Miracle-dz/UniFAR-FTUs huggingface dataset:
Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy

Significance Strategies to improve efficacy and reduce side effects of immune checkpoint blockade (ICB) therapy are clinically relevant. Here, we described a transdermal cold atmospheric plasma (CAP)-mediated ICB therapy. Local delivery of CAP through hollow-structured microneedles as microchannels promote the release of tumor-associated antigens by CAP. The subsequent T cell-mediated immune response can be augmented by the immune checkpoint inhibitors delivered via microneedles, resulting in enhanced local and systemic anticancer immunity. The synergism between CAP and ICB integrated with microneedles provides a platform technique for cancer treatment and other diseases in a minimally invasive manner. Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.
Interpersonal Risk Factors for Suicide in Cocaine Dependence: Association with Self-Esteem, Personality Traits, and Childhood Abuse.

OBJECTIVE Studies have linked cocaine dependence to suicidality. According to the Interpersonal Theory of Suicide, suicidal behavior becomes likely with the simultaneous presence of perceived burdensomeness (PB), lack of (or thwarted) belongingness (TB), and acquired fearlessness about death (FAD). Here, we examined personality and other variables, including depression, self-esteem, childhood abuse, and substance use, as predictors of these risk factors in cocaine-dependent individuals (CDs). METHODS Seventy CDs and 70 healthy controls (HCs) participated. We examined group differences in a group-by-sex analysis of variance and identified predictors of PB, TB, and FAD in stepwise regressions. RESULTS CDs exhibited elevated PB and TB but not FAD, compared to HCs. CDs also exhibited elevated harm avoidance, novelty seeking, depression, and lower self-esteem and reward dependence. Females reported elevated sexual abuse, harm avoidance, reward dependence, depression, but lower FAD, relative to males, among CDs and HCs. Among CDs, PB was predicted by lower self-esteem and greater emotional abuse; TB was predicted by lower self-esteem and reward dependence, as well as greater emotional and sexual abuse; and FAD was predicted by lower harm avoidance and greater physical abuse. CONCLUSIONS Interventions targeting suicidality in cocaine dependence should take into consideration self-esteem, personality traits, and childhood abuse.
Serum leptin, resistin, and adiponectin levels in obese and non-obese patients with newly diagnosed type 2 diabetes mellitus

Abstract Disturbances in adipocytokine profiles can contribute to peripheral insulin resistance and impairment of insulin production, which are 2 primary pathophysiological mechanisms involved in type 2 diabetes mellitus (T2DM). Previous studies of disturbed adipocytokine profiles have resulted in ambiguous findings; therefore, we conducted the current study comparing leptin, resistin, and adiponectin concentrations in patients with newly diagnosed T2DM who had normal body mass index (BMI) and those who were obese. We studied a population-based cohort of healthy participants and those with newly diagnosed T2DM. A normal BMI group was randomly selected; age- and sex-matched obese participants were recruited. Circulating leptin, resistin, and adiponectin concentrations were measured and compared between groups using analysis of variance; binary logistic regression analysis was then performed to compare the normal BMI and obese groups. In total, 85 healthy participants and 38 patients with diabetes (19 with normal BMI and 17 who were obese) were enrolled. After adjustment for BMI and waist circumference, the median leptin concentration was higher in the obese group (6.77 (3.89–10.73) ng/mL) than in the normal BMI group (1.69 (0.80–3.89) ng/mL) (P = .007), whereas the median adiponectin concentration was lower in the obese group (1.03 (0.75–2.36) μg/mL vs 3.36 (0.59–7.63) μg/mL, P = . 03). In addition, the adiponectin/leptin ratio was higher in the normal BMI group (145.6 (41.3–495.9) ng/mL) than in the obese group (20.55 (8.74–36.94) ng/mL, P = . 002). Compared with the normal BMI T2DM group, the obese T2DM group exhibited a disturbed adipocytokine profile in the form of a significantly increased leptin concentration and reduced adiponectin level. Further studies are needed to determine the causal relationship for this difference and evaluate its importance for personalized diabetic treatment.
Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1

Occurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibitor decitabine (DAC) with the histone deacetylase inhibitor entinostat (ENT) in bladder cancer cells with different platinum sensitivities: J82, cisplatin-resistant J82CisR, and RT-112. Intermittent treatment of J82 cells with cisplatin resulted in the six-fold more cisplatin-resistant cell line J82CisR. Combinations of DAC and/or ENT plus cisplatin could not reverse chemoresistance. However, the combination of DAC and ENT acted cytotoxic in a highly synergistic manner as shown by Chou-Talalay analysis via induction of apoptosis and cell cycle arrest. Importantly, this effect was cancer cell-selective as no synergism was found for the combination in the non-cancerous urothelial cell line HBLAK. Expression analysis indicated that epigenetic treatment led to up-regulation of forkhead box class O1 (FoxO1) and further activated proapoptotic Bim and the cell cycle regulator p21 and reduced expression of survivin in J82CisR. In conclusion, the combination of DAC and ENT is highly synergistic and has a promising potential for therapy of bladder cancer, particularly in cases with platinum resistance.
Gestational Exercise and Maternal and Child Health: Effects until Delivery and at Post-Natal Follow-up

We studied the influence of pregnancy exercise on maternal/offspring cardiometabolic health until delivery and at follow-up. We pooled data from two randomized controlled trials from our group that were performed following the same methodology (one unpublished). We also collected follow-up data de novo from the participants of both trials and their offspring. In total, 1348 women with uncomplicated, singleton gestations were assigned to an intervention (n = 688, performing a supervised, moderate-intensity exercise program (three sessions/week)) or control group (n = 660). Maternal outcomes were excessive gestational weight gain (EGWG), gestational hypertension/diabetes and, at follow-up, return to pre-pregnancy weight within six months, hypertension, overweight/obesity, and other cardiometabolic conditions. Offspring outcomes were macrosomia and low-birthweight and, at follow-up, overweight/obesity, low-weight, and cardiometabolic conditions. Adherence to the intervention, which proved safe, was > 95%. Pregnancy exercise reduced the risk of EGWG, gestational hypertension, and diabetes (adjusted odds ratio (OR) and 95% confidence interval: 0.60 (0.46–0.79), 0.39 (0.23–0.67), and 0.48 (0.28–0.84)), and it was associated with a greater likelihood of returning to pre-pregnancy weight (2.37 (1.26–4.54)) and a lower risk of maternal cardiometabolic conditions (0.27 (0.08–0.95)) at the end of follow-up (median 6.1 years (interquartile range 1.8)). Pregnancy exercise also reduced the risk of macrosomia (0.36 (0.20–0.63)) and of childhood overweight/obesity during the first year (0.20 (0.06–0.63)). Our findings suggest that pregnancy exercise might protect maternal/offspring health.
Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases

Independent of cathepsin K, the osteoclast-derived matrix metalloproteinases MMP9 and MMP14 codependently drive bone resorption. Codependent deconstruction Bone homeostasis encompasses a balancing act between formation of new bone and remodeling and resorption of existing bone. For patients with bone-wasting disorders such as osteoporosis, bone resorption predominates. To identify potential therapeutic targets in maladaptive bone resorption, Zhu et al. investigated mechanisms of collagenolytic activity in osteoclasts. They found that dual deletion of the matrix metalloproteinases MMP9 and MMP14 inhibited murine and human osteoclast activity, increased bone density, and prevented against pathogenic bone loss in mice. Dual targeting of MMP9 and MMP14 could potentially help treat bone-wasting diseases. Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K–null mice, as well as cathepsin K–mutant humans, continue to remodel bone and degrade collagen by as-yet-undefined effectors. Here, we identify a cathepsin K–independent collagenolytic system in osteoclasts that is composed of a functionally redundant network of the secreted matrix metalloproteinase MMP9 and the membrane-anchored matrix metalloproteinase MMP14. Unexpectedly, whereas deleting either of the proteinases individually leaves bone resorption intact, dual targeting of Mmp9 and Mmp14 inhibited the resorptive activity of mouse osteoclasts in vitro and in vivo and human osteoclasts in vitro. In vivo, Mmp9/Mmp14 conditional double-knockout mice exhibited marked increases in bone density and displayed a highly protected status against either parathyroid hormone– or ovariectomy-induced pathologic bone loss. Together, these studies characterize a collagenolytic system operative in mouse and human osteoclasts and identify the MMP9/MMP14 axis as a potential target for therapeutic interventions for bone-wasting disease states.
Hormetic effect of glyphosate persists during the entire growth period and increases sugarcane yield.

BACKGROUND Stimulation of plant growth by low doses of a toxic compound is defined as a hormetic effect. Exposure of plants to low doses of glyphosate can cause stimulatory effects on growth or other variables. Sugarcane is the major biofuel and sugar-production crop cultivated in Brazil, but its expansion to new areas is limited; therefore, there is a demand for new technologies to improve sugarcane production per unit area. The use of pesticides to stimulate growth through the hormetic effect might be a suitable strategy to increase sugarcane yields. The purpose of this research was to investigate the effect of a low dose of glyphosate on metabolic compound accumulation, leaf phosphorus (P) concentration, and morphological variables across a one-year sugarcane cycle, as well as to determine whether the glyphosate effect was sustained and effective in improving the yield and technological quality of the sugarcane at harvest. RESULTS The application of a low dose of glyphosate led to higher concentrations of shikimic acid and quinic acid, higher leaf P concentrations, and improved plant growth, yield, and technological quality of the sugarcane, by increasing the Brix% juice, pol% cane, total recoverable sugar, tons of culms per hectare, and tons of pol per hectare, relative to the results for an untreated control. CONCLUSIONS The increased growth stimuli, observed through several variables, promoted an improvement in sugarcane yield. Therefore, the application of a low dose of glyphosate to sugarcane is a promising practice for crop management. This article is protected by copyright. All rights reserved.
Prevalence of alexithymia and associated factors among medical students at King Abdulaziz University: a cross-sectional study

ABSTRACT BACKGROUND: Medical students are at higher risk of developing alexithymia due to the nature of their studies. OBJECTIVES: Determine the prevalence of alexithymia and potential risk factors among medical students in Saudi Arabia. DESIGN: A cross-sectional analytic study. SETTINGS: University medical school. PATIENTS AND METHODS: An institutional cross-sectional survey of medical students was conducted using the Toronto Alexithymia Scale (TAS-20) to assess the prevalence of alexithymia and potentially associated factors (gender, parental marital status, grade point average, status of accommodations, smoking status, year of study, childhood abuse, a history of mental illness, and physical activity). MAIN OUTCOME MEASURES: Gender, parental marital status, grade point average, status of accommodations, smoking status, year of study, childhood abuse, a history of mental illness, and physical activity. SAMPLE SIZE: 347. RESULTS: The prevalence of alexithymia among medical students was 49% (95% confidence interval [43.8–54.2]). A binary logistic regression model showed significant associations between alexithymia and academic year of study (lower risk of alexithymia in the clerkship (5th, 6th years); odds ratio [OR]: 0.43, 95% CI: 0.26–0.72), smoking (OR: 3.52, 95% CI: 1.60–3.34), grade point average (lowest; OR: 10.44, 95% CI: 4.24–25.77), history of childhood abuse (OR: 2, 95% CI: 1.20–8.77), and history of psychiatric illness (OR: 14.40, 95% CI: 4.76–21.06). CONCLUSION: Almost half of the medical students suffer from alexithymia. Increasing the awareness about alexithymia among students and directing them where to seek help would facilitate the management of these problems. LIMITATIONS: Limited only to medical students from the second year to the sixth year in a single medical college, which affects generalizability. The cross-sectional design might have also limited generalizability. CONFLICT OF INTEREST: None.
The Outrage Effect of Personal Stake, Dread, and Moral Nature on Fine Dust Risk Perception Moderated by Media Use

ABSTRACT Outrage factors are perceived characteristics of risk that provoke emotional responses and influence risk perception by individuals. We investigated outrage factors that are associated with risk perception regarding fine dust. A nationwide online survey (N = 1,000) measured the magnitude of 14 perceived outrage factors and media use in a South Korean population. As a result, the hypothetical three outrage factors of personal stake, dread, and moral nature were found to be influential. The risk perception increased when people perceived that the environmental hazard has personal implications or is associated with fearful images and irresponsible government/corporate actions. The risk perception was also heightened when fine dust was thought to cause large-scale damage to many people simultaneously. Those using news media frequently showed higher risk perception than those using it less frequently. However, heavy media users were affected to a lesser degree by the outrage effects voluntariness and effects on children. The implications of the direct and indirect outrage effect are discussed in light of risk perception studies.
Nutritive vitamins as epidrugs

Abstract Epigenetic modifications play an important role in disease pathogenesis and therefore are a focus of intense investigation. Epigenetic changes include DNA, RNA, and histone modifications along with expression of non-coding RNAs. Various factors such as environment, diet, and lifestyle can influence the epigenome. Dietary nutrients like vitamins can regulate both physiological and pathological processes through their direct impact on epigenome. Vitamin A acts as a major regulator of above-mentioned epigenetic mechanisms. B group vitamins including biotin, niacin, and pantothenic acid also participate in modulation of various epigenome. Further, vitamin C has shown to modulate both DNA methylation and histone modifications while few reports have also supported its role in miRNA-mediated pathways. Similarly, vitamin D also influences various epigenetic modifications of both DNA and histone by controlling the regulatory mechanisms. Despite the information that vitamins can modulate the epigenome, the detailed mechanisms of vitamin-mediated epigenetic regulations have not been explored fully and hence further detailed studies are required to decipher their role at epigenome level in both normal and disease pathogenesis. The current review summarizes the available literature on the role of vitamins as epigenetic modifier and highlights the key evidences for developing vitamins as potential epidrugs.
The intersection of nitrogen nutrition and water use in plants: new paths toward improved crop productivity

Abstract Water and nitrogen availability limit crop productivity globally more than most other environmental factors. Plant availability of macronutrients such as nitrate is, to a large extent, regulated by the amount of water available in the soil, and, during drought episodes, crops can become simultaneously water and nitrogen limited. In this review, we explore the intricate relationship between water and nitrogen transport in plants, from transpiration-driven mass flow in the soil to uptake by roots via membrane transporters and channels and transport to aerial organs. We discuss the roles of root architecture and of suberized hydrophobic root barriers governing apoplastic water and nitrogen movement into the vascular system. We also highlight the need to identify the signalling cascades regulating water and nitrogen transport, as well as the need for targeted physiological analyses of plant traits influencing water and nitrogen uptake. We further advocate for incorporation of new phenotyping technologies, breeding strategies, and agronomic practices to improve crop yield in water- and nitrogen-limited production systems.
Sustainable Work Performance: The Roles of Workplace Violence and Occupational Stress

The purpose of this study is to analyze the relationships between workplace violence, occupational stress, and sustainable work performance. Multiple dimensions of workplace violence (harassment, mobbing, ostracism, and stalking) were used in this study. A questionnaire survey was used, composed of 48 items with a 5-point Likert scale (1, strongly disagree, to 5, strongly agree). Data were collected from 15 hospitals in the vicinity of Karachi, Lahore, and Islamabad, Pakistan. The target population of this study consisted of doctors, nurses, and paramedical staff. We distributed 500 questionnaires among the target population. In total, 345 usable questionnaires were returned, resulting in a response rate of 69%. Partial least squares structural equation modeling was used to test the direct and indirect effects. The results of this study highlight that in both direct and indirect relationships, workplace violence negatively influences sustainable work performance. The findings of this study are as follows: First, harassment reduces employee morale, which consistently lessens employees’ work performance. Second, mobbing at the workplace reduces productivity, increases levels of stress, anxiety, depression, and irritability, and increases low work engagement, work absences, and work destruction. Third, ostracism at the workplace reduces motivation among workers and organizations, which reduces work efficiency. Work performance is undermined due to stalking at the workplace because it creates a bad image and brings toxicity among colleagues and peers. Fourth, occupational stress is considered a stigma among employees who are facing stress at the workplace. We can conclude that if employees are happy and healthy, they can be their most productive. So, organizations need to construct a culture where employees can be at their best and shine.
Pulmonary Vein Enlargement as an Independent Predictor for New-Onset Atrial Fibrillation

Pulmonary vein (PV) enlargement is associated with atrial fibrillation (AF). However, the predictive value of PV volume for new-onset AF has not been determined. We retrospectively assessed and enrolled non-AF subjects who underwent echocardiography and cardiac CT angiography (CCTA) around the same time and evaluated the development of AF longitudinally. PV volume was assessed by estimating the three-dimensional CCTA-derived mid-diastolic PV volume from the ostium to tertiary branches. Overall, 1105 subjects were enrolled. Among them, 29 developed AF during a mean follow-up of 4.28 ± 3.08 years after baseline CCTA and echocardiography. The AF group had a higher proportion of older aged subjects, a higher ratio of early mitral flow velocity (E) to early mitral annular tissue velocity (Em), higher Em, and larger left atrial (LAVI) and PV (PVVI) volume indices. PVVI was independently associated with male sex, left ventricular dimension, E/Em and LAVI. AF incidence increased markedly across each baseline PVVI tertile (2.2%, 5.1%, and 10.8%). In the multivariate Cox model, increased PVVI was independently associated with new-onset AF (hazard ratio (HR) = 5.401, 4.931–6.193, p = 0.007). Based on the analysis of multimodal cardiac imaging, our results provide mechanistic insights into PV remodeling and its potential role as a link between diastolic dysfunction and developing AF.
Effects of Exercise Training on Anxious–Depressive-like Behavior in Alzheimer Rat

ABSTRACT Purpose This study aimed to examine the effects of treadmill training on anxious–depressive-like behaviors of transgenic Alzheimer rats in the early stage of Alzheimer’s disease (AD) and provided evidence of exercise in alleviating fear-avoidance behavior deficits. Methods Male 2-month-old TgF344-AD and wild-type rats were divided into wild-type (n = 9), AD (n = 8), and AD + treadmill exercise (Exe) groups (n = 12). After 8 months of exercise, the passive avoidance test, Barnes maze task, novel object recognition test, and object location test were used to measure learning and memory function. The open-field test, elevated plus maze, sucrose preference test, and forced swim test were conducted to determine the anxious–depressive-like behavior of AD rats. Immunofluorescence staining, Western blot analysis, enzyme-linked immunosorbent assay analysis, and related assay kits were used to measure inflammatory cytokines, oxidative stress, amyloid-β production, and tau hyperphosphorylation. Results Behavioral tests revealed that 12-month-old animals did not show any spatial learning and memory deficits but did display anxious–depressive-like behavior (open field, center time: P = 0.008; center entries: P = 0.009; line crossings: P = 0.001). However, long-term exercise significantly inhibited anxious–depressive-like behavior in AD rats (center time: P = 0.016; center entries: P = 0.004; line crossings: P = 0.033). In addition, these animals displayed increased amyloid-β deposition, tau hyperphosphorylation, microgliosis, inflammatory cytokines release, and oxidative damage, which were attenuated significantly by long-term exercise training. Conclusion Long-term exercise training alleviated anxious–depressive-like behavior and improved fear-avoidance behavior in transgenic AD rats, supporting exercise training as an effective approach to prevent anxiety, depression, and fear-avoidance behavior deficits in the early stages of AD pathogenesis.