Miracle-dz/UniFAR-FTUs huggingface dataset:
Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner

Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2–3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.
Hormonal Contraceptive Use in Football Codes in Australia

The recent launch of the new National elite women's football competitions in Australia has seen a 20–50% increase in grassroots female participation. With the growing participation across grassroots to elite competitions, understanding the health of female athletes should be prioritized. In elite level athletes, hormonal contraceptive (HC) use is common (~50%), however, little is known about the prevalence and reasons for use and disuse of HC in elite female football athletes. As such, the impact of HC use is often not considered when monitoring the health of female footballers. This study involved a subset of data collected as part of a larger questionnaire investigating menstrual cycle function, hormonal contraception use, and the interaction with training load volume and perceived performance in elite female football code athletes. A total of 177 participants completed the questionnaire across three football codes within Australia (rugby league, rugby union/sevens, Australian football). One third (n = 58) of athletes were currently using HC, predominately in the form of an oral contraceptive pill (OC, n = 47). Reasons for use included: to avoid pregnancy (71%); to control/regulate cycle (38%); and to reduce menstrual pain (36%). However, most athletes using an OC (89%) could not identify the type of pill used (e.g., mono-, bi-, or triphasic). The main reason for disuse was due to the negative side effects (n = 23), such as mood swings, weight gain, and depression/anxiety. Comparing HC users and non-users, there were no statistical differences in the number of reported menstrual symptoms, use of medication to relieve menstrual pain, or frequency for needing to adapt training due to their menstrual cycle (p > 0.05). Since most athletes were unaware of the type of OC they used, female football athletes require further education about the different types of HC, and specifically OC, available to them. Similarities in the symptoms experienced, pain management, and training adaptation requirements between groups suggests that HC use may not have the intended outcome for certain athletes. As such, greater awareness of athlete's personal experiences with the menstrual cycle, how HC may influence their experience, and acknowledgment of non-pharmacological methods to help manage menstrual cycle related symptoms are warranted.
Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.
Measurements of cell density of three freshwater phytoplankters by density gradient centrifugation1

Density gradients of a modified silica sol (Percoll) were used to measure the densities of three freshwater phytoplankters of simple geometry. To check the validity of these measurements cell densities were calculated from a modification of Stokes’ law, which describes the dependence of sinking velocity (V) on cell shape (gb), nominal diameter (D), and density (p’): v = OYP’ - P> 18rl+ ’ Sinking velocities used in these calculations were measured fluorometrically, and with an inverted microscope. Comparison of the data derived from Percoll, with those obtained from the inverted microscope, showed precise agreement over a range of density values. This comparison suggests that direct measurement of cell density can be obtained from Percoll gradients. The ability to independently measure cell density and sinking velocity allows the determination of the coefficient of form resistance (4) and the elucidation of the relationships between sinking velocity, cell shape, and cell density. Values of $ calculated for approximately spherical Chlorococcum sp. were 1.02, 1.06, and 1.04, while for Chlorella vulgaris, a prolate spheroid, values were 0.98 and 1.07. Disk-shaped Cyclotella meneghiniana gave a #I value of 1.03.
Proto-Oncogenes and Cell Cycle Gene Expression in Normal and Neoplastic Oral Epithelial Cells Stimulated With Soluble Factors From Single and Dual Biofilms of Candida albicans and Staphylococcus aureus

This study was aimed at analyzing proto-oncogenic signaling pathway activation in normal oral keratinocytes (NOK-si) and neoplastic cell lines (SCC 25 and Detroit 562) stimulated with metabolites (soluble factors) from single and dual biofilms of Candida albicans and Staphylococcus aureus. Soluble factors (SF) from early (16-h) and mature (36-h) biofilms of C. albicans and S. aureus were collected and incubated with cell cultures, which were subsequently evaluated using gene expression via RT-qPCR, cell viability via AlamarBlueTM, and flow cytometry cell cycle analysis. In general, exposure to the SF of early and mature biofilms from C. albicans and dual species caused a major reduction in NOK-si cell viability and enhanced the sub G0 phase. This led to a decrease in gene expression. However, in this cell line, SF of S. aureus biofilms upregulated the CDKN1A gene followed by the maintenance of cell viability and a significant increase in the G2/M population. For tumor cells, SCC 25 and Detroit 562, the stimuli of SF biofilms upregulated oncogenes such as hRAS and mTOR, as well as Bcl-2 and CDKN1A. SCC 25 and Detroit 562 cells could survive even after 24 h of stimuli from both SF (early and mature). This occurred without significant changes taking place in the cell cycle progression for SCC 25, and with a significant tendency to increase the G2/M phase for Detroit 562. These results point to the fact that metabolites from prevalent clinical fungal and bacterial biofilms, C. albicans and S. aureus, can disrupt the homeostasis of normal and neoplastic oral epithelial cells. This changes proto-oncogenes’ expression, specifically PI3KCA, hRAS, mTOR, BRAF, and cell cycle genes CDKN1A and Bcl-2, thus causing a disturbance in cell viability, survival, and the cell cycle profile.
Impacts of Global Change on the Spatial Dynamics of Treeline in Venezuelan Andes

The treeline in the Andes is considered an essential ecotone between the Montane forest and Páramo. This treeline in the Venezuelan Andes corresponds with a transitional ecosystem defined as the Páramo forest. In this work, we identify and analyze the impact of climate warming and land transformation as agents altering the Páramo forest ecosystem’s spatial dynamics along the Venezuelan Andes’ altitudinal gradient. We carry out multitemporal studies of 57 years of the land transformation at different landscapes of the Cordillera de Mérida and made a detailed analysis to understand the replacement of the ecosystems potential distribution. We found that the main ecosystem transition is from Páramo to the Páramo forest and from Páramo to the Montane forest. Based on the difference between the current lower Páramo limit and the Forest upper limit for 1952, the treeline border’s displacement is 72.7 m in the 57 years of study, representing ∼12.8 m per decade. These changes are mainly driven by climate warming and are carried out through an ecological process of densification of the woody composition instead of the shrubland structure. We found that Páramo forest ecosystems practically have been replaced by the Pastures and fallow vegetation, and the Crops. We present a synthesis of the transition and displacement of the different ecosystems and vegetation types in the treeline zone. The impact of climate warming and deforestation on the Páramo forest as a representative ecosystem of the treeline shows us that this study is necessary for an integrated global change adaptation plan.
The Role of CXCL13 in Antibody Responses to HIV-1 Infection and Vaccination

CXCL13 signals through the G protein-coupled chemokine receptor CXCR5 to drive development of secondary lymphoid tissue as well as B cell and Tfh cell trafficking to germinal centers (GC), which leads to the differentiation of B cells to plasma cells and memory B cells. CXCL13 has been proposed as a general plasma biomarker for GC activities. In HIV-1 infected individuals, plasma CXCL13 levels have been associated with the rate of disease progression to AIDS. Moreover, CXCL13 production has been reported to be increased in HIV-1-infected lymph nodes, which may drive increased downregulation of CXCR5. In this review, we address the role of CXCL13 in HIV-1 infected individuals with regard to GC formation, generation of broadly neutralizing antibodies after infection and vaccination, and AIDS-related B cell lymphoma.
Precipitation Changes Regulate Plant and Soil Microbial Biomass Via Plasticity in Plant Biomass Allocation in Grasslands: A Meta-Analysis

In theory, changes in the amount of rainfall can change plant biomass allocation and subsequently influence coupled plant-soil microbial processes. However, testing patterns of combined responses of plants and soils remains a knowledge gap for terrestrial ecosystems. We carried out a comprehensive review of the available literature and conducted a meta-analysis to explore combined plant and soil microbial responses in grasslands exposed to experimental precipitation changes. We measured the effects of experimental precipitation changes on plant biomass, biomass allocation, and soil microbial biomass and tested for trade-offs between plant and soil responses to altered precipitation. We found that aboveground and belowground plant biomass responded asynchronically to precipitation changes, thereby leading to shifts in plant biomass allocation. Belowground plant biomass did not change under precipitation changes, but aboveground plant biomass decreased in precipitation reduction and increased in precipitation addition. There was a trade-off between responses of aboveground plant biomass and belowground plant biomass to precipitation reduction, but correlation wasn't found for precipitation addition. Microbial biomass carbon (C) did not change under the treatments of precipitation reduction. Increased root allocation may buffer drought stress for soil microbes through root exudations and neutralize microbial responses to precipitation reduction. However, precipitation addition increased microbial biomass C, potentially reflecting the removal of water limitation for soil microbial growth. We found that there were positive correlations between responses of aboveground plant biomass and microbial biomass C to precipitation addition, indicating that increased shoot growth probably promoted microbial responses via litter inputs. In sum, our study suggested that aboveground, belowground plant biomass and soil microbial biomass can respond asynchronically to precipitation changes, and emphasizes that testing the plant-soil system as a whole is necessary for forecasting the effects of precipitation changes on grassland systems.
Microbiologically-Synthesized Nanoparticles and Their Role in Silencing the Biofilm Signaling Cascade

The emergence of bacterial resistance to antibiotics has led to the search for alternate antimicrobial treatment strategies. Engineered nanoparticles (NPs) for efficient penetration into a living system have become more common in the world of health and hygiene. The use of microbial enzymes/proteins as a potential reducing agent for synthesizing NPs has increased rapidly in comparison to physical and chemical methods. It is a fast, environmentally safe, and cost-effective approach. Among the biogenic sources, fungi and bacteria are preferred not only for their ability to produce a higher titer of reductase enzyme to convert the ionic forms into their nano forms, but also for their convenience in cultivating and regulating the size and morphology of the synthesized NPs, which can effectively reduce the cost for large-scale manufacturing. Effective penetration through exopolysaccharides of a biofilm matrix enables the NPs to inhibit the bacterial growth. Biofilm is the consortia of sessile groups of microbial cells that are able to adhere to biotic and abiotic surfaces with the help extracellular polymeric substances and glycocalyx. These biofilms cause various chronic diseases and lead to biofouling on medical devices and implants. The NPs penetrate the biofilm and affect the quorum-sensing gene cascades and thereby hamper the cell-to-cell communication mechanism, which inhibits biofilm synthesis. This review focuses on the microbial nano-techniques that were used to produce various metallic and non-metallic nanoparticles and their “signal jamming effects” to inhibit biofilm formation. Detailed analysis and discussion is given to their interactions with various types of signal molecules and the genes responsible for the development of biofilm.
Biodiversity and Human Health Interlinkages in Higher Education Offerings: A First Global Overview

Introduction: Biodiversity is inextricably linked to human health. As an important area of research of the Convention on Biological Diversity and a key avenue for the dissemination of biodiversity and health knowledge, we investigated how well-embedded biodiversity and health interlinkages are in institutional higher education offerings. Methods: Using One Health education programs as a starting point, we collected a global list of institutions potentially carrying out education in the links between biodiversity and health through previously published research, academic partners of global conglomerates, and our own networks. We then analyzed the offerings from these institutions to determine the degree of integration of biodiversity and health interlinkages. Results: We found 105 educational offerings in biodiversity and health interlinkages from 89 institutions in 30 countries. These were primarily found in faculties of public health, veterinary sciences, and medicine, with varying degrees of coverage of the interlinkages. Conclusion: Education incorporating the links between biodiversity and health exists globally, but should be more widely integrated, particularly through inter-faculty and inter-institutional collaboration.
Polluted Air Exposure Compromises Corneal Immunity and Exacerbates Inflammation in Acute Herpes Simplex Keratitis

Air pollution is a serious environmental issue worldwide in developing countries’ megacities, affecting the population’s health, including the ocular surface, by predisposing or exacerbating other ocular diseases. Herpes simplex keratitis (HSK) is caused by the herpes simplex virus type 1 (HSV-1). The primary or recurring infection in the ocular site causes progressive corneal scarring that may result in visual impairment. The present study was designed to study the immunopathological changes of acute HSK under urban polluted air, using the acute HSK model combined with an experimental urban polluted air exposure from Buenos Aires City. We evaluated the corneal clinical outcomes, viral DNA and pro-inflammatory cytokines by RT-PCR and ELISA assays, respectively. Then, we determined the innate and adaptive immune responses in both cornea and local lymph nodes after HSV-1 corneal by immunofluorescence staining and flow cytometry. Our results showed that mice exposed to polluted air develop a severe form of HSK with increased corneal opacity, neovascularization, HSV-1 DNA and production of TNF-α, IL-1β, IFN-γ, and CCL2. A high number of corneal resident immune cells, including activated dendritic cells, was observed in mice exposed to polluted air; with a further significant influx of bone marrow-derived cells including GR1+ cells (neutrophils and inflammatory monocytes), CD11c+ cells (dendritic cells), and CD3+ (T cells) during acute corneal HSK. Moreover, mice exposed to polluted air showed a predominant Th1 type T cell response over Tregs in local lymph nodes during acute HSK with decreased corneal Tregs. These findings provide strong evidence that urban polluted air might trigger a local imbalance of innate and adaptive immune responses that exacerbate HSK severity. Taking this study into account, urban air pollution should be considered a key factor in developing ocular inflammatory diseases.
Benefits of Expressive Writing on Healthcare Workers’ Psychological Adjustment During the COVID-19 Pandemic

COVID-19 outbroke in Wuhan, China, in December 2019 and promptly became a pandemic worldwide, endangering health and life but also causing mild-to-severe psychological distress to lots of people, including healthcare workers (HCWs). Several studies have already showed a high prevalence of depression, anxiety, and post-traumatic symptoms in HCWs but less is known about the efficacy of psychological interventions for relieving their mental distress. The aims of this study were: (1) to evaluate the psychological adjustment of Italian HCWs during the COVID-19 pandemic; (2) to investigate the efficacy of an expressive writing (EW) intervention, based on Pennebaker’s paradigmatic protocol, on their psychological adjustment; (3) to analyze if outcomes of EW vary in function of individual differences (age, gender, marital status, and baseline values of symptoms). Fifty-five HCWs were randomly assigned to one of two writing conditions: EW (n = 30) or neutral writing (NW; n = 25). Psychological adjustment (in terms of ptsd, depression and global psychopathology’s symptoms, perceived social support, and resilience) was assessed before and after three writing sessions. Participants who received the EW intervention showed higher improvements in ptsd, depression, and global psychopathology symptoms. Improvements in EW group varied in function of age, gender, marital status, and baseline values: young, men, married participants and those who had higher baseline scores showed a higher reduction of psychological distress symptoms while women, single and those who had lower baseline value showed increased social support, and resilience. In conclusion, the EW intervention had positive effects which varied in function of individual differences on HCWs’ psychological health.
Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects

The increasing incidence of geriatric patients with multiple myeloma has elevated concerns in clinical practice. While the introduction of novel therapeutic agents has substantially improved outcomes in younger patients with myeloma, poorer outcomes remain in older patients. Managing older patients requires a multidisciplinary team approach to consider factors that may influence both treatment selection and outcomes. Aging is associated with remodeling of vital organs, physiological downregulations of basal metabolism, susceptibility to multiple comorbidities with ultimate frailty, thereby contributing to the underrepresentation and exclusion of very old patients from clinical trials. Therefore, timely confirmation of a precise diagnosis is crucial for prompt initiation of treatment if the desired outcome is to be achieved. Adequate and judicious assessment using comprehensive geriatric assessment tools minimizes toxicities and treatment discontinuation. Initiating treatment with combinational therapy requires knowledge of indications and anticipated outcomes, as well as individualized therapy with appropriate dose-adjustment. Individualized therapy based on good clinical acumen and best practices obverts unwanted polypharmacy, preventing iatrogenic harm. This review will therefore address the approaches and challenges faced in managing myeloma in geriatric patients aged 80 years and older, highlighting recommended therapeutic strategies and future prospective regimens.
Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

Strokes are the most common types of cerebrovascular disease and remain a major cause of death and disability worldwide. Cerebral ischemic stroke is caused by a reduction in blood flow to the brain. In this disease, two major zones of injury are identified: the lesion core, in which cells rapidly progress toward death, and the ischemic penumbra (surrounding the lesion core), which is defined as hypoperfusion tissue where cells may remain viable and can be repaired. Two methods that are approved by the Food and Drug Administration (FDA) include intravenous thrombolytic therapy and endovascular thrombectomy, however, the narrow therapeutic window poses a limitation, and therefore a low percentage of stroke patients actually receive these treatments. Developments in stem cell therapy have introduced renewed hope to patients with ischemic stroke due to its potential effect for reversing the neurological sequelae. Over the last few decades, animal tests and clinical trials have been used to treat ischemic stroke experimentally with various types of stem cells. However, several technical and ethical challenges must be overcome before stem cells can become a choice for the treatment of stroke. In this review, we summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. We also discuss new developing trends in this field.