the pandemic.

Results

The most commonly reported hardships were increases in food prices and food insecurity; roughly 18% of households reported experiencing at least 1 hardship. Common coping strategies included asking for help from family or friends (55.6%). Only 2.8% of households reported seeking government assistance. Households headed by younger individuals, males, and unemployed individuals were at greater risk of experiencing hardships. Government closure of businesses was strongly associated with household hardships.

Conclusions

Households in the Bamako HDSS experienced a variety of hardships during the pandemic— the most prevalent hardships were increases in local food prices and food insecurity. The association between government closure of businesses and household hardships points to the need for balancing public health measures with socioeconomic considerations. Households headed by individuals with lower education and/or unemployed were at greater risk of experiencing a hardship. Future policies and interventions should target aid to households reflecting these characteristics.
Drivers of disengagement from care during the first six months on antiretroviral therapy for HIV in South Africa: a mixed-methods study
Authors: Maskew Mhairi , Mutanda Nyasha , Scott Nancy , Morgan Allison , Benade Mariet , Ntjikelane Vinolia , Sande Linda , Malala Lufuno , Manganye Musa , Rosen Sydney
Published: December 2024

Introduction

For clients on HIV treatment in sub-Saharan Africa, disengagement from HIV care in the early treatment period is a critical obstacle to achieving UNAIDS’s second 95 target. While South Africa’s Differentiated Service Delivery Guideline on Fast Track Initiation and Counseling (FTIC) define normative procedures, the effect of guideline implementation and the underlying drivers of disengagement remain unclear.

Methods

The PREFER mixed-methods study enrolled a prospective cohort of adult clients initiating ART, returning to care after a period of disengagement or already on ART for ≤6 months at 18 public sector healthcare facilities in South Africa. A survey collected data on demographic and clinical characteristics and preferences of participants who were followed up through routinely-collected medical visit records for up to 7 months after treatment initiation to estimate continuity of HIV care (attended all scheduled visits within 28 days). Focus group discussions (FGDs) were conducted approximately 12 months after enrollment among a subset of participants who had expressed concerns about treatment retention.

Results

During the study period 7/9/2022-30/6/2023, PREFER-SA enrolled 1,049 participants (72% female, median age=33 years, 24% with CD4 count<200cells/mm3); 122 of whom also participated in focus group discussions. By 6 months on ART, 23% were not continuously in HIV care. Those newly initiating ART at study enrollment were more likely to have disengaged or interrupted treatment by 6 months as those who had remained in care for ≥1 visit. Disengagement was also more likely among men and younger (18-24 years) participants, those reporting food scarcity, and those initiated on regimens other than Dolutegravir. Disengagement did not differ by gender, relationship status, or CD4 count. Qualitative FGD results suggest participants experience barriers to adherence within and between all levels of the socio-ecologic model. Challenges related to the facility experience were most prominent.

Conclusions

Among adults initiating or re-initiating ART in South Africa, the highest risk of disengagement is immediately after initiation. We identified several potentially modifiable individual and social characteristics associated with early disengagement. Improving the patient facility experience and strengthening implementation of SA’s Service Delivery Guidelines may increase retention during the early treatment period.
FMT Restores Colonic Protein Biosynthesis and Cell Proliferation in Patients with RecurrentClostridioides difficileDisease
Authors: Moreau G. Brett , Young Mary , Behm Brian , Tanyüksel Mehmet , Ramakrishnan Girija , Petri William A.
Published: December 2024

RecurrentC. difficileinfection (CDI) is a major health threat with significant mortality and financial costs. Fecal Microbiota Transplantation (FMT) is an effective therapy, however the mechanisms by which it acts, particularly on the host, are poorly understood. Here we enrolled a prospective cohort of human patients with recurrent CDI (n=16) undergoing FMT therapy. Colonic biopsies were collected and bulk RNA sequencing was performed to compare changes in host gene expression pre- and two months post-FMT. Transcriptional profiles were significantly altered after FMT therapy, with many differentially expressed genes (∼15% of annotated genes detected). Enrichment analysis determined that these changes were reflective of increased protein production post-FMT, with enrichment of pathways such as Ribosome Biogenesis, Protein Processing, and signaling pathways (Myc, mTORc1, E2F) associated with cell proliferation and protein biosynthesis. Histology of H&E-stained biopsies identified a significant increase in colonic crypt length post-FMT, suggesting that this treatment promotes cell proliferation. Crypt length was significantly correlated with enriched Myc and mTOR signaling pathways as well as genes associated with polyamine biosynthesis, providing a potential mechanism through which this may occur. Finally, signaling pathways upstream of Myc and mTOR, notably IL-33 Signaling and EGFR ligands, were significantly upregulated, suggesting that FMT may utilize these signals to promote cell proliferation and restoration of the intestine.
Adaptive cellular evolution in the intestinal tracts of hyperdiverse African cichlid fishes
Authors: Fages Antoine , Luxey Maëva , Ronco Fabrizia , Huyghe Charlotte E.T. , Menon P. Navaneeth Krishna , Indermaur Adrian , Salzburger Walter , Tschopp Patrick
Published: December 2024

Adaptations related to how nutrients are acquired and processed play a central role in the colonization of novel ecological niches and, therefore, in organismal diversification. While the evolution of feeding structures has been studied extensively in this context, the nature of dietary adaptations in the digestive tract remains largely unexplored. Here, we investigate the cellular and molecular basis of dietary adaptations in the massive radiation of cichlid fishes in Lake Tanganyika using comprehensive single-cell transcriptomic data derived from the intestines of 24 endemic cichlid species with distinct habitats and diets. We show that, at the cellular level, dietary adaptations are primarily driven by anterior enterocytes, and that both the relative abundance and gene expression profiles of these cells have evolved in response to rapid dietary specializations. These dietary adaptations are driven by rapidly evolving cell population-specific genes, suggesting that alterations in epithelial cell specification programs and molecular makeup promote ecological diversification.
Sociodemographic Determinants of Multidrug-Resistant Tuberculosis in Lesotho: A Case-Control Study
Authors: Yahaya Jerry Yakubu
Published: December 2024

The emergence of multidrug-resistant tuberculosis (MDR-TB) poses a significant challenge to tuberculosis control efforts in Lesotho. To better understand the occurrence of MDR-TB, it is crucial to identify the sociodemographic risk factors associated with the disease. Despite the critical importance of this issue, there is a gap in the literature regarding how sociodemographic variables influence MDR-TB outcomes in Lesotho. This case-control study aimed to assess the association between age, employment, income, sex, education, and place of residence and the risk of MDR-TB. Additionally, the relationship between HIV status and MDR-TB was examined. Drawing on the health belief model and social cognitive theory, the study employed a retrospective case-control design and a proportionate stratified random sample of 306 participants from 12 TB clinics across Lesotho, collected between March 2021 and February 2022. Participants included confirmed TB patients aged 18 and above. Data analysis involved Chi-square tests and multivariate logistic regression to identify significant sociodemographic factors associated with MDR-TB. Results showed that increased age beyond 18–26 years and higher income levels (above $1,026.00) were significantly associated with reduced odds of MDR-TB (OR = 0.8, 95% CI [0.673, 0.991], p = 0.040; OR = 0.5, 95% CI [0.222, 0.943], p = 0.034). Conversely, the absence of a caregiver increased the odds of MDR-TB by 80% (OR = 1.8, 95% CI [1.039, 3.110], p = 0.036). These findings underscore the need for targeted public health interventions and education campaigns to address the role of caregivers in preventing MDR-TB transmission and to improve knowledge about infection control, particularly among younger patients. Furthermore, improving the socioeconomic conditions of TB patients, particularly those who are poor and vulnerable, is essential for reducing the risk of MDR-TB. Addressing these sociodemographic determinants can significantly enhance the effectiveness of MDR-TB control strategies in Lesotho.
Evolutionary Flexibility of Ribosome Biogenesis in Bacteria
Authors: Amikura Kazuaki , Ishii Shun’ichi , Shimizu Yoshihiro , Suzuki Shino
Published: December 2024

Ribosomes are essential for protein synthesis and require ribosome biogenesis factors (RBFs) for assembly. To uncover the evolutionary diversity of ribosome biogenesis, we analyzed over 30,000 bacterial genomes and revealed that Candidate Phyla Radiation (CPR), also known as the phylum Patescibacteria, characterized by reduced genomes and smaller ribosomes, has about half the average number of RBFs compared with non-CPR bacteria. Notably, key RBFs such as der, obgE, and rbfA, considered indispensable, are conserved in only around 20%–70% of CPR genomes. Since such repertoires were not observed in reduced genomes of other phyla, CPR presumably diverged early in bacterial evolution. We further confirmed that ribosomal structural changes correlate with reduced RBFs, evidencing co-evolution between RBFs and the ribosome. These findings suggest that ribosomal biogenesis is more flexible than recognized, and the small cell and genome sizes of CPR bacteria and their early divergence may influence the unusual repertoires of RBFs.

Teaser

Ribosome biogenesis in CPR bacteria was unexpectedly flexible, challenging traditional views of this essential process in evolution.
Influenza A virus-induced PI4P production at the endoplasmic reticulum involves ATG16L1 and promotes the egress of viral ribonucleoproteins
Authors: Alemany Carla , Graça Juliane Da , Giai-Gianetto Quentin , Paisant Sylvain , Dupont Maud , Douché Thibaut , Isel Catherine , Delevoye Cédric , Danglot Lydia , Matondo Mariette , Morel Etienne , Brault Jean-Baptiste , Naffakh Nadia
Published: December 2024

The genomic RNAs of influenza A viruses (IAVs) are replicated in the nucleus of infected cells in the form of viral ribonucleoproteins (vRNP) before being exported to the cytoplasm. The small GTPase RAB11A is involved in the transport of vRNPs to the sites of viral assembly at the plasma membrane, but the molecular mechanisms involved remain largely unknown. Here we show that IAV infection remodels the architecture of the endoplasmic reticulum (ER) sheets, where vRNPs tend to accumulate in the absence of RAB11A. To decipher the interplay between RAB11A, vRNPs and the ER, we investigated viral-induced perturbations of RAB11A proximity interactome. To this end, we generated cells stably expressing a TurboID-RAB11A fusion protein and performed biotin-based proximity labeling upon viral infection. We found that cellular regulators of phophatidylinositol-4-phosphate (PI4P) homeostasis, including the autophagic and stress response protein ATG16L1, are significantly enriched at the vicinity of RAB11A in infected cells. Infection induces an increase in cellular PI4P levels in an ATG16L1-dependent manner, while ATG16L1 relocalizes to ER membranes upon infection. Depletion of ATG16L1 decreases the co-distribution of vRNPs with PI4P punctae on ER membranes, and reduces the accumulation of vRNPs at the plasma membrane as well as the production of IAV infectious particles. Our data extend to IAVs the notion that viruses can modulate the metabolism and localization of phosphoinositides to control host membrane dynamics and point to the ER as an essential platform for vRNP transport. They provide evidence for a pivotal role of ATG16L1 in regulating the identity of endomembranes and coordinating RAB11A and PI4P-enriched membranes to ensure delivery of vRNPs to the plasma membrane.
Downregulation of O-GlcNAcylation enhances etoposide-induced p53-mediated apoptosis in HepG2 human liver cancer cells
Authors: Lee Jaehoon , Han Byung-Cheol , Koo Gi-Bang , Park Jihye , Kwon Mijin , Lee Seung-Ho
Published: December 2024

Etoposide, an anticancer drug that inhibits topoisomerase II, is commonly used in combination chemotherapy. However, the impact of O-GlcNAcylation regulation on etoposide's anticancer effects has rarely been investigated. This study evaluated the effect of etoposide on cellular O-GlcNAcylation and whether modulating this process enhances etoposide-induced apoptosis. O-GlcNAc expression was measured after 24 h of etoposide treatment, and the effect of O-GlcNAc transferase (OGT) inhibition by OSMI-1 on etoposide's anticancer activity in HepG2 human liver cancer cells was quantitatively analyzed. Additionally, molecular analyses were used to confirm that the observed effects were mediated by p53-induced apoptosis. Etoposide reduced O-GlcNAcylation in a dose-dependent manner without directly interacting with OGT. Cotreatment with 20 μM of OSMI-1 lowered the IC50 value for cell viability by approximately 1.64-fold to 60.68 μM and increased the EC50 value for cytotoxicity by around 4.07-fold to 43.41 μM. Furthermore, this synergistic effect was linked to the activation of the p53/caspase-3/PARP1 pathway. These findings suggest that downregulating O-GlcNAcylation may enhance the efficacy of etoposide-based chemotherapy and help overcome tumor resistance.
The RBR E3 ubiquitin ligase HOIL-1 can ubiquitinate diverse non-protein substratesin vitro
Authors: Wang Xiangyi S. , Jiou Jenny , Cerra Anthony , Cobbold Simon A. , Jochem Marco , Mak Ka Hin Toby , Corcilius Leo , Payne Richard J. , Goddard-Borger Ethan D. , Komander David , Lechtenberg Bernhard C.
Published: December 2024

HOIL-1 is a RING-between-RING (RBR)-family E3 ubiquitin ligase and component of the linear ubiquitin chain assembly complex (LUBAC). While most E3 ubiquitin ligases conjugate ubiquitin to protein lysine sidechains, HOIL-1 has been reported to ubiquitinate hydroxyl groups in protein serine and threonine sidechains and glucosaccharides, such as glycogen and its building block maltose,in vitro. However, HOIL-1 substrate specificity is currently poorly defined. Here we show that HOIL-1 is unable to ubiquitinate lysine but can efficiently ubiquitinate serine as well as a variety of model and physiologically relevant di- and monosaccharidesin vitro. We identify a critical catalytic histidine residue, His510, in the flexible catalytic site of HOIL-1 that enables this O-linked ubiquitination and prohibits ubiquitin discharge onto lysine sidechains. Finally, we utilise HOIL-1’sin vitronon-proteinaceous ubiquitination activity and an engineered, constitutively active HOIL-1 variant to produce preparative amounts of different ubiquitinated saccharides that can be used as tool compounds and standards in the rapidly emerging field of non-proteinaceous ubiquitination.
Role of a FAD-dependent monooxygenase in diazo group functionalisation of kinamycin inStreptomyces ambofaciens
Authors: Vicente Cláudia M , Boutilliat Alexis , Hôtel Laurence , Paris Cédric , Aigle Bertrand
Published: December 2024

Kinamycin biosynthesis is a complex process which has been extensively studied over the years, yet specific enzymatic steps continue to be unveiled. A diazo group present in the molecule is responsible for the promising antitumoral activity of kinamycins but its specific installation inStreptomyces ambofaciensis not fully understood. In this study, we explore the diazo functionalization of kinamycin in this strain. A new FAD-dependent monooxygenase is identified which is essential for kinamcyin biosynthesis. In its absence, stealthin C accumulates instead likely as a pathway shunt-product. Furthermore, as a result of the position of the gene encoding this monooxygenase, namedalp2F, we also propose new boundaries of the kinamycin biosynthetic gene cluster resulting in a large cluster spanning over 72kb. This work paves the way for the continued understanding of the biosynthetic steps that are characteristic of diazo-containing natural products, and provides new biocatalysts for molecular engineering and accelerate bioactive compounds production.
Direct Feature Identification from Raman Spectra and Precise Data-driven Classification of Phytopathogens at Single Conidium-Species Level
Authors: Xu Xinze , Cheng Zhang , Liu Wenbo , Lin Chunhua , Miao Weiguo , Yuan Heyang
Published: December 2024

Conidia can cause outbreaks of fungal plant diseases, resulting in significant losses in crop yield and economy. Traditional diagnosis of phytopathogenic conidia based on morphology and molecular biology is time-consuming, labor-intensive, and often fails to differentiate fungal conidia. To overcome these challenges, a new classification approach was developed in this study by integrating Raman spectroscopy with data-driven modeling. Eight fungal species were selected and characterized using Raman spectra. Three characteristic Raman wavenumbers at 1003 to 1005 cm-1, 1153 to 1157 cm-1, and 1515 to 1522 cm-1shared a consistent pattern across species and could be attributed to carotenoids. Clustering of the Raman spectra using principal component analysis (PCA) showed substantial overlap, indicating inaccurate classification of conidia. Three data-driven models, support vector machines (SVMs), decision trees (DTs), and eXtreme Gradient Boosting Forest (XGBoost) were trained with three categories of features (number of peaks, maximum peak, and curve roughness) identified within eight characteristic wavenumber ranges, The optimal SVM, DT, and XGBoost determined by hyperparameter tuning achieved prediction precision of 0.88, 0.88, and 0.96, respectively. PCA-XGBoost trained by feeding principal components of PCA to XGBoost achieved prediction precision of 0.94, suggesting that features extracted from the raw datasets outperformed those extracted with PCA in terms of data-driven classification. This study has demonstrated the great potential of Raman spectroscopy combined with data-driven modeling for classification of phytopathogenic conidia.
Dysregulated RNA splicing induces regeneration failure in alcohol-associated liver disease
Authors: Chembazhi Ullas V. , Bangru Sushant , Dutta Rajesh , Das Diptatanu , Peiffer Brandon , Natua Subhashis , Toohill Katelyn , Leona Aurelia , Purwar Ishita , Bhowmik Anuprova , Goyal Yogesh , Sun Zhaoli , Diehl Anna Mae , Kalsotra Auinash
Published: December 2024

Individuals with progressive liver failure are at a high risk of mortality without liver transplantation. However, our understanding of derailed regenerative responses in failing livers is limited. Here, we performed comprehensive multi-omic profiling of healthy and diseased human livers using bulk and single-nucleus RNA-plus ATAC-seq. We report that hepatic immune milieu alterations in alcohol-associated liver disease (ALD) prevent hepatocytes from transitioning to a proliferative progenitor-like state, trapping them into an unproductive intermediate state. We discovered striking changes in RNA binding protein (RBP) expression, particularly ESRP, PTBP, and SR families, that cause misregulation of developmentally controlled RNA splicing in ALD. Our data pinpoint ESRP2 as a pivotal disease-sensitive RBP and support a causal role of its deficiency in ALD pathogenesis. Notably, splicing defects in ESRP2-targetsTcf4andSlk, amongst others, directly alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways, which are critical for normal liver regeneration. We demonstrate that changes in stromal cell populations enrich failing ALD livers with TGF-β, which suppresses ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. This unprecedented account of transcriptional and post-transcriptional dysregulation in ALD suggests that targeting misspliced RNAs could improve recovery and serve as biomarkers for poor ALD outcomes.
Ultra-Efficient Integration of Gene Libraries onto Yeast Cytosolic Plasmids
Authors: Pisera Alexander (Olek) , Yu Yutong , Williams Rory L. , Liu Chang C.
Published: December 2024

Efficient methods for diversifying genes of interest (GOIs) are essential in protein engineering. For example, OrthoRep, a yeast-based orthogonal DNA replication system that achieves the rapidin vivodiversification of GOIs encoded on a cytosolic plasmid (p1), has been successfully used to drive numerous protein engineering campaigns. However, OrthoRep-based GOI evolution has almost always started from single GOI sequences, limiting the number of locations on a fitness landscape from where evolutionary search begins. Here, we present a simple approach for the high-efficiency integration of GOI libraries onto OrthoRep. By leveraging integrases, we demonstrate recombination of donor DNA onto the cytosolic p1 plasmid at exceptionally high transformation efficiencies, even surpassing the transformation efficiency of standard circular plasmids into yeast. We demonstrate our method’s utility through the straightforward construction of mock nanobody libraries encoded on OrthoRep, from which rare binders were reliably enriched. Overall, integrase-assisted manipulation of yeast cytosolic plasmids should enhance the versatility of OrthoRep in continuous evolution experiments and support the routine construction of large GOI libraries in yeast in general.
Intact messenger RNA exists in human blood plasma and urine, and their purified macromolecular compartments
Authors: Verwilt Jasper , Verniers Kimberly , De Geyter Sofie , Roelandt Sofie , Pinheiro Cláudio , Hendrix An , Mestdagh Pieter , Vandesompele Jo
Published: December 2024

It is generally assumed that extracellular long RNA molecules in biofluids are fragmented. Few studies have indirectly hinted at the existence of possibly functional, intact long RNA transcripts. In search for such RNA molecules, we developed a long-read full transcript sequencing workflow for low-input and low-quality samples. We applied our method to human blood plasma, urine, and their isolated macromolecular compartments, in parallel with total RNA sequencing. This approach enabled us to find intact messenger RNA molecules in human biofluids and macromolecular compartments. We showed that the full-length transcriptome of human urine and blood plasma differs, but we also reveal intact messenger RNA molecules shared between biofluids. In addition, we show that these intact molecules are differentially distributed over fractionated macromolecular compartments. This study provides a foundation for future extracellular RNA studies to elucidate the human biofluid full-length transcriptome.