bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuberculosis research advances and future trends: A bibliometric knowledge mapping approach
Authors: Abdelwahab Siddig Ibrahim , Taha Manal Mohamed Elhassan , Albasheer Osama , Alharbi Abdullah , Ahmed Anas A. , Abdelmola Amani , Ali Suhaila A. , El Hassan Lamyaa A.M. , Darraj Majid , Mohamed Amal H. , Yassin Abuobaida , Hakami Nasser
Published: July 2024

The Gulf Cooperation Council (GCC) countries are more vulnerable to many transmissible diseases, including tuberculosis (TB). This study is to identify the scientific publications related to TB in the GCC countries using topic modeling and co-word analysis. A bibliometric analytic study. The R-package, VOSviewer software, IBM SPPS, and Scopus Analytics were used to analyze performance, hotspots, knowledge structure, thematic evolution, trend topics, and inter-gulf and international cooperation on TB in the past 30 years (1993–2022). A total of 1999 publications associated with research on GCC-TB were published. The annual growth rate of documents was 7.76%. Saudi Arabia is the most highly published, followed by the United Arab Emirates, Kuwait, Qatar, Oman, and Bahrain. The most-cited GC country is Kingdom Saudi Arabia, followed by Kuwait. One hundred sixty research institutions contributed to the dissemination of TB-related knowledge in the GCC, where the highest publishing organizations were King Saud University (Kingdom Saudi Arabia; n = 518). The number of publications related to TB is high in GCC Countries. The current tendencies indicated that GCC scholars are increasingly focused on deep learning, chest X-ray, molecular docking, comorbid covid-19, risk factors, and Mycobacterium bovis.
Exploring depressive symptoms and coping strategies in Chinese women facing infertility: A cross-sectional observational study
Authors: Song Guihong , Liu Haiyun , Zhang Zhirong , Liu Nannan , Jiang Shuai , Du Jing
Published: July 2024

Infertility can lead to significant psychological distress among women, yet the roles of hope and resilience in mitigating depressive symptoms remain inadequately explored, particularly within the Chinese context. We performed a cross-sectional observational study to investigate the psychological impacts of infertility among Chinese women as well as to discern whether hope and resilience can influence their depressive symptoms. We recruited 364 Chinese women seeking infertility treatment in the Shandong region. Participants completed validated assessments including the Hospital Anxiety and Depression Scale, Connor–Davidson Resilience Scale, and Herth Hope Index. Demographic and clinical data were also collected. We observed elevated levels of depressive symptoms and anxiety among women with infertility. Particularly, demographic factors such as an older age, rural residence, lower income, lower education, adverse life events, and longer infertility duration were associated with increased depressive symptoms. Individuals who experienced adverse life events were at a 2.42-fold increased risk of developing depressive symptoms (P = .04). Depressive symptoms were inversely correlated with both hope levels (r = ‐0.25; P < .05) and resilience levels (r = ‐0.32; P < .05). Hope levels were positively correlated with resilience (R = 0.67; P < .05). After controlling for the interaction of hope and resilience, we found that only depressive symptoms and resilience were negatively correlated. The psychological burden of infertility among Chinese women is widespread and affects many individuals from different demographic backgrounds. Interventions aimed at increasing resilience may be helpful to mitigate depressive symptoms.
Usefulness of net retrieval devices for central airway obstruction caused by blood clots during extracorporeal membrane oxygenation: Case series
Authors: Tanaka Satoshi , Yoshimura Nobuaki , Asakawa Ryo , Tobita Satoshi , Yaga Moto , Ueno Kiyonobu
Published: July 2024

Rationale:

Extracorporeal membrane oxygenation (ECMO) is the last trump card for severe respiratory failure. The main complications of ECMO are bleeding and thrombosis, both of which can be life-threatening. Large blood clots can cause central airway obstruction (CAO) during ECMO, and CAO should be removed as soon as possible because of asphyxiation. However, there is no comprehensive reports on its frequency and management. The purpose of this study is to share therapeutic experiences for rare and serious conditions and provide valuable insights.

Patient concerns:

We report 3 patients placed on ECMO for severe respiratory failure.

Diagnosis:

CAO due to large blood clots occurred during ECMO in all 3 patients.

Interventions:

Large blood clots were removed using flexible bronchoscopy, grasping forceps, and net retrieval devices in all 3 patients.

Outcomes:

In all 3 patients, large blood clots were removed multiple times during ECMO. The patients’ respiratory conditions improved and they were eventually weaned off the ECMO.

Lessons:

CAO due to large blood clots during ECMO is rare. The frequency of CAO requiring bronchoscopic removal was estimated to be approximately 1,5%. When this occurs, clots should be removed as soon as possible. Net retrieval devices are useful tools for the collection of large blood clots.
Endogenous endophthalmitis caused by Streptococcus mitis: A case report
Authors: Nakayama Saki , Itagaki Hideya , Abe Yoshinobu , Matumura Nobutoshi , Endo Tomoyuki
Published: July 2024

Rationale:

Endogenous endophthalmitis is a rare disease caused by hematogenous intraocular metastasis of bacteria from an infectious source. Diagnosing endogenous endophthalmitis is challenging for non-ophthalmologists. However, ophthalmic diseases can cause irreversible vision loss, making prompt diagnosis and treatment critical. Here we present a rare case of endogenous endophthalmitis initially misdiagnosed as a cataract.

Patient concerns:

An 84-year-old Japanese man presented to the emergency department with fever and dysmotility. The patient was aware of a left subconjunctival hemorrhage and cloudy cornea upon arrival at the hospital, but he misunderstood it as a fall-induced subconjunctival hemorrhage and age-related cataracts.

Diagnoses:

On the day following admission, petechial hemorrhage on the eyelid conjunctiva and the detection of Streptococcus mitis in the blood culture results led us to suspect endophthalmitis rather than cataracts. A definitive diagnosis of endophthalmitis was made through ophthalmologic examinations, and endophthalmitis was considered secondary to endocarditis.

Interventions:

Subsequently, antimicrobial treatment was continued.

Outcomes:

However, the patient developed myocardial infarction and died on the ninth day of hospitalization.

Lessons:

Two important lessons were learned from the examination of this case of endogenous endophthalmitis caused by S mitis. First, endophthalmitis and cataracts can be misdiagnosed. Because the symptoms of endophthalmitis and cataracts, such as decreased vision, photophobia, and blurred vision, are similar, the eye must be cautiously examined. Second, endocarditis caused by S mitis may lead to endogenous endophthalmitis. Although S mitis is not pathogenic, endogenous endophthalmitis may occur in patients with certain risk factors, such as older age, cancer, and immunosuppression.
Prognostic value of lactate dehydrogenase to absolute lymphocyte count ratio and albumin to fibrinogen ratio in diffuse large B-cell lymphoma
Authors: Shi Xuebing , Wu Changping , Deng Wenxia , Wu Jing
Published: July 2024

With the continuous improvement of treatment strategy, the prognostic value of international prognostic index (IPI) alone is limited for diffuse large B-cell lymphoma (DLBCL). Our study aims to explore the effect of lactate dehydrogenase (LDH)to absolute lymphocyte count (ALC) ratio (LAR) and albumin to fibrinogen ratio (AFR) on the prognosis of patients with DLBCL. The venous blood LDH, ALC, albumin and fibrinogen within 1 week before the first chemotherapy in 74 DLBCL patients were collected to calculate the LAR and AFR values. The impact of LAR and AFR on the progression-free survival (PFS) of patients with DLBCL was studied by the survival analysis. The area under the receiver operating characteristic curve (AUC) and concordance index (C-index) were used to analyze the predictive efficiency of each model for the PFS of DLBCL patients. Cox univariate analysis suggested that elevated LAR (P < .001) and decreased AFR (P < .001) were risk factors for PFS in DLBCL patients. Multivariate analysis revealed that LAR (P < .001) and AFR (P = .004) were 2 independent prognostic parameters. The AUC values of IPI, AFR + IPI, LAR + IPI and AFR + LAR + IPI to predict the PFS of DLBCL patients were 0.806 (95%CI 0.707–0.905, P < .001), 0.839 (95%CI 0.747–0.932, P < .001), 0.851 (95%CI 0.764–0.938, P < .001), and 0.869 (95%CI 0.787–0.952, P < .001), respectively. The C-index values of above 4 models were 0.802 (95%CI 0.629–0.975, P < .001), 0.842 (95% CI 0.735–0.949, P < .001), 0.846 (95%CI 0.716–0.976, P < .001), and 0.864 (95%CI 0.781–0.941, P < .001), respectively. The results suggest that both LAR and AFR are independent prognostic factors for PFS in DLBCL patients. Furthermore, their combination with IPI has better predictive efficiency for the prognosis of DLBCL patients.
The efficacy of early extracorporeal shockwave lithotripsy for the treatment of 5 to 10 mm upper ureteral stones: An observational study
Authors: Aydamirov Mubariz , Karkin Kadir , Altunkol Adem , Vuruskan Ediz , Kaplan Eyup , Gurlen Guclu , Aksay Bugra , Akgun Omer Faruk , Gozukara Keremhan , Ortaoglu Ferhat , Tunckiran Muslum Ahmet
Published: July 2024

This study aimed to determine the effectiveness of extracorporeal shockwave lithotripsy (SWL) performed in the early period (within the first 24 hours). Data of patients who underwent SWL with a diagnosis of unilateral radiopaque 5 to 10 mm upper ureteral stones were retrospectively examined. Patients were divided into 2 groups. Group 1 (early SWL) consisted of patients with SWL performed within 24 hours after the onset of colic pain (<24 hours), while group 2 (deferred SWL) comprised patients with SWL performed 24 hours or more from the onset of pain (≥24 hours). The primary endpoint of the study was planned to determine 1-month SFR in both groups. The secondary endpoint was determined to be the factor affecting SWL success. The mean age of 216 patients (130 men, 86 women) included in this study was 46.5 ± 12.1 years. SFR within 1 month was detected in 175 patients (81%). In the early SWL group, the average number of SWL sessions was fewer (1.26 vs 1.83 P = .026) and the time to the stone-free state was shorter (11 vs 15.4 days P = .044). SFR within 1 month was higher in the early SWL group (85.5% vs 71.8% P = .036). In multivariate analysis, stone size, Hounsfield Units, and early SWL were predictive factors for SWL success. Performing SWL within the first 24 hours is highly effective in patients with symptomatic 5 to 10 mm upper ureteral stones.
Key elements of Korean medicine treatment for idiopathic short-stature: A qualitative SWOT analysis based on Korean medicine doctors’ views
Authors: Jang Soobin , Park Seokyung , Lee Boram
Published: July 2024

The objective of this study was to explore the key elements of Korean medicine (KM) treatment for idiopathic short stature (ISS) by analyzing the strengths, weaknesses, opportunities, and threats (SWOT). This was a qualitative study of interviews with 7 KM doctors who had at least 3 years of experience in KM treatment for ISS. Based on the content, a SWOT and a cross-SWOT analysis were conducted. A SWOT of KM treatment for ISS was derived as follows: Strengths included the additional positive health promotion effects and fewer possibilities of adverse effects. Weaknesses included insufficient long-term evidence on the effect and safety and difficulty in predicting prognosis for ISS treatment in KM. Opportunities included a growing interest in height growth in general and the need for parental involvement in children height growth. Threats included the limited use of diagnostic devices and relatively high medical costs due to non-coverage by national health insurance. This study suggests that the safety and clinical effectiveness evidence of KM treatment for height growth should be guaranteed through well-designed large-scale long-term studies. Various strategies are needed to promote the use of diagnostic and evaluation devices for ISS treatment in KM clinical settings.
Unveiling the unprecedented – Very late brain metastasis in cholangiocarcinoma: A case report and comprehensive analysis
Authors: Cha Seungah , Lee Chang-Hoon , Jang Kyu Yun , Jeon So-Yeon
Published: July 2024

Rationale:

Cholangiocarcinoma (CCA) frequently invades nearby lymph nodes, the liver, and lungs. The liver and lungs are also common anatomic sites for the first recurrence of CCA. However, metastasis to the brain is exceptionally rare.

Patient concerns:

A 79-year-old male patient who was diagnosed with distal CCA and underwent pylorus-preserving pancreaticoduodenectomy along with adjuvant chemotherapy 13-years ago visited the neurosurgery outpatient department. He complained of dysarthria and right leg weakness that had started 7 days previously.

Diagnoses:

Brain computed tomography (CT) showed a 32 mm × 28 mm mass in the left frontal lobe with peripheral ring enhancement and vasogenic edema. A tumor mass removal operation was performed, and pathological examination revealed metastatic adenocarcinoma. Immunohistochemistry analysis revealed negativity for thyroid transcription factor-1 and napsin A, and positivity for cytokeratin (CK)7, CK20, and CK19. Simultaneously, Chest CT, abdomen–pelvis CT and 18-Fluoro-deoxyglucose positron emission tomography showed only two small nodules in the left upper lung, with no evidence of locoregional recurrence in the abdominal cavity. Considering these CT, positron emission tomography-CT, and pathologic findings, very late recurrence of biliary tract cancer with brain and lung metastases was suggested.

Interventions and outcomes:

A therapeutic plan involving systemic chemotherapy with gemcitabine and cisplatin was proposed, but the patient refused further chemotherapy.

Lessons:

This case highlights the unpredictable nature of metastatic patterns in CCA, where brain metastasis occurs very late, preceding locoregional recurrence in the liver. This challenges conventional expectations and underscores the need for vigilant surveillance and consideration of atypical metastatic sites in long-term survivors of CCA.
Addressing the Health Needs of LGBTQ Persons in Medical Curricula: A Review of Educational Programs
Authors: Khalfe Nasim , Stephens Matthew , Albaba Dania , Gordon Mollie R. , Coverdale John
Published: July 2024

Objective:

Given the vulnerability of and the importance of caring for the specific health care needs of the growing lesbian, gay, bisexual, transgender, and queer (LGBTQ) population, the authors attempted to identify all educational interventions in psychiatric settings with quantitative outcomes targeting medical students, residents, and physicians in postgraduate settings. To gain insight from other disciplines that have published research in this area, a second objective was to review studies in teaching in those other disciplines. The authors sought to describe the methods of selected studies.

Methods:

The authors searched the published English-language literature indexed in PubMed, EMBASE, and PsycINFO using key terms for health care education concerning LGBTQ populations. The authors described and critically appraised studies with quantitative outcomes designed to enhance knowledge, skills, and attitudes in treating the LGBTQ community.

Results:

Of the 15 trials identified, 10 included medical students, 4 included internal medicine residents or medical school faculty, and 1 included oncologists. We did not find any randomized controlled trials or controlled nonrandomized trials of curricula dedicated to teaching learners in psychiatry. All of the studies included a presurvey, followed by an educational intervention and then a postsurvey assessment. The educational interventions, outcome measures, and quality of studies varied widely. Four studies enrolled self-identified members of the LGBTQ community as trainers and facilitators of the educational interventions.

Conclusions:

The lack of high-quality controlled studies indicates the need to develop evidence-based curricula to support the education of the psychiatric workforce to provide for the special needs of LGBTQ persons.
Treating Malignant Catatonia With Liquid Amantadine: A Case Report and Literature Review
Authors: Bulleit Christina , Rho Jonathan , Fleisch Sheryl B. , Radhakrishnan Nila S.
Published: July 2024

Malignant catatonia (MC) is a complex, life-threatening condition characterized by motor dysregulation and autonomic instability, which requires prompt and effective treatment. There are some limitations to the current recommendations for treating MC, including barriers to receiving ECT, failure to respond to benzodiazepines, or benzodiazepine intolerance. To the authors’ knowledge, there are 3 case reports in the literature describing the use of amantadine in the treatment of MC. We present the case of a 51-year-old female with a history of multiple medical and psychiatric conditions who was admitted to the hospital for altered mental status. During her admission, she developed symptoms that raised concern about MC, which was initially managed with lorazepam. However, due to concerns about severe respiratory compromise, lorazepam was discontinued, and the patient was started on liquid amantadine. She showed marked reduction in the symptoms of malignant catatonia, and the autonomic instability resolved after she was started on amantadine. The patient was eventually discharged home with outpatient follow-up scheduled. Our case report shows successful treatment of MC with liquid amantadine in a patient who was unable to tolerate escalating doses of benzodiazepines. The positive response to amantadine suggests that it may be a useful treatment option for MC. While further studies are needed, clinicians should consider the use of amantadine in the treatment of MC, especially in patients who are unable to tolerate benzodiazepines, who have failed to respond to treatment with benzodiazepines, or who are being treated in institutions where the availability of ECT is limited. Amantadine may be more readily accessible given its multiple formulations and wide availability.
Integrative analysis of single-cell gene expression: A comprehensive database approach
Authors: Truong Linh , Truong Thao , Nguyen Huy
Published: July 2024

The exponential growth of single-cell datasets provides unprecedented opportunities to advance our understanding of complex biological systems. However, effectively locating and integrating related studies for meaningful insights remains challenging. Traditional databases primarily index basic metadata, which necessitates time-consuming downloading and re-filtering based on gene expression and cell type or tissue composition, followed by computationally intensive aggregation. This process often results in excessively large datasets that are difficult to analyze effectively, further complicated by batch effects. To address these issues, we have developed a computational approach to efficiently extract and index both expression data and annotations. Our comprehensive database incorporates detailed author annotations and gene expression profiles, enabling refined searches and integrated analyses to uncover common biological patterns while accounting for the repeatability of patterns across multiple studies and mitigating batch effects. This approach significantly reduces computational demands and enhances the accessibility and utility of single-cell transcriptomics data for the broader research community. In the first version, we release a human database comprising 244 datasets from 236 cell types, 35 tissues, and 31 conditions.
Multivariate Neural Patterns of Reward and Anxiety in Adolescents with Anorexia Nervosa
Authors: Peel Hayden J , Reggente Nicco , Strober Michael , Feusner Jamie
Published: July 2024

People with anorexia nervosa (AN) commonly exhibit elevated anxiety and atypical reward responsiveness. To examine multivariate neural patterns associated with reward and the impact of anxiety on reward, we analyzed fMRI data from a monetary reward task using representational similarity analysis, a multivariate approach that measures trial by trial consistency of neural responses. Twenty-five adolescent girls with AN and 22 mildly anxious controls lacking any history of AN were presented personalized anxiety-provoking or neutral words before receiving a reward, and neural response patterns in reward regions were analyzed. Consistent with our preregistered hypothesis, AN participants showed lower representational similarity than controls during neutral-word rewarded trials. Within groups, controls showed significant representational similarity in reward circuit regions including the left nucleus accumbens, left basolateral amygdala, and left medial orbitofrontal cortex, which were not observed in AN. Further, reward-related prefrontal cognitive control areas - left ventrolateral prefrontal cortex and left dorsolateral prefrontal cortex - showed significant representational similarity in both groups, but a larger spatial extent in controls. Contrary to predictions, there were no significant between-group differences for the effects of anxiety-words on reward representational similarity, and representational similarity did not predict longitudinal symptom change over six months. Overall, the results demonstrate relatively inconsistent trial-by-trial responses to reward receipt in the neutral state in AN compared with controls in both reward circuit and cognitive control regions, but no significant differential effects of anxiety states on reward responses. These results add to dynamic understandings of reward processing in AN that have potential implications for planning and guiding reward-focused interventions.
Development and Validation of Novel Cell-free Direct Neutralization Assay for SARS-CoV-2
Authors: Lim Ji Youn , Fiore Alyssa , Le Bruce , Minzer Corinne , White Halle , Burinski Krystle , Janwari Humaira , Wright David , Perebikovsky Sasha , Davis Ralph , Okrongly David , Srinivasan Aravind
Published: July 2024

Neutralizing antibody titer elicited through infection or vaccination is accepted as a reliable surrogate for protection from SARS-CoV-2 infection, hospitalization, and mortality. The gold standard for measuring neutralizing antibody levels relies on culturing live virus in the presence of a target cell and quantitating the level where 50% of the target cells are infected. These assays have numerous technical challenges, not the least is the requirement for a BSL-3 laboratory to perform the live virus testing. We developed the Q-NAb IgG Test for the quantitative determination of neutralizing antibodies against SARS-CoV-2 variants, traceable to WHO International Standards. The test utilizes a novel Fusion Protein that mimics the Spike receptor binding domain docked to the human ACE2 protein and effectively blocks non-neutralizing antibodies in the sample. After pre-blocking sequesters the non-neutralizing antibodies from the samples, direct binding of the residual neutralizing antibodies to variant RBDs coated in the wells of the microtiter plate is measured with a fluorescent secondary antibody. Results of the Q-NAb IgG Test agree with a live virus Microneutralization Assay for both the Ancestral strain (WA1-2020) and the Omicron BA.5 (COR-22-063113/2022) variant (Spearman’s correlation, ρ = 0.87 and 0.92, respectively). The analytical performance (LoB, LoD, LoQ, linearity, precision, and interference) of the Q-NAb IgG Test was established along with sensitivity and specificity using a panel of monoclonal neutralizing and non-neutralizing anti-SARS-CoV-2 antibodies. Clinical sensitivity and specificity using pre-pandemic, convalescent, and vaccinated serum and plasma samples is also reported. The advantages of the Q-NAb IgG Test are its strong correlation to live virus neutralization tests, traceability to WHO International Standards, convenient microtiter plate format, low sample volume requirements, and suitability for a BSL-2 laboratory.
Peripheral Neuropathy in Cancer Patients- Multifactorial Contributors to Dose Limiting and Chronic Toxicity
Authors: Li Tiffany , Timmins Hannah C , Horvath Lisa G , Harrison Michelle , Grimison Peter , Friedlander Michael , Marx Gavin , Boyle Frances , Wyld David , Henderson Robert , King Tracy , Baron-Hay Sally , Kiernan Matthew C , Barnes Elizabeth H , Goldstein David , Park Susanna B
Published: July 2024

Background and Objective

Chemotherapy-induced peripheral neuropathy (CIPN) is a complex and dose-limiting toxicity of anticancer treatments with chronic symptoms leading to increased disability and reduced quality of life. The present study evaluated clinical risk factors associated with development of chronic, severe and dose-limiting CIPN, utilising a comprehensive multi-modal battery of neuropathy assessment.

Methods

Baseline clinical risk factors were investigated in patients who had completed neurotoxic chemotherapy (including taxanes, platinums and haematological cancer therapies). CIPN was assessed using neurological evaluation (Total Neuropathy Score, sural nerve conduction studies), patient reported outcome measure (EORTC QLQ-CIPN20), and clinically graded neuropathy (NCI-CTCAE). Multivariate models of risk factors associated with development of chronic, severe and dose-limiting CIPN were evaluated using backwards stepwise regression model building.

Results

The study recruited 903 patients (age 61 (IQR 50-69) years) who were assessed 12 (IQR 6-24) months post neurotoxic treatment. 73% of patients presented with CIPN at time of assessment, with 37% having moderate to severe symptoms. 32% of patients experienced neurotoxic treatment dose modification due to CIPN. Across the various CIPN assessment approaches, risk factors for chronic CIPN included older age, diabetes diagnosis, higher BMI and prior exposure to neurotoxic treatment (all P<0.05). Risk factors for severe CIPN included older age, higher BMI, prior neurotoxic treatment and female sex (all P<0.05), whereas risk factors for dose-limiting CIPN included older age and female sex (all P<0.05).

Discussion

This study identified baseline clinical risk factors associated chronic, severe and dose-limiting CIPN. Closer monitoring of these vulnerable cohorts will allow for timely CIPN management, including referral pathways to intervention and rehabilitation therapies which will ultimately lead to improved CIPN morbidity.
Recovery from Heart Failure is a Vascular Recovery
Authors: Ranka Rajul K. , Gupta Krishan , Naegele Felix , Lu Alexander J. , Li Shuang , Graber Michael , Carter Kaylee N. , Mojiri Anahita , Zhang Lili , Bhimaraj Arvind , Lai Li , Youker Keith A. , Chen Kaifu , Cooke John P.
Published: July 2024

Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with limited treatment options. Heart transplantation is an end stage option but limited by donor availability. Left-ventricular assist device (LVAD) implantation serves as a bridging strategy for patients awaiting a transplant. Intriguingly, LVAD support (typically for 6-12 months before heart transplantation) is often associated with some level of improvement in cardiac function and histology. In rare cases, LVAD support can improve cardiac function sufficiently to avoid heart transplantation after LVAD removal. The underlying mechanisms of this improvement in cardiac function are not understood. Here, we provide evidence that the improvement in cardiac function post-LVAD is associated with a reduction in fibrosis and an increase in capillary density. This heart failure recovery (HFR) is also associated with an angiogenic cell fate transition. We observed a distinct pro-angiogenic phenotype of cardiac non-myocytes isolated from post-LVAD hearts. Single-nuclei RNA sequencing of pre- and post-LVAD cardiac tissue reveals a fibroblast subtype that undergoes mesenchymal to endothelial transition (MEndoT), potentially facilitating HFR. In a murine model of HFR, lineage tracing studies confirm that MEndoT is associated with the increase in capillary density and perfusion during HFR. In summary, our results support the new concept that HFR is associated with a reduction in interstitial cardiac fibrosis, an increase in capillary density and perfusion, that is due in part to an angiogenic cell fate transition. Our work represents a shift in the conceptual framework regarding mechanisms of HFR, and a new therapeutic avenue for exploration.
Combined effects of pharmacological interventions and intermittent theta-burst stimulation on motor sequence learning
Authors: Kim Hakjoo , Kornman Paul T. , Kweon Jamie , Wassermann Eric M. , Wright David L. , Li Johnson , Brown Joshua C.
Published: July 2024

Drugs that modulate N-methyl-D-aspartate (NMDA) or γ-Aminobutyric acid type A (GABAA) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age ± SD: 31.56 ± 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABAAreceptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.
Amidase and Lysozyme Dual Functions in TseP Reveal a New Family of Chimeric Effectors in the Type VI Secretion System
Authors: Wang Zeng-Hang , An Ying , Zhao Ting , Pei Tong-Tong , Wang Dora Yuping , Liang Xiaoye , Qin Wenming , Dong Tao
Published: July 2024

Peptidoglycan (PG) serves as an essential target for antimicrobial development. An overlooked reservoir of antimicrobials lies in the form of PG-hydrolyzing enzymes naturally produced for polymicrobial competition, particularly those associated with the type VI secretion system (T6SS). Here we report that a T6SS effector TseP, fromAeromonas dhakensis, represents a family of effectors with dual amidase-lysozyme activities.In vitroPG-digestion coupled with LC-MS analysis revealed the N-domain’s amidase activity, which is neutralized by either catalytic mutations or the presence of the immunity protein TsiP. The N-domain, but not the C-domain, of TseP is sufficient to restore T6SS secretion in T6SS-defective mutants, underscoring its critical structural role. Using pull-down and secretion assays, we showed that these two domains interact directly with a carrier protein VgrG2 and can be secreted separately. Homologs inAeromonas hydrophilaandPseudomonas syringaeexhibited analogous dual functions. Additionally, N- and C-domains display distinctive GC contents, suggesting an evolutionary fusion event. By altering the surface charge through structural-guided design, we engineered the TsePC4+effector that successfully lyses otherwise resistantBacillus subtiliscells, enabling the T6SS to inhibitB. subtilisin a contact-independent manner. This research uncovers TseP as a new family of bifunctional chimeric effectors targeting PG, offering a potential strategy to harness these proteins in the fight against antimicrobial resistance.

Significance Statement

Antimicrobial resistance urgently demands global interventions, and the bacteria cell wall remains a promising target. Our research introduces a novel family of bifunctional, cell-wall-damaging T6SS effectors. More importantly, we demonstrate an effective strategy to enable an otherwise ineffective enzyme to target both Gram-negative and Gram-positive bacteria. Our findings highlight a promising path forward using cell-wall-damaging effectors, a largely untapped resource, in the fight against antimicrobial resistance.
A central research portal for mining pancreatic clinical and molecular datasets and accessing biobanked samples
Authors: Oscanoa J. , Ross-Adams H , Dayem Ullah Abu Z M , Kolvekar TS , Sivapalan L , Gadaleta E , Thorn GJ , Abdollahyan M , Imrali A , Saad A , Roberts R , Hughes C ,   PCRFTB, Kocher HM , Chelala C
Published: July 2024

The Pancreatic Expression Database (PED) is a powerful resource dedicated to the mining and analysis of pancreatic -omics datasets. Here, we demonstrate the biological interpretations that are possible because of vital updates that have transformed PED into a dynamic analytics hub accommodating an extensive range of publicly available datasets. PED now hosts clinical and molecular datasets from four primary sources (Cancer Genome Atlas, International Cancer Genome Consortium, Cancer Cell Line Encyclopaedia and Genomics Evidence Neoplasia Information Exchange) that together form the foundation of omics profiling of pancreatic malignancies and related lesions (n=7,760 specimens). Several user-friendly analytical tools to explore and integrate the molecular data derived from these primary specimens and cell lines are now available. Crucially, PED is integrated as the data access point for Pancreatic Cancer Research Fund Tissue Bank – the only national pancreatic cancer biobank in the UK. This will pioneer a new era of biobanking to promote collaborative studies and effective sharing of multi-modal molecular, histopathology and imaging data from biobank samples (>60,000 specimens from >3,400 cases and controls; 2,037 H&E images from 349 donors) and accelerate validation ofin silicofindings in patient-derived material. These updates place PED at the analytical forefront of pancreatic biomarker-based research, providing the user community with a distinct resource to facilitate hypothesis-testing on public data, validate novel research findings, and access curated, high-quality patient tissues for translational research. To demonstrate the practical utility of PED, we investigate somatic variants associated with established transcriptomic subtypes and disease prognosis: several patient-specific variants are clinically actionable and may be leveraged for precision medicine.
A Quantitative Study to Assess the Effect of a Community-Academy Partnership Event on Knowledge, Awareness, and Engagement Against Substance Abuse
Authors: Dixit Smriti , Sharma Sadhana , Sharma Neha , Patel Manisha
Published: July 2024

The objective of this study is to assess the quantitative effects of the community-academy partnership event, called Chaitanya Utsav, on the levels of knowledge, awareness, and engagement in combating drug misuse in the local community. The research aims to evaluate the impact of these joint endeavours on the participants’ knowledge and attitudes regarding substance usage, as well as their participation in preventative efforts. Structured questionnaires were used to obtain data from participants both before and after the event. Important indicators consist of variations in knowledge levels, awareness of drug addiction challenges, and the degree of community engagement in associated activities. Initial results demonstrate significant improvements in all three domains, highlighting the effectiveness of collaborations between communities and academic institutions in addressing substance dependence. This study emphasizes the crucial role that such collaborations play in fostering informed and proactive communities, serving as an outline for similar initiatives in multiple domains.
Suicide Risk in Borderline Personality Disorder: a Machine Learning Tool based on Clinical and MRI Data
Authors: Crema Claudio , Boccali Alberto , Martinelli Alessandra , De Francesco Silvia , Meloni Serena , Baronio Cesare M. , Pedrini Laura , Lanfredi Mariangela , Archetti Damiano , Redolfi Alberto , Rossi Roberta
Published: July 2024

Borderline Personality Disorder (BPD) is a complex mental condition. Individuals with BPD have an average of three lifetime suicide attempts, and 10% of them die by suicide. Understanding risk factors linked to suicidal behaviors is crucial for effective intervention strategies. In recent years, machine learning (ML) approaches for predicting suicide risk in persons with mental disorders have been developed, but a reliable, BPD-specific tool is lacking. In this work, we developed DRAMA-BPD (Detecting Risk factors for suicide Attempts with Machine learning Approaches in Borderline Personality Disorder), a second-opinion tool to assess suicide risk in individuals with BPD. DRAMA-BPD, built upon a Support Vector Machine (SVM) classifier, is trained on the CLIMAMITHE (CLM) dataset, which encompasses sociodemographic, clinical, emotional assessments, and MRI data. Feature selection revealed that 6 out of the 7 most important features are MRI-derived, and a comprehensive review was conducted to ensure consistency with existing scientific literature. The classifier achieved an overall Area Under the Curve (AUC) of 0.73, Precision (P) of 0.75, Recall (R) of 0.70, and F1-score of 0.72. Tests were conducted on the independent SUDMEX_CONN dataset, yielding an AUC of 0.59, P of 0.46, R of 0.92, and F1 of 0.62. While there is a significant imbalance between Precision and Recall, these results demonstrate the potential utility of the proposed model.
Does household income predict health and educational outcomes in childhood better than neighbourhood deprivation?
Authors: Skarda Ieva , Cookson Richard , Gilbert Ruth
Published: July 2024

Background Public health research and prevention policies often use the small area Index of Multiple Deprivation (IMD) at neighbourhood level to proxy individual socio-economic status because it is readily available. We investigated what household income adds to IMD in early childhood for predicting adverse health in adolescence. Methods Using data from the Millennium Cohort Study, we analysed IMD and self-reported equivalised household income (ages 0-5) to predict outcomes at age 17: poor academic achievement, psychological distress, poor health, smoking, and obesity. Predictions were compared using IMD quintiles alone, household income alone, and both together. Results Household income was a stronger and more consistent predictor of age 17 outcomes than IMD and revealed inequalities within neighbourhoods. Decreasing household income showed steep gradients in educational attainment and smoking across all IMD quintiles, and moderate gradients in obesity, psychological distress, and poor health in most quintiles. IMD did not predict smoking or psychological distress within any income group, or educational attainment within the poorest income group. Conclusion Household income is associated with inequality gradients within all quintiles of neighbourhood IMD. Early childhood public health strategies should consider household income in combination with neighbourhood deprivation.
Conformations of a Low-Complexity Protein in Homogeneous and Phase-Separated Frozen Solutions
Authors: Wilson C. Blake , Lee Myungwoon , Yau Wai-Ming , Tycko Robert
Published: July 2024

Solutions of the intrinsically disordered, low-complexity domain of the FUS protein (FUS-LC) undergo liquid-liquid phase separation (LLPS) below temperatures TLLPSin the 20-40° C range. To investigate whether local conformational distributions are detectably different in the homogeneous and phase-separated states of FUS-LC, we performed solid state nuclear magnetic resonance (ssNMR) measurements on solutions that were frozen on sub-millisecond time scales after equilibration at temperatures well above (50° C) or well below (4° C) TLLPS. Measurements were performed at 25 K with signal enhancements from dynamic nuclear polarization. Crosspeak patterns in two-dimensional (2D) ssNMR spectra of rapidly frozen solutions in which FUS-LC was uniformly15N,13C-labeled were found to be nearly identical for the two states. Similar results were obtained for solutions in which FUS-LC was labeled only at Thr, Tyr, and Gly residues, as well as solutions of a FUS construct in which five specific residues were labeled by ligation of synthetic and recombinant fragments. These experiments show that local conformational distributions are nearly the same in the homogeneous and phase-separated solutions, despite the much greater protein concentrations and more abundant intermolecular interactions within phase-separated, protein-rich “droplets”. Comparison of the experimental results with simulations of the sensitivity of 2D crosspeak patterns to an enhanced population of β-strand-like conformations suggests that changes in conformational distributions are no larger than 5-10%.

Statement of Significance

Liquid-liquid phase separation (LLPS) in solutions of proteins with intrinsically disordered domains has attracted recent attention because of its relevance to multiple biological processes and its inherent interest from the standpoint of protein biophysics. The high protein concentrations and abundant intermolecular interactions within protein-rich, phase-separated “droplets” suggests that conformational distributions of intrinsically disordered proteins may differ in homogeneous and phase-separated solutions. To investigate whether detectable differences exist, we performed experiments on the low-complexity domain of the FUS protein (FUS-LC) in which FUS-LC solutions were first equilibrated at temperatures well above or well below their LLPS transition temperatures, then rapidly frozen and examined at very low temperatures by solid state nuclear magnetic resonance (ssNMR) spectroscopy. The ssNMR data for homogeneous and phase-separated frozen solutions of FUS-LC were found to be nearly identical, showing that LLPS is not accompanied by substantial changes in the local conformational distributions of this intrinsically disordered protein.
Local DNA compaction creates TF-DNA clusters that enable transcription
Authors: Chabot Noémie M. , Purkanti Ramya , Del Panta Ridolfi Alessia , Nogare Damian Dalle , Oda Haruka , Kimura Hiroshi , Jug Florian , Dal Co Alma , Vastenhouw Nadine L.
Published: July 2024

Transcription factor (TF) clusters have been suggested to facilitate transcription. The mechanisms driving the formation of TF clusters and their impact on transcription, however, remain largely unclear. This is mostly due to the lack of a tractable system. Here, we exploit the transcriptional activation ofmir430in zebrafish embryos to simultaneously follow the dynamic formation of a large Nanog cluster, the underlying DNA, and transcription output by live imaging at high temporal and spatial resolution. We find that the formation of a Nanog cluster that can support transcription requires local DNA compaction. This brings more Nanog-binding sites into the cluster, and therefore more Nanog. Importantly, we find that Nanog stabilizes this TF-DNA cluster, which emphasizes the interdependent relationship between TFs and DNA dynamics in cluster formation. Once the Nanog-DNA cluster at themir430locus reaches a maximum amount of Nanog, transcription begins. This maximum is a locus-intrinsic feature, which shows that the locus self-regulates the recruitment of an optimal amount of Nanog. Our study supports a model in which endogenous TF clusters positively impact transcription and form through a combination of DNA binding and local DNA compaction.
Distinct mechanisms of inhibition of Kv2 potassium channels by tetraethylammonium and RY785
Authors: Zhang Shan , Stix Robyn , Orabi Esam A , Bernhardt Nathan , Faraldo-Gomez Jose D
Published: July 2024

Voltage-gated K+ channels play central roles in human physiology, both in health and disease. A repertoire of inhibitors that are both potent and specific would therefore be of great value, not only as pharmacological agents but also as research tools. The small molecule RY785 has been described as particularly promising in this regard, as it selectively inhibits channels in the Kv2 subfamily with high potency. Kv2 channels are expressed in multiple cell types in humans, and are of particular importance for neuronal function. The mechanism of action of RY785 has not yet been determined at the molecular level, but functional studies indicate it differs from that of less specific inhibitors, such as quaternary-ammonium compounds or aminopyridines; RY785 is distinct also in that it is electroneutral. To examine this mechanism at the single-molecule level, we have carried out a series of all-atom molecular dynamics simulations based on the experimental structure of the Kv2.1 channel in the activated, open state. First, we report a 25-microsecond trajectory calculated in the absence of any inhibitor, under an applied voltage of 100 mV, which demonstrates outward K+ flow under simulation conditions at rates comparable to experimental measurements. Additional simulations in which either RY785 or tetraethylammonium (TEA) is introduced in solution show both inhibitors spontaneously enter the channel through the cytoplasmic gate, with distinct effects. In agreement with prior structural studies, we observe that TEA binds to a site adjacent to the selectivity filter, on the pore axis, thereby blocking the flow of K+ ions. RY785, by contrast, binds to the channel walls, off-axis, and allows K+ flow while the cytoplasmic gate remains open. The observed mode of RY785 binding, however, indicates that its mechanism of action is to stabilize and occlude a semi-open state of the gate, by bridging hydrophobic protein-protein interactions therein; this hypothesis would explain the puzzling experimental observation that RY785 recognition influences the gating currents generated by the voltage sensors, 3 nm away.