Miracle-dz/UniFAR-FTUs huggingface dataset:
Avenues for antifungal drug discovery and development: where to now?

An increasing clinical burden of fungal disease is associated with chronic (e.g. chronic pulmonary aspergillosis), systemic (e.g. candidemia and cryptococcal meningoencephalitis), and recurrent (e.g. vulvovaginal candidiasis) infections. Patient populations, such as those with drug-induced immunosuppression or comorbidities including HIV or stem cell and solid organ transplantation, are at high risk of lifethreatening invasive fungal infections (IFIs) [1]. Additionally, the development of resistance to current antifungal therapies, including the emergence of multi-drug resistant species of Candida auris [2] and the increased incidence of voriconazoleresistant Aspergillus fumigatus isolates [3], underscore the need for new approaches in the management of fungal diseases. Discovery and development of agents that overcome resistance mechanisms is crucial. Common mechanisms responsible for innate and acquired drug resistance include the overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily (MFS) transporters [4]. Additionally, single mutations in genes of drug targets are also responsible for the development of resistance as it happens in the case of triazoles and mutations of lanosterol 14α-demethylase (Erg11p/ CYP51) [5]. Antifungal treatments under evaluation can be grouped into four categories: a. new antifungal classes, b. new agents that belong to an existing class of antifungal agents, c. new indications for established antifungal agents, and d. new antifungal strategies. Table 1 notes some ongoing clinical trials evaluating antifungal agents. The chemical structures of some representative antifungal agents under clinical drug discovery evaluation are presented in Figure 1. This editorial outlines some new antifungal concepts and strategies at different stages of evaluation that may supplement the limited existing options for antifungal therapy.
Poststroke activity engagement in community dwellers: Association with illness perceptions and perceived environment

Objectives To investigate whether individuals’ poststroke activity engagement is associated with their perceptions of stroke, as well as their perceptions of physical and social environment. Design Cross-sectional study. Setting Participants were recruited from eight rehabilitation settings in Beijing, China. Participants A total of 202 dyads of community dwellers with stroke and their primary caregivers. Main Measures Activity engagement measured by the Assessment of Life Habits; stroke individuals’ and caregivers’ illness perceptions measured by the Stroke-Specific Illness Perceptions Questionnaire – Revised; and stroke individuals’ perceived social and physical environment measured by the Social Support Survey and abbreviated Neighborhood Environment Walkability Scale. Results A total of 202 dyads of individuals with stroke and their caregivers participated in the study with mean ages of 61.3 (8.3) and 52.6 (11.6), respectively. On average, stroke individuals scored 7.61 (1.42) on the daily activities subscale, indicating that they completed personal level activities without assistance but with some difficulty. They scored 6.21 (2.21) on the social roles subscale, suggesting that individuals completed societal level activities with assistive devices and with some difficulty. Illness perceptions correlated significantly with personal level activity engagement (change in R-squared = 0.029; p = 0.049), and perceived accessibility and heterogeneity correlated significantly with societal level activity engagement (change in R-squared = 0.025; p = 0.011). Conclusions Poststroke activity engagement is associated not only with stroke individuals’ performance skills but also with their perceptions of stroke, and how they perceive their physical environment. The findings may assist clinicians’ decision making when developing comprehensive, targeted interventions for improving activity engagement and maximizing recovery after stroke.
Cigar Harm Beliefs and Associations with Cigar Use among Young Adults

Abstract Background: Cigar use, including little cigars and cigarillos (LCCs) and large traditional cigars, continues to harm young adults. Research on harm beliefs about cigars, particularly large cigars, is sparse. The current study examined cigar harm beliefs and associations with cigar use. Methods: Data are from a 2019 survey of a young adult cohort study recruited in fall 2010. Participants were asked questions about their beliefs about the harm of LCC and large cigar use. Those reporting ever use of cigars were asked how frequently they inhale the smoke into their lungs. Results: Participants (N = 1910) were 51.9% female with a mean age of 26.7 (SD = 0.6). Ever cigar use was 44.2% for large cigars and 43% for LCCs. Compared to those who have never used large cigars or LCCs, those reporting ever use of large cigars or LCCs reported lower harm beliefs about inhaling harmful chemicals and becoming addicted (ps <.0001). Those who reported higher harm beliefs also reported inhaling the smoke into their lungs more frequently for large cigars and LCCs (ps<.05). Conclusions: Cigar use harm beliefs were lower among participants reporting ever use of cigars compared to those reporting never use. Contrary to predictions, those reporting greater harm beliefs were more likely to report inhaling smoke more frequently than those with lower harm beliefs.
Gratitude and internalizing/externalizing symptoms among adolescents after the Wenchuan earthquake: Mediating roles of social support and resilience.

INTRODUCTION Adolescents are susceptible to exhibiting internalizing and externalizing symptoms following natural disasters. However, little is known regarding factors that may influence these symptoms from the perspective of positive psychology. The current study examined whether and how social support and resilience mediated the association between gratitude and adolescents' internalizing and externalizing symptoms. METHOD The participants were 765 Chinese adolescents exposed to the Wenchuan earthquake (41.8% male, mean age 17.46 years), who were enrolled in a three-wave longitudinal study with data spanning 1 year. All adolescents completed self-report questionnaires on gratitude at 18 months postearthquake (T18m ), social support and resilience at 24 months (T24m ), and internalizing and externalizing symptoms at 18 months (T18m ) and 30 months (T30m ). RESULTS The results showed that social support (T24m ) and resilience (T24m ) serially mediate the relationship between gratitude (T18m ) and internalizing (β = -.003, 95% confidence interval [CI]= -0.006, -0.001) or externalizing (T30m ) symptoms (β = -.004, 95% CI= -0.004, -0.001). Social support (T24m ) acts as a mediator only between gratitude (T18m ) and internalizing symptoms (T30m ) (β = -.021, 95% CI = -0.044, -0.004), while not being a significant predictor for externalizing symptoms (T30m ). CONCLUSION By highlighting the mechanisms by which gratitude longitudinally attenuates adolescents' internalizing, externalizing, and total symptoms, our findings may provide clinical practitioners with important information regarding intervention design.
Deconvolution analysis of cell‐type expression from bulk tissues by integrating with single‐cell expression reference

To understand phenotypic variations and key factors which affect disease susceptibility of complex traits, it is important to decipher cell‐type tissue compositions. To study cellular compositions of bulk tissue samples, one can evaluate cellular abundances and cell‐type‐specific gene expression patterns from the tissue transcriptome profiles. We develop both fixed and mixed models to reconstruct cellular expression fractions for bulk‐profiled samples by using reference single‐cell (sc) RNA‐sequencing (RNA‐seq) reference data. In benchmark evaluations of estimating cellular expression fractions, the mixed‐effect models provide similar results as an elegant machine learning algorithm named cell‐type identification by estimating relative subsets of RNA transcripts (CIBERSORTx), which is a well‐known and reliable procedure to reconstruct cell‐type abundances and cell‐type‐specific gene expression profiles. In real data analysis, the mixed‐effect models outperform or perform similarly as CIBERSORTx. The mixed models perform better than the fixed models in both benchmark evaluations and data analysis. In simulation studies, we show that if the heterogeneity exists in scRNA‐seq data, it is better to use mixed models with heterogeneous mean and variance–covariance. As a byproduct, the mixed models provide fractions of covariance between subject‐specific gene expression and cell types to measure their correlations. The proposed mixed models provide a complementary tool to dissect bulk tissues using scRNA‐seq data.
Weaknesses of research methodologies on musculoskeletal disorders associated with mobile touch‐screen devices

The objective of the currently study is to point out the weaknesses of some recent researches, which were done about the effects or symptoms of using Touch Screen Mobile Devices on the human musculoskeletal system. In this article, we reviewed the research processes performed in recent 26 randomly selected papers about musculoskeletal disorder to clarify the common weaknesses of these published articles. The electronic database search and reference search were conducted in four different databases: Medline, PubMed, Web of Science, and Scopus. We noticed that none of the reviewed papers had performed the experimental design phase of a scientific research. Additionally they had not validated the assumptions of the statistical methods used in their researches. Therefore, their findings are doubtful. In this article, we proposed practical outlines for a reliable experimental research.
Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Abstract Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.
A Randomized, Triple-Blind, Comparator-Controlled Parallel Study Investigating the Pharmacokinetics of Cannabidiol and Tetrahydrocannabinol in a Novel Delivery System, Solutech, in Association with Cannabis Use History

Background: An oral route of administration for tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ9-THC, 11-OH-THC, and 11-nor-9-carboxy-Δ9-THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. Materials and Methods: Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design. To evaluate the pharmacokinetics of Δ9-THC, CBD, 11-OH-THC, and THC-COOH, blood was collected at pre-dose (t=0) and 10, 20, 30, and 45, min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h post-dose after a single dose of Solutech (10.0 mg Δ9-THC, 9.76 mg CBD) or MCT (10.0 mg Δ9-THC, 9.92 mg CBD). Heart rate and blood pressure were measured at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Relationships between cannabis use history, body mass index, sex, and pharmacokinetic parameters were investigated. Safety was assessed before and at 48 h post-acute dose. Results: Acute consumption of Solutech provided a significantly greater maximum concentration (Cmax), larger elimination and absorption rate constants, faster time to Cmax and lag time, and half-life for all analytes compared to MCT-oil (p<0.001). In addition, cannabis use history had a significant influence on the pharmacokinetic parameters of CBD, Δ9-THC, 11-OH-THC, and THC-COOH. On average, participants with later age of first use had higher Δ9-THC, CBD, and THC-COOH Cmax and later time-to-Cmax and half-life for Δ9-THC, CBD, THC-COOH, and 11-OH-THC than those with earlier age of first use (p≤0.032). Those with more years of recreational cannabis use had higher area under the curve for Δ9-THC and CBD, Cmax for CBD, and longer 11-OH-THC half-life than those with less (p≤0.048). Conclusion: This study demonstrated that consumption of Solutech enhanced most pharmacokinetics parameters measured compared to MCT-oil. Participant's cannabis use history, including their age of first use and number of years using cannabis significantly impacted pharmacokinetic parameters investigated. Acute consumption of both products was found to be safe and well tolerated. The results suggest that Solutech may optimize bioavailability from cannabis formulations.
Perineal bowel evisceration after extralevator abdominoperineal excision and vertical rectus abdominis myocutaneous flap closure

Abstract Introduction Perineal bowel evisceration is a rare complication after extralevator abdominoperineal excision (ELAPE). This surgical technique is used to resect low rectal and anal cancer, with a lower likelihood of positive surgical margins, but resulting in a larger perineal defect. A vertical rectus abdominis myocutaneous (VRAM) flap allows filling of the empty pelvic space and closure of the defect in the pelvic floor. Case presentation A 77-year-old woman, with a hysterectomy in her medical history, underwent an ELAPE followed by reconstruction of the perineal defect with a VRAM flap after neoadjuvant radiotherapy for a moderately differentiated invasive adenocarcinoma of the distal rectum. The postoperative course was complicated with a herniation of the perineal wound and evisceration of a bowel loop. Conclusion Closure of the perineal defect after ELAPE remains a challenge, especially in cases where several risk factors for delayed wound healing, flap failure and perineal herniation are present.
Individuals with highly superior autobiographical memory do not show enhanced creative thinking

ABSTRACT Creative ideas are thought to result from flexible recombination of concepts from memory. A growing number of behavioural and neuroscientific studies provide evidence of a link between episodic memory and divergent thinking; however, little is known about the potential contributions of autobiographical memory to creative ideation. To provide a novel perspective on this issue, we assessed measures of divergent and convergent creative thinking in a cohort (n = 14) of rare individuals showing Highly Superior Autobiographical Memory (HSAM). The HSAM cohort completed memory tasks in addition to a battery of creativity measures, including the Alternative Uses Task, Consequences Task and Remote Associates Task. We performed statistical analyses to establish whether there were any significant differences between HSAM and controls (n = 28) across these measures. Although HSAM participants were superior in the recall of autobiographical events compared to controls, we observed no overall difference between the groups in relation to the creativity measures. These findings suggest that the constructive episodic processes relevant to creative thinking are not enhanced in individuals with HSAM, perhaps because they are compulsively and narrowly focused on consolidation and retrieval of autobiographical events.
Clinical grade ACE2 as a universal agent to block SARS‐CoV‐2 variants

The recent emergence of multiple SARS‐CoV‐2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS‐CoV‐2 variants. Here, we report that all SARS‐CoV‐2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by all current VOC strains with markedly enhanced potency when compared to reference SARS‐CoV‐2 isolates. Effective inhibition of infections with SARS‐CoV‐2 variants was validated and confirmed in two independent laboratories. These data show that SARS‐CoV‐2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan‐SARS‐CoV‐2 therapeutic.
Auditory perceptual learning in autistic adults

The automatic retuning of phoneme categories to better adapt to the speech of a novel talker has been extensively documented across various (neurotypical) populations, including both adults and children. However, no studies have examined auditory perceptual learning effects in populations atypical in perceptual, social, and language processing for communication, such as populations with autism. Employing a classic lexically‐guided perceptual learning paradigm, the present study investigated perceptual learning effects in Australian English autistic and non‐autistic adults. The findings revealed that automatic attunement to existing phoneme categories was not activated in the autistic group in the same manner as for non‐autistic control subjects. Specifically, autistic adults were able to both successfully discern lexical items and to categorize speech sounds; however, they did not show effects of perceptual retuning to talkers. These findings may have implications for the application of current sensory theories (e.g., Bayesian decision theory) to speech and language processing by autistic individuals.
Substance Use Disorder and Anxiety, Depression, Eating Disorder, PTSD, and Phobia Comorbidities Among Individuals Attending Residential Substance Use Treatment Settings

Abstract Objective: Mental health comorbidities among individuals with a substance use disorder are common. This study provides an analysis of the prevalence, risk factors, and treatment outcomes (depression, anxiety and stress, and cravings) of individuals with comorbid depression, anxiety, posttraumatic stress disorder (PTSD), obsessive compulsive disorders (OCD), and/or eating disorders attending residential substance use treatment centers. Methods: Intake and three-month post-discharge assessments of 603 (69.3% men) people attending residential substance use treatment services were conducted using the Mental Health Screening Scale, Addiction Severity Index, Depression, Anxiety Stress Scale, and a cravings measure. Results: Anxiety disorders were common (94.5%), followed by depression (89.6%), PTSD (62.0%), OCD (33.7%), and eating disorders (21.4%). Nearly a quarter reported two comorbidities and 8.5% reported five comorbidities. Higher comorbidity levels were associated with having poorer mental health but not cravings at three-month post-discharge follow-up. Conclusions: Comorbidity is common and complex in presentations to residential substance use treatment settings. Higher levels of comorbidity are linked to poorer mental health, which remains over time.
“The ubiquitin ligase SIAH2 is a female-specific regulator of circadian rhythms and metabolism”

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used SIAH2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of SIAH2-deficiency on the regulation of rhythmically expressed genes in the liver. The absence of SIAH2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic transcriptome in the liver by increasing the number of day-time expressed genes, and flipping the rhythmic expression from nighttime expressed genes to the daytime. These effects are not readily explained by effects on known sexually dimorphic pathways in females. Moreover, loss of SIAH2 in females, not males, preferentially altered the expression of transcription factors and genes involved in regulating lipid and lipoprotein metabolism. Consequently, SIAH2-deficient females, but not males, displayed disrupted daily lipid and lipoprotein patterns, increased adiposity and impaired metabolic homeostasis. Overall, these data suggest that SIAH2 may be a key component of a female-specific circadian transcriptional output circuit that directs the circadian timing of gene expression to regulate physiological rhythms, at least in the liver. In turn, our findings imply that sex-specific transcriptional mechanisms may closely interact with the circadian clock to tailor overt rhythms for sex-specific needs.
A new spirostanol steroid and a new spirostanol steroidal saponin from Aspidistra triradiata and their cytotoxic activities

Abstract A new spirostanol steroid, aspidiata A (1), and a new spirostanol steroidal saponin, aspidiata B (2), along with three known compounds, paris saponin VII (3), daucosterol (4), and (25R)-spirostane-1β,2β,3β,4β,5β,6β-hexol (5), were isolated from whole plants of Aspidistra triradiata collected in Vietnam. Their chemical structures were established by spectroscopic analysis and comparison with previously published data. Compound 3 showed strong cytotoxicity against LU-1, Hep-G2, MCF-7, and KB human cancer cell lines with half maximal inhibitory concentration (IC50) values ranging from 0.57 to 1.23 µM. Compound 5 exhibited weak cytotoxic activity against the LU-1 cell line, with an IC50 value of 95.81 µM. Graphical Abstract
Concepções de agricultores ecológicos do Paraná sobre alimentação saudável

OBJETIVO: Descrever as concepcoes de agricultores ecologicos sobre alimentacao saudavel. METODOS: Estudo com abordagem qualitativa. Entre janeiro e fevereiro de 2007, foram realizadas entrevistas em profundidade com o apoio de um roteiro com 11 mulheres e um homem residentes em comunidade agricola de Rio Branco do Sul, PR, selecionados aleatoriamente dentre as 20 familias de agricultores ecologicos desse municipio. RESULTADOS: Tres categorias de analise foram identificadas: "tomada de consciencia da alimentacao saudavel", "capacidade de compra" e "terra saudavel". O significado da alimentacao saudavel para as mulheres agricultoras envolve a ideia de que os alimentos devem ser naturais, sem agrotoxicos nem produtos quimicos industrializados. Cotidianamente o consumo de frutas, verduras e legumes somado ao basico feijao, arroz e carne deve ser abundante e a composicao do prato deve visar a prevencao de obesidade e doencas cronico-degenerativas. O cuidado com os recursos naturais para garantir a producao de alimentos saudaveis, a seguranca alimentar, a sustentabilidade do meio ambiente e a vida futura do planeta integram o conceito de alimentacao saudavel. CONCLUSOES: O conhecimento, a autocritica e o discernimento acompanharam as concepcoes em relacao a alimentacao saudavel.