Miracle-dz/UniFAR-FTUs huggingface dataset:
Actives from MMV Open Access Boxes? A suggested way forward

It is estimated that more than 1 billion people across the world are affected by a neglected tropical disease (NTD) that requires medical intervention. These diseases tend to afflict people in areas with high rates of poverty and cost economies billions of dollars every year. Collaborative drug discovery efforts are required to reduce the burden of these diseases in endemic regions. The release of “Open Access Boxes” is an initiative launched by Medicines for Malaria Venture (MMV) in collaboration with its partners to catalyze new drug discovery in neglected diseases. These boxes are mainly requested by biology researchers across the globe who may not otherwise have access to compounds to screen nor knowledge of the workflow that needs to be followed after identification of actives from their screening campaigns. Here, we present guidelines on how to move such actives beyond the hit identification stage, to help in capacity strengthening and enable a greater impact of the initiative.
Maximizing Cochlear Implant Outcomes with Short-Term Aural Rehabilitation

Abstract Background Increasing numbers of adults are receiving cochlear implants (CIs) and many achieve high levels of speech perception and improved quality of life. However, a proportion of implant recipients still struggle due to limited speech recognition and/or greater communication demands in their daily lives. For these individuals a program of aural rehabilitation (AR) has the potential to improve outcomes. Purpose The study investigated the effects of a short-term AR intervention on speech recognition, functional communication, and psychosocial outcomes in post lingually deafened adult CI users. Research Design The experimental design was a multisite clinical study with participants randomized to either an AR treatment or active control group. Each group completed 6 weekly 90-minute individual treatment sessions. Assessments were completed pretreatment, 1 week and 2 months post-treatment. Study Sample Twenty-five post lingually deafened adult CI recipients participated. AR group: mean age 66.2 (48–80); nine females, four males; months postactivation 7.7 (3–16); mean years severe to profound deafness 18.4 (2–40). Active control group: mean age 62.8 (47–85); eight females, four males; months postactivation 7.0 (3–13); mean years severe to profound deafness 18.8 (1–55). Intervention The AR protocol consisted of auditory training (words, sentences, speech tracking), and psychosocial counseling (informational and communication strategies). Active control group participants engaged in cognitive stimulation activities (e.g., crosswords, sudoku, etc.). Data Collection and Analysis Repeated measures ANOVA or analysis of variance, MANOVA or multivariate analysis of variance, and planned contrasts were used to compare group performance on the following measures: CasperSent; Hearing Handicap Inventory; Nijmegen Cochlear Implant Questionnaire; Client Oriented Scale of Improvement; Glasgow Benefit Inventory. Results The AR group showed statistically significant improvements on speech recognition performance, psychosocial function, and communication goals with no significant improvement seen in the control group. The two groups were statistically equivalent on all outcome measures at preassessment. The robust improvements for the AR group were maintained at 2 months post-treatment. Conclusion Results of this clinical study provide evidence that a short-term AR intervention protocol can maximize outcomes for adult post lingually deafened CI users. The impact of this brief multidimensional AR intervention to extend CI benefit is compelling, and may serve as a template for best practices with adult CI users.
Meikin synergizes with shugoshin to protect cohesin Rec8 during meiosis I

In this study, Ma et al. set out to study the mechanism of centromeric cohesion protection by Moa1/meikin during meiosis I. Using genetic and fluorescence microscopy approaches in fission yeast, the authors show that Moa1-Plo1 phosphorylates Rec8, which is required for Sgo1-PP2A to protect centromeric cohesion by antagonizing CK1-mediated phosphorylation of the cohesion subunit Rec8.
4-(2,5-Dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide improves monoclonal antibody production in a Chinese hamster ovary cell culture

There is a continuous demand to improve monoclonal antibody production for medication supply and medical cost reduction. For over 20 years, recombinant Chinese hamster ovary cells have been used as a host in monoclonal antibody production due to robustness, high productivity and ability to produce proteins with ideal glycans. Chemical compounds, such as dimethyl sulfoxide, lithium chloride, and butyric acid, have been shown to improve monoclonal antibody production in mammalian cell cultures. In this study, we aimed to discover new chemical compounds that can improve cell-specific antibody production in recombinant Chinese hamster ovary cells. Out of the 23,227 chemicals screened in this study, 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide was found to increase monoclonal antibody production. The compound suppressed cell growth and increased both cell-specific glucose uptake rate and the amount of intracellular adenosine triphosphate during monoclonal antibody production. In addition, the compound also suppressed the galactosylation on a monoclonal antibody, which is a critical quality attribute of therapeutic monoclonal antibodies. Therefore, the compound might also be used to control the level of the galactosylation for the N-linked glycans. Further, the structure-activity relationship study revealed that 2,5-dimethylpyrrole was the most effective partial structure of 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide on monoclonal antibody production. Further structural optimization of 2,5-dimethylpyrrole derivatives could lead to improved production and quality control of monoclonal antibodies.
Main-chain biodegradable liquid crystal derived from cholesteryl derivative end-capped poly(trimethylene carbonate): synthesis and characterisation

ABSTRACT Main-chain biodegradable liquid crystal derived from cholesteryl derivative end-capped poly(trimethylene carbonate) was investigated. The novel liquid crystal was synthesised via ring-opening polymerisation of trimethylene carbonate initiated by cholesteryl derivative with an alkyl spacer and end primary hydroxyl group, without any catalyst. The chemical structure of resulting polymers was verified by 1H NMR. Liquid crystalline properties were validated by X-ray diffraction, differential scanning calorimetry, and polarising optical microscopy. The results showed that all the synthesised polymers Chol-(CH2)2-(TMC)n exhibited mesomorphism in particular temperature ranges because of the introduction of the cholesteryl derivative moiety. Graphical Abstract
MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback

Positive feedback driven by transcriptional regulation has long been considered a key mechanism underlying cell lineage segregation during embryogenesis. Using the developing spinal cord as a paradigm, we found that canonical, transcription‐driven feedback cannot explain robust lineage segregation of motor neuron subtypes marked by two cardinal factors, Hoxa5 and Hoxc8. We propose a feedback mechanism involving elementary microRNA–mRNA reaction circuits that differ from known feedback loop‐like structures. Strikingly, we show that a wide range of biologically plausible post‐transcriptional regulatory parameters are sufficient to generate bistable switches, a hallmark of positive feedback. Through mathematical analysis, we explain intuitively the hidden source of this feedback. Using embryonic stem cell differentiation and mouse genetics, we corroborate that microRNA–mRNA circuits govern tissue boundaries and hysteresis upon motor neuron differentiation with respect to transient morphogen signals. Our findings reveal a previously underappreciated feedback mechanism that may have widespread functions in cell fate decisions and tissue patterning.
Maduramicin induces cardiotoxicity via Rac1 signaling‐independent methuosis in H9c2 cells

Maduramicin frequently induces severe cardiotoxicity in target and nontarget animals in clinic. Apoptotic and non‐apoptotic cell death mediate its cardiotoxicity; however, the underlying non‐apoptotic cell death induced by maduramicin remains unclear. In current study, a recently described non‐apoptotic cell death “methuosis” caused by maduramicin was defined in mammalian cells. Rat myocardial cell H9c2 was used as an in vitro model, showing excessively cytoplasmic vacuolization upon maduramicin (0.0625–5 μg/mL) exposure for 24 h. Maduramicin‐induced reversible cytoplasmic vacuolization of H9c2 cells in a time‐ and concentration‐dependent manner. The vacuoles induced by maduramicin were phase lucent with single membrane and were not derived from the swelling of organelles such as mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus. Furthermore, maduramicin‐induced cytoplasmic vacuoles are generated from micropinocytosis, which was demonstrated by internalization of extracellular fluid‐phase marker Dextran‐Alexa Fluor 488 into H9c2 cells. Intriguingly, these cytoplasmic vacuoles acquired some characteristics of late endosomes and lysosomes rather than early endosomes and autophagosomes. Vacuolar H+‐ATPase inhibitor bafilomycin A1 efficiently prevented the generation of cytoplasmic vacuoles and decreased the cytotoxicity of H9c2 cells triggered by maduramicin. Mechanism studying indicated that maduramicin activated H‐Ras‐Rac1 signaling pathway at both mRNA and protein levels. However, the pharmacological inhibition and siRNA knockdown of Rac1 rescued maduramicin‐induced cytotoxicity of H9c2 cells but did not alleviate cytoplasmic vacuolization. Based on these findings, maduramicin induces methuosis in H9c2 cells via Rac‐1 signaling‐independent seriously cytoplasmic vacuolization.
Pickering emulsion gels based on insoluble chitosan/gelatin electrostatic complexes

Food-grade colloidal particles or complexes made from natural polymers via noncovalent interactions can be good candidates for applications in food and non-food industries. In this work, insoluble chitosan/gelatin-B (CH/GB) complex particles were used for the first time as effective Pickering emulsifiers to make long-term stable oil-in-water emulsions and emulsion gels by one-step homogenization. The CH/GB complexes were only formed in the oppositely charged pH region via electrostatic complexation of CH and GB, and the pH showed a remarkable effect on the surface activity of CH/GB mixed systems. The presence of CH/GB insoluble complexes significantly decreased the surface tension of the oil/water interface, therefore benefitting the formation of smaller emulsion droplet sizes and effectively hindering droplet coalescence, as supported by the increase of emulsion long-term stability. Increasing the oil volume fraction considerably accelerated the formation of a droplet network structure, resulting in a solid-like thermoreversible emulsion gel with tunable viscoelastic properties. Our results suggest that CH/GB insoluble complex particles are promising particulate emulsifiers for the preparation of surfactant-free Pickering emulsions as well as emulsion gels.
Inferring Effective Connectivity Networks From fMRI Time Series With a Temporal Entropy-Score

Inferring brain-effective connectivity networks from neuroimaging data has become a very hot topic in neuroinformatics and bioinformatics. In recent years, the search methods based on Bayesian network score have been greatly developed and become an emerging method for inferring effective connectivity. However, the previous score functions ignore the temporal information from functional magnetic resonance imaging (fMRI) series data and may not be able to determine all orientations in some cases. In this article, we propose a novel score function for inferring effective connectivity from fMRI data based on the conditional entropy and transfer entropy (TE) between brain regions. The new score employs the TE to capture the temporal information and can effectively infer connection directions between brain regions. Experimental results on both simulated and real-world data demonstrate the efficacy of our proposed score function.
Citric Acid in Drug Formulations Causes Pain by Potentiating Acid-Sensing Ion Channel 1

Pain at the injection site is a common complaint of patients receiving therapeutic formulations containing citric acid. Despite the widely acknowledged role of acid-sensing ion channels (ASICs) in acid-related perception, the specific ASIC subtype mediating pain caused by subcutaneous acid injection and the mechanism by which citrate affects this process are less clear. Here, male mice subjected to intraplantar acid injection responded by executing a withdrawal reflex, and this response was abolished by ASIC1 but not ASIC2 knockout. Although intraplantar injection of neutral citrate solution did not produce this response, intraplantar injection of acidic citrate solution produced a withdrawal reflex greater than that produced by acidity alone. Consistent with the behavioral data, neutral citrate failed to produce an electrophysiological response in HEK293 cells, which express ASIC1, but acidic citrate produced a whole-cell inward current greater than that produced by acidity alone. Saturating the intracellular solution with citrate had no effect on the potentiating effect of extracellular citrate, suggesting that citrate acted extracellularly to potentiate ASIC1. Moreover, exposure to citrate immediately before acid stimulation failed to potentiate ASIC1 currents, which ruled out the involvement of a metabotropic receptor gated by a citrate metabolite. Finally, removal of calcium ions from the extracellular solution mimicked the potentiating effect of citrate and prevented citrate from further potentiating ASIC1. Our data demonstrate that ASIC1 is necessary for the nociceptive response caused by subcutaneous acid infusion and that neutral citrate, despite not inducing ASIC1 currents or nociceptive behavior on its own, potentiates acid nociception by removing the inhibitory effect of extracellular calcium ions on ASIC1. SIGNIFICANCE STATEMENT Citric acid is a common ingredient used in pharmaceutical formulations. Despite the widespread clinical use of these formulations, it remains unclear how citric acid causes pain when injected into patients. We identified ASIC1 as the key receptor used to detect injection-site pain caused by acid, and we showed that neutral citrate does not stimulate ASIC1; instead, citrate substantially potentiates ASIC1 activation when injected simultaneously with acid. In addition, we demonstrated that citrate potentiates ASIC1 by removing the inhibitory action of calcium on the extracellular side of the receptor. Given that injection-site pain is the primary complaint of patients receiving citrate-containing medical products, our data provide mechanistic insight into a common medical complaint and suggest a means of avoiding injection pain.
The role of foreign technologies and R&D in innovation processes within catching-up CEE countries

Prior research showed that there is a growing consensus among researchers, which point out a key role of external knowledge sources such as external R&D and technologies in enhancing firms´ innovation. However, firms´ from catching-up Central and Eastern European (CEE) countries have already shown in the past that their innovation models differ from those applied, for example, in Western Europe. This study therefore introduces a novel two-staged model combining artificial neural networks and random forests to reveal the importance of internal and external factors influencing firms´ innovation performance in the case of 3,361 firms from six catching-up CEE countries (Czech Republic, Slovakia, Poland, Estonia, Latvia and Lithuania), by using the World Banks´ Enterprise Survey data from 2019. We confirm the hypothesis that innovators in the catching-up CEE countries depend more on internal knowledge sources and, moreover, that participation in the firms groups represents an important factor of firms´ innovation. Surprisingly, we reject the hypothesis that foreign technologies are a crucial source of external knowledge. This study contributes to the theories of open innovation and absorptive capacity in the context of selected CEE countries and provides several practical implications for firms.
Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science, this issue p. eabg2538, p. 725 Children whose parents had been exposed to radiation from the Chernobyl accident had no excess germline mutations. Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987–2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
Lu177‐PSMA therapy for men with advanced prostate cancer: 18 months survival analysis in a single Australian tertiary institution

Radioligand therapies, or ‘theranostics’, have an emerging role in patients with metastatic castration‐resistant prostate cancer (mCRPC). Lutetium‐177 (Lu), targeting prostate‐specific membrane antigen (PSMA), has demonstrated promising outcomes including reduced disease progression and improved overall survival. We aim to determine overall survival demonstrated by our LuPSMA patient cohort to date.
Inoculation of pear flowers with Metschnikowia reukaufii and Acinetobacter nectaris enhances attraction of honeybees and hoverflies, but does not increase fruit and seed set

Currently, one of the most important challenges is to provide sufficient and affordable food and energy for a fast-growing world population, alongside preserving natural habitats and maintaining biodiversity. About 35% of the global food production depends on animals for pollination. In recent years, an alarming worldwide decline in pollinators has been reported, putting our food production under additional pressure. Therefore, there is an urgent need to find sustainable ways to ensure this crucial ecosystem service. Recent studies have shown that floral nectar is generally colonized by microorganisms, specifically yeasts and bacteria, which may alter nectar chemistry and enhance attraction of pollinators. In this study, we investigated changes in pollinator foraging behavior and pollination success in European pear (Pyrus communis L.) cultivars ‘Regal Red’ and ‘Sweet Sensation’ (red sports of ‘Doyenné de Comice’) after flower inoculation with the typical nectar-inhabiting microorganisms Metschnikowia reukaufii and Acinetobacter nectaris, and a combination of both. Pollination success was monitored by measuring the number of flower visits, fruit set and seed set in two consecutive years, 2019 and 2020. Results revealed that application of a mixture of M. reukaufii and A. nectaris resulted in significantly higher visitation rates of honeybees and hoverflies. By contrast, no effects on flower visits were found when yeasts and bacteria were applied separately. Fruit set and seed set were not significantly affected by any of the inoculation treatments. The only factors affecting fruit set were initial number of flower clusters on the trees and the year. The absence of treatment effects can most likely be attributed to the fact that pollination was not a limiting factor for fruit set in our experiments. Altogether, our results show that inoculation of flowers with nectar microbes can modify pollinator foraging patterns, but did not lead to increased pollination success under the conditions tested.
Cancer survivors’ perceived vulnerability to COVID-19 and impacts on cognitive, affective, and behavioral responses to the pandemic

Abstract Study objectives Given the uncertainty COVID-19 has caused for individuals with prior medical conditions, we examined the extent to which cancer survivors consider themselves at risk for the global COVID-19 pandemic (henceforth COVID), both in general and due to their cancer history. Additionally, we evaluated whether perceived vulnerability to COVID among cancer survivors predicts their cognitive/affective and behavioral responses to the pandemic. Design/sample Cancer survivors who completed primary cancer treatment (median months since treatment = 33.00) and were enrolled in prior behavioral trials with our research team (N = 146) completed two surveys in May-July 2020 (95.89% retention). Methods Participants rated perceived next-year risk of infection and of dying from COVID. We adapted established scales to assess perceived vulnerability to COVID generally versus as a cancer survivor, catastrophizing about possible COVID symptoms, COVID-related contamination fears, and adherence to COVID prevention behaviors. Findings In May 2020, on a 1-100 scale with 0 = no chance and 100 = definitely will occur, cancer survivors reported a chance in the next year of contracting COVID of M = 39.94 (SD = 23.90), and dying from COVID of M = 24.46 (SD = 24.84). Cancer survivors reported somewhat greater vulnerability to COVID compared to same-aged peers, increased contamination fears, and high adherence to COVID prevention measures. Similar findings emerged six weeks later, suggesting stability over time. In simple linear regression models, both general and cancer survivor-specific perceived COVID vulnerability predicted COVID symptom catastrophizing and contamination fears; in multivariable models, only general vulnerability remained a significant predictor. General perceived vulnerability and contamination fears predicted greater adherence to COVID prevention behaviors. Conclusions Cancer survivors perceived elevated vulnerability to COVID even years after treatment, which predicted adherence to COVID prevention behaviors. Future research should identify the optimal balance between supporting cancer survivors’ concerns and minimizing negative impacts on quality of life.