Miracle-dz/UniFAR-FTUs huggingface dataset:
LUZP1 Controls Cell Division, Migration and Invasion Through Regulation of the Actin Cytoskeleton

LUZP1 is a centrosomal and actin cytoskeleton-localizing protein that regulates both ciliogenesis and actin filament bundling. As the cytoskeleton and cilia are implicated in metastasis and tumor suppression, we examined roles for LUZP1 in the context of cancer. Here we show that LUZP1 exhibits frequent genomic aberrations in cancer, with a predominance of gene deletions. Furthermore, we demonstrate that CRISPR/Cas9-mediated loss of Luzp1 in mouse fibroblasts promotes cell migration and invasion features, reduces cell viability, and increases cell apoptosis, centriole numbers, and nuclear size while altering the actin cytoskeleton. Loss of Luzp1 also induced changes to ACTR3 (Actin Related Protein 3, also known as ARP3) and phospho-cofilin ratios, suggesting regulatory roles in actin polymerization, beyond its role in filament bundling. Our results point to an unprecedented role for LUZP1 in the regulation of cancer features through the control of actin cytoskeleton.
Microzoning Tsunami Hazard by Combining Flow Depths and Arrival Times

Tsunami hazard is typically assessed from inundation flow depths estimated from one or many earthquake scenarios. However, information about the exact time when such inundation occurs is seldom considered, yet it is crucial for pedestrian evacuation planning. Here, we propose an approach to estimating tsunami hazard by combining tsunami flow depths and arrival times to produce a nine-level, qualitative hazard scale that is translated into a simple tsunami hazard map. To do this, one of the most populated regions of the coast of Chile is considered as the sample site, using a large set of 2,800 tsunamigenic sources from earthquakes with magnitudes in the range M w 8.6 − 9.2 , modeled from generation to inundation at high resolution. Main outcomes show great dependency of the hazard categorization on the tsunami time arrival, and less to the flow depths. Also, these results demonstrate that incorporating different sources of variability such as different earthquake magnitudes and locations as well as stochastic slip distributions is essential. Moreover, this proof-of-concept exercise clearly shows that the qualitative hybrid categorization of the tsunami hazard allows for its more effective understanding, which can be beneficial for designing mitigation strategies such as evacuation planning, and its management.
Using Underwater Pulse Oximetry in Freediving to Extreme Depths to Study Risk of Hypoxic Blackout and Diving Response Phases

Deep freediving exposes humans to hypoxia and dramatic changes in pressure. The effect of depth on gas exchange may enhance risk of hypoxic blackout (BO) during the last part of the ascent. Our aim was to investigate arterial oxygen saturation (SpO2) and heart rate (HR) in shallow and deep freedives, central variables, which have rarely been studied underwater in deep freediving. Four male elite competitive freedivers volunteered to wear a newly developed underwater pulse oximeter for continuous monitoring of SpO2 and HR during self-initiated training in the sea. Two probes were placed on the temples, connected to a recording unit on the back of the freediver. Divers performed one “shallow” and one “deep” constant weight dive with fins. Plethysmograms were recorded at 30 Hz, and SpO2 and HR were extracted. Mean ± SD depth of shallow dives was 19 ± 3 m, and 73 ± 12 m for deep dives. Duration was 82 ± 36 s in shallow and 150 ± 27 s in deep dives. All divers desaturated more during deeper dives (nadir 55 ± 10%) compared to shallow dives (nadir 80 ± 22%) with a lowest SpO2 of 44% in one deep dive. HR showed a “diving response,” with similar lowest HR of 42 bpm in shallow and deep dives; the lowest value (28 bpm) was observed in one shallow dive. HR increased before dives, followed by a decline, and upon resurfacing a peak after which HR normalized. During deep dives, HR was influenced by the level of exertion across different diving phases; after an initial drop, a second HR decline occurred during the passive “free fall” phase. The underwater pulse oximeter allowed successful SpO2 and HR monitoring in freedives to 82 m depth – deeper than ever recorded before. Divers’ enhanced desaturation during deep dives was likely related to increased exertion and extended duration, but the rapid extreme desaturation to below 50% near surfacing could result from the diminishing pressure, in line with the hypothesis that risk of hypoxic BO may increase during ascent. Recordings also indicated that the diving response is not powerful enough to fully override the exercise-induced tachycardia during active swimming. Pulse oximetry monitoring of essential variables underwater may be an important step to increase freediving safety.
Lack of Adiponectin Drives Hyperosteoclastogenesis in Lipoatrophic Mice

Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPARγ-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlighted the dual bone phenotype of PPARγ null mice: one the one hand, the increased bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPARγ deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explored the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPARγ deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibited mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.
Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies

Recombinant adeno-associated virus (rAAV) has attracted a significant research focus for delivering genetic therapies to target cells. This non-enveloped virus has been trialed in many clinical-stage therapeutic strategies but important obstacle in clinical translation is the activation of both innate and adaptive immune response to the protein capsid, vector genome and transgene product. In addition, the normal population has pre-existing neutralizing antibodies against wild-type AAV, and cross-reactivity is observed between different rAAV serotypes. While extent of response can be influenced by dosing, administration route and target organ(s), these pose concerns over reduction or complete loss of efficacy, options for re-administration, and other unwanted immunological sequalae such as local tissue damage. To reduce said immunological risks, patients are excluded if they harbor anti-AAV antibodies or have received gene therapy previously. Studies have incorporated immunomodulating or suppressive regimens to block cellular and humoral immune responses such as systemic corticosteroids pre- and post-administration of Luxturna® and Zolgensma®, the two rAAV products with licensed regulatory approval in Europe and the United States. In this review, we will introduce the current pharmacological strategies to immunosuppress or immunomodulate the host immune response to rAAV gene therapy.
Use of Chronic Prescription Medications and Prevalence of Polypharmacy in Survivors of Childhood Cancer

Background As survivors of childhood cancer age, development of cancer treatment-related chronic health conditions often occur. This study aimed to describe the pattern of chronic prescription medication use and identify factors associated with polypharmacy among survivors of childhood cancer. Methods This was a retrospective study conducted at the pediatric oncology long-term follow-up clinic in Hong Kong. Eligible subjects included survivors who were (1) diagnosed with cancer before 18 years old, (2) were at least 3 years post-cancer diagnosis and had completed treatment for at least 30 days, and (3) receiving long-term follow-up care at the study site between 2015 and 2018. Dispensing records of eligible survivors were reviewed to identify medications taken daily for ≥30 days or used on an “as needed” basis for ≥6 months cumulatively within the past 12-month period. Polypharmacy was defined as the concurrent use of ≥5 chronic medications. Multivariable log-binomial modeling was conducted to identify treatment and clinical factors associated with medication use pattern and polypharmacy. Results This study included 625 survivors (mean current age = 17.9 years, standard deviation [SD] = 7.2 years) who were 9.2 [5.2] years post-treatment. Approximately one-third (n = 219, 35.0%) of survivors were prescribed at least one chronic medication. Frequently prescribed medication classes include systemic antihistamines (26.5%), sex hormones (19.2%), and thyroid replacement therapy (16.0%). Overall prevalence of polypharmacy was 5.3% (n = 33). A higher rate of polypharmacy was found in survivors of CNS tumors (13.6%) than in survivors of hematological malignancies (4.3%) and other solid tumors (5.3%) (P = .0051). Higher medication burden was also observed in survivors who had undergone cranial radiation (RR = 6.31; 95% CI = 2.75–14.49) or hematopoietic stem-cell transplantation (HSCT) (RR = 3.53; 95% CI = 1.59–7.83). Conclusion Although polypharmacy was observed in a minority of included survivors of childhood cancer, chronic medication use was common. Special attention should be paid to survivors of CNS tumors and survivors who have undergone HSCT or cranial radiation. These individuals should be monitored closely for drug–drug interactions and adverse health outcomes that may result from multiple chronic medications, particularly during hospitalization in an acute care setting.
Identification of Prognostic Related Genes of Tumor Microenvironment Derived From Esophageal Cancer Patients

Background and Objective: Esophageal cancer (ESCA) is a commonly occurring cancer worldwide with poor survival and limited therapeutic options. Due to the lack of biomarkers that facilitate early detection, its treatment remains a great challenge. This study aims at identifying the tumor microenvironment (TME)-related genes, which might affect prognosis and accelerate clinical treatment for ESCA patients. Methods: We integrated the expression profiles from ESCA patients in The Cancer Genome Atlas. Then, we determined the stromal and immune scores of each sample using the R package. The Gene Expression Omnibus database was used to validate the expression profile of the key genes. Results: Tumor mutational burden showed a significant difference between the groups of ESCA patients with high and low ESTIMATE scores. We identified 859 intersection genes among patients with different immune and stromal scores. Moreover, gene ontology analysis demonstrated that these 859 intersection genes were closely related to adaptive immune response and regulation of lymphocyte activation. Kyoto Encyclopedia of Genes and Genomes showed the enrichment of cytokine-cytokine receptor interaction and chemokine signaling pathway in the TME. Furthermore, the protein–protein interaction network consisted of 175 nodes. We selected 35 hub genes, including ITGAM, CXCL10, CCR2, CCR5, and CCR1. Of these, 23 intersection genes predicted the overall survival rate. C1QA and FCER1G correlated with overall survival of the ESCA patients in the two databases. Conclusion: We identified a set of stromal and immune score-related prognostic differentially expressed genes that could influence the complexity of the TME. C1QA and FCER1G were identified and validated with respect to their role in the progression of ESCA.
The Prevalence of Depression and Its Association With Quality of Life Among Pregnant and Postnatal Women in China: A Multicenter Study

Background: This study examined the prevalence of depressive symptoms (depression hereafter) and its association with quality of life (QOL) among pregnant and postnatal women in China. Methods: In this multi-center, cross-sectional study, 1,060 pregnant and postnatal women from eight hospitals were assessed. Depression and QOL were measured using the Edinburgh Postnatal Depression Scale and the World Health Organization Quality of Life Questionnaire - brief version, respectively. Results: The prevalence of depression was 7.45% (95% CI: 5.87–9.04%) in the sample. Women with depression had lower QOL in physical, psychological, social and environmental domains compared to those without. Women with physical comorbidities were more likely to suffer from depression (OR = 2.391, 95% CI = 1.384–4.130, P = 0.002). Conclusion: Due to its negative association with QOL, increased attention should be paid to depression in pregnant and postnatal women. Regular screening assessment and preventive measures should be adopted to reduce risk of depression in this population.
The Degradation of Airway Epithelial Tight Junctions in Asthma Under High Airway Pressure Is Probably Mediated by Piezo-1

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+]i) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+]i/calpain signaling in the regulation of small airway TJs under extra pressure stimulation.
Particle Collection in Imhoff Sedimentation Cones Enriches Both Motile Chemotactic and Particle-Attached Bacteria

Marine heterotrophic microorganisms remineralize about half of the annual primary production, with the microbiomes on and around algae and particles having a major contribution. These microbiomes specifically include free-living chemotactic and particle-attached bacteria, which are often difficult to analyze individually, as the standard method of size-selective filtration only gives access to particle-attached bacteria. In this study, we demonstrated that particle collection in Imhoff sedimentation cones enriches microbiomes that included free-living chemotactic bacteria and were distinct from particle microbiomes obtained by filtration or centrifugation. Coastal seawater was collected during North Sea phytoplankton spring blooms, and the microbiomes were investigated using 16S rRNA amplicon sequencing and fluorescence microscopy. Enrichment factors of individual operational taxonomic units (OTUs) were calculated for comparison of fractionated communities after separation with unfractionated seawater communities. Filtration resulted in a loss of cells and yielded particle fractions including bacterial aggregates, filaments, and large cells. Centrifugation had the lowest separation capacity. Particles with a sinking rate of >2.4 m day–1 were collected in sedimentation cones as a bottom fraction and enriched in free-living chemotactic bacteria, i.e., Sulfitobacter, Pseudoalteromonas, and Vibrio. Subfractions of these bottom fractions, obtained by centrifugation, showed enrichment of either free-living or particle-attached bacteria. We identified five distinct enrichment patterns across all separation techniques: mechano-sensitive and mechano-stable free-living bacteria and three groups of particle-attached bacteria. Simultaneous enrichment of particle-attached and chemotactic free-living bacteria in Imhoff sedimentation cones is a novel experimental access to these groups providing more insights into the diversity, structure, and function of particle-associated microbiomes, including members of the phycosphere.
Deep Brain Stimulation in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis on Efficacy and Safety

Objective: Deep brain stimulation (DBS) has shown promising outcomes as new therapeutic opportunities for patients with treatment-resistant depression (TRD) who do not respond adequately to several consecutive treatments. This study aims to systematically review and conduct a meta-analysis on the efficacy and safety of DBS for TRD. Method: The literature was comprehensively reviewed using Medline, Google scholar, Cochrane library, Embase, and World Health Organization International Clinical Trials Registry Platform until January 2019. The studied outcomes included response, remission, recurrence, and adverse events (AEs) rates, and were reported as the rate ratio (RR) or pooled estimate with a 95% confidence interval (95% CI). Heterogeneity was measured by an I-square test and a sensitive analysis. Results: A total of 17 studies involving 7 DBS targets were included. For efficacy, DBS treatment was statistically beneficial for TRD, and the response, remission, and recurrence rates were 56% (ranging from 43 to 69%), 35% (ranging from 27 to 44%), and 14% (ranging from 4 to 25%), respectively. However, only two randomized-controlled trials (RCTs) considered the invalidity of DBS (RR = 1.45, 95% CI = 0.50–4.21). For safety, the AEs rate was 67% (ranging from 54 to 80%). The AEs were common and moderate, but the problems related to suicide and suicidal ideation should not be underestimated. Conclusion: These findings suggest that DBS for TRD is considered promising, which should be confirmed by well-designed and large sample studies. Future basic research and comprehensive clinical trials are needed to reach better understanding on the mechanisms of action and optimal targeted structure.
Harnessing Clinical Trial Capacity to Mitigate Zoonotic Diseases: The Role of Expert Scientists in Ethiopia

Background: The emergence and resurgence of zoonotic diseases have continued to be a major threat to global health and the economy. Developing countries are particularly vulnerable due to agricultural expansions and domestication of animals with humans. Scientifically sound clinical trials are important to find better ways to prevent, diagnose, and treat zoonotic diseases, while there is a lack of evidence to inform the clinical trials' capacity and practice in countries highly affected with the diseases. This study aimed to investigate expert scientists' perceptions and experiences in conducting clinical trials toward zoonotic diseases in Ethiopia. Methods: This study employed a descriptive, qualitative study design. It included major academic and research institutions in Ethiopia that had active engagements in veterinary and public health researches. It included the National Veterinary Institute, the National Animal Health Diagnostic and Investigation Center, the College of Veterinary Medicine at Addis Ababa University, the Ethiopian Public Health Institute, the Armauer Hansen Research Institute, and the College of Health Sciences at Addis Ababa University. In-depth interviews were conducted with expert scientists. Data were collected from October 2019 to April 2020. Data analysis was undertaken using open code 4.03 for qualitative data analysis. Results: Five major themes, with 18 sub-themes, emerged from the in-depth interviews. These were: challenges in the prevention, control, and treatment of zoonotic diseases; One Health approach to mitigate zoonotic diseases; personal and institutional experiences in conducting clinical trials on zoonotic diseases; barriers in conducting clinical trials toward zoonotic diseases; and strategies that promote conducting clinical trials on zoonotic diseases. Conducting clinical trials on zoonotic diseases in Ethiopia is hampered by a lack of clearly articulated ethics and regulatory frameworks, trial experts, financial resources, and good governance. Conclusion: In Ethiopia, conducting clinical trials on zoonotic diseases deserves due attention. Strengthening institutional and human resources capacity is a pre-condition to harness effective implementation of clinical trials on zoonotic diseases in the country. In Ethiopia where skilled human resource is scarce, One Health approach has the potential to form multidisciplinary teams to systematically improve clinical trials capacity and outcomes in the country.
Role of NFAT in Chronic Lymphocytic Leukemia and Other B-Cell Malignancies

In recent years significant progress has been made in the clinical management of chronic lymphocytic leukemia (CLL) as well as other B-cell malignancies; targeting proximal B-cell receptor signaling molecules such as Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3Kδ) has emerged as a successful treatment strategy. Unfortunately, a proportion of patients are still not cured with available therapeutic options, thus efforts devoted to studying and identifying new potential druggable targets are warranted. B-cell receptor stimulation triggers a complex cascade of signaling events that eventually drives the activation of downstream transcription factors including Nuclear Factor of Activated T cells (NFAT). In this review, we summarize the literature on the expression and function of NFAT family members in CLL where NFAT is not only overexpressed but also constitutively activated; NFAT controls B-cell anergy and targeting this molecule using specific inhibitors impacts on CLL cell viability. Next, we extend our analysis on other mature B-cell lymphomas where a distinct pattern of expression and activation of NFAT is reported. We discuss the therapeutic potential of strategies aimed at targeting NFAT in B-cell malignancies not overlooking the fact that NFAT may play additional roles regulating the inflammatory microenvironment.