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AbstractBackgroundAimsStudy designMethodologyResultsConclusionPre-frontal cortex operates a combination of emotional, cognitive and behavioural functions. Understanding the symptoms of pre-frontal cortex lesions serves as paramount for accurate diagnosis and management.This review aims to determine an association between the causes of prefrontal cortex lesions and the resulting symptoms, as well as the ideal form of treatment.A systematic review through utilisation of 3 databases was done using the keywords “Prefrontal cortex lesions,” “dysfunction,” “symptoms,” &” treatment”RCTs, observational studies, and systematic reviews were searched using Cochrane/EMBASE, PubMed/Medline, and Pedro between 1948 and2024. Studies published in English only were included, and two reviewers were involved in the data extraction processResults showed a notable correlation between right-handed individuals and prefrontal cortex lesions with cognition impairment, particularly executive dysfunction, being the most prevalent symptom. Emotional instability followed as the second most common issue, while aphasia remained the primary language deficit. Noninvasive brain stimulation emerged as an effective treatment option for various prefrontal cortex-related disordersFurther investigation is needed to understand the mechanism linking handedness to lesion occurrence. Noninvasive brain stimulation should be prioritised for treating prefrontal injuries [ABSTRACT FROM AUTHOR]

Objective: Craniopharyngiomas (CPG) have complex treatment challenges due to their proximity to vital structures, surgical and radiotherapeutic complexities, and the tendency for recurrence. The aim of this study was to identify the prevalence of endocrine and metabolic comorbidities observed during initial diagnosis and long-term follow-up in a nationwide cohort of pediatric CPG patients. A further aim was to highlight the difficulties associated with CPG management. Methods: Sixteen centers entered CPG patients into the ÇEDD NET data system. The clinical and laboratory characteristics at presentation, administered treatments, accompanying endocrine, metabolic, and other system involvements, and the patient's follow-up features were evaluated. Results: Of the 152 evaluated patients, 64 (42.1%) were female. At presentation, the mean age was 9.1±3.67, ranging from 1.46 to 16.92, years. The most common complaints at presentation were headache (68.4%), vision problems (42%), short stature (15%), and nausea and vomiting (7%). The surgical procedures were gross total resection (GTR) in 97 (63.8%) and subtotal resection in 55 (36.2%). Radiotherapy (RT) was initiated in 11.8% of the patients. Histopathological examination reported 92% were adamantinamatous type and 8% were papillary type. Postoperatively, hormone abnormalities consisted of thyroid-stimulating hormone (92.1%), adrenocorticotropic hormone (81%), antidiuretic hormone (79%), growth hormone (65.1%), and gonadotropin (43.4%) deficiencies. Recombinant growth hormone treatment (rhGH) was initiated in 27 (17.8%). The study showed hesitancy among physicians regarding rhGH. The median survival without relapse was 2.2 years. Median (range) time of relapse was 1.82 (0.13-10.35) years. Relapse was related to longer followups and reduced GTR rates. The median follow-up time was 3.13 years. Among the last follow-up visits, the prevalence of obesity was 38%, but of these, 46.5% were already obese at diagnosis. However, 20% who were not obese at baseline became obese on follow-up. Permanent visual impairment was observed in 26 (17.1%), neurological deficits in 13 (8.5%) and diabetes mellitus in 5 (3.3%) patients. Conclusion: Recurrence was predominantly due to incomplete resection and the low rate of postoperative RT. Challenges emerged for multidisciplinary regular follow ups. It is suggested that early interventions, such as dietary restrictions and increased exercise to prevent obesity, be implemented. [ABSTRACT FROM AUTHOR]

Background: Male infertility presents global challenges, as current drug-based treatments demonstrate limited effectiveness due to an incomplete understanding of dysfunctions within the reproductive system. However, there is growing optimism surrounding natural products, particularly flavonoids, which offer promising therapeutic options. Extensive research has unveiled the positive impact of flavonoids on testicular structure, spermatogenesis, and sperm quality. Main body: Flavonoids have diverse functions such as immune-stimulating, anti-inflammatory, and antioxidative effects. These properties make them potential inhibitors of male reproductive system problems. This narrative review aims to evaluate the effects of different flavonoids on male reproductive disorders by examining the phytochemical ingredients, traditional applications, potential pharmacological actions, documented effects, and therapeutic applications of flavonoids in functional abnormalities of the male reproductive system. Conclusion: This review elaborates on the scientific study findings of flavonoids and recommends their use in male infertility. [ABSTRACT FROM AUTHOR]

Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1‐deficient mice are resistant to metastasis and further protected by combined immune‐checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF‐β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK‐target cell responses, which is dysregulated and hijacked by tumors during metastatic progression. [ABSTRACT FROM AUTHOR]

Objective：To investigate the effect of ultrasound combined with transcutaneous electrical nerve stimulation on pain and function of knee joint in patients with knee osteoarthritis. Method：A total of 122 patients with knee osteoarthritis graded 1 to 3 according to Kellgren-Lawrence (K-L) classification were randomly divided into the experimental group (n=61）and the control group（n=61). The patients in the experimental group were treated with ultrasound combined with transcutaneous electrical nerve stimulation on the basis of conventional rehabilitation treatment, and the patients in the control group were only treated with ultrasound on the basis of conventional rehabilitation treatment. The Visual Analogue Scale (VAS) for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), walking ability rating scale and 6-minute walk distance were used to evaluate the pain and function of knee joint before treatment, 4 weeks after treatment and 3 months after treatment. Result：Before treatment, there was no significant difference between the experimental group and the control group. After 4 weeks of treatment, the VAS score, WOMAC pain and function scores of the two groups were significantly decreased （P<0.05). Improvements in walking ability scores and 6-minute walk distance were significant in both groups （P<0.05). No significant changes were observed in the WOMAC stiffness score between the two groups (P>0.05）, The VAS score, WOMAC pain and function score, walking ability score and 6-minute walk distance in the experimental group had statistical significance when compared with those in the control group (P<0.05). At follow- up, except for the WOMAC stiffness score and function score, there were significant differences when compared with those before treatment in the two groups (P< 0.05). The VAS score, WOMAC pain score, walking ability score and 6-minute walk distance in the experimental group were significantly improved than those in the control group (P<0.05). Conclusion: Ultrasound combined with transcutaneous electrical nerve stimulation could significantly relieve pain, enhances walking function and improve walking ability in people with knee osteoarthritis, but does not have a marked effect on joint stiffness. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the accumulation of amyloid β and phosphorylated τ protein aggregates in the brain, which leads to the loss of neurons. Under the microscope, the function of mitochondria is uniquely primed to play a pivotal role in neuronal cell survival, energy metabolism, and cell death. Research studies indicate that mitochondrial dysfunction, excessive oxidative damage, and defective mitophagy in neurons are early indicators of AD. This review article summarizes the latest development of mitochondria in AD: 1) disease mechanism pathways, 2) the importance of mitochondria in neuronal functions, 3) metabolic pathways and functions, 4) the link between mitochondrial dysfunction and mitophagy mechanisms in AD, and 5) the development of potential mitochondrial-targeted therapeutics and interventions to treat patients with AD. [ABSTRACT FROM AUTHOR]

This report emphasizes the need for interdisciplinary collaboration in diagnosing and treating pediatric obstructive sleep apnea (OSA). OSA, affecting 1% to 4% of children, often results from adenotonsillar hypertrophy, craniofacial disorders, or obesity. While adenotonsillectomy is the primary treatment, about 75% of children, especially those with craniofacial disorders or obesity, continue to experience OSA symptoms post-surgery. To address these cases, several medical fields emphasize the necessity and demand for interdisciplinary collaboration in managing pediatric OSA. Therefore, the authors aimed to develop the Pediatric Obstructive Sleep Apnea Diagnostic Examination Form (POSADEF). This form, based on clinical experience and the literature, captures craniofacial and functional characteristics linked to pediatric OSA. A case study of an eight-year-old girl with OSA, who was unsuccessfully treated with adenotonsillectomy, underlines the importance of the diagnostic examination form. The orthodontic assessment revealed craniofacial disorders and subsequent treatment with maxillary expansion and functional appliance therapy resolved her OSA symptoms. This case demonstrates the value of POSADEF in enabling comprehensive evaluation and treatment across medical disciplines. POSADEF is designed to assist health care professionals in diagnosing craniofacial and orofacial anomalies contributing to pediatric OSA. [ABSTRACT FROM AUTHOR]

Occult lymph node metastasis (OLNM) is one of the main causes of regional recurrence in inoperable N0 non‐small cell lung cancer (NSCLC) patients following stereotactic ablation body radiotherapy (SABR) treatment. The integration of immunotherapy and SABR (I‐SABR) has shown preliminary efficiency in mitigating this recurrence. Therefore, it is necessary to explore the functional dynamics of critical immune effectors, particularly CD8+ T cells in the development of OLNM. In this study, tissue microarrays (TMAs) and multiplex immunofluorescence (mIF) were used to identify CD8+ T cells and functional subsets (cytotoxic CD8+ T cells/predysfunctional CD8+ T cells (CD8+ Tpredys)/dysfunctional CD8+ T cells (CD8+ Tdys)/other CD8+ T cells) among the no lymph node metastasis, OLNM, and clinically evident lymph node metastasis (CLNM) groups. As the degree of lymph node metastasis escalated, the density of total CD8+ T cells and CD8+ Tdys cells, as well as their proximity to tumor cells, increased progressively and remarkably in the invasive margin (IM). In the tumor center (TC), both the density and proximity of CD8+ Tpredys cells to tumor cells notably decreased in the OLNM group compared with the group without metastasis. Furthermore, positive correlations were found between the dysfunction of CD8+ T cells and HIF‐1α+CD8 and cancer microvessels (CMVs). In conclusion, the deterioration in CD8+ T cell function and interactive dynamics between CD8+ T cells and tumor cells play a vital role in the development of OLNM in NSCLC. Strategies aimed at improving hypoxia or targeting CMVs could potentially enhance the efficacy of I‐SABR. [ABSTRACT FROM AUTHOR]

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Arteriovenous fistula dysfunction (AVF) is a frequent and often unforeseeable complication in hemodialysis patients, and the most common cause is venous outflow stenosis resulting from neointimal hyperplasia and outward remodeling. Currently, there have been few effective prevention and treatment measures for AVF, therefore, this paper reviews the interventions and preventive measures of the AVF. [ABSTRACT FROM AUTHOR]

Objectives: this study sheds light on disciplinary evidence and defines its features to ascertain if an employee has committed a disciplinary offence while carrying out his job duties. It demonstrates how the Administrative Investigation Committee can establish the burden of proof. Research Problem: the adequacy of organising special rules of evidence before the Administrative Investigation Committee to detect behavioural violations. The Jordanian legislator addressed these rules in Article 146/b/2 of the Jordanian Civil Service Law No. 9 of 2020. However, these rules are not integrated, as it is assumed that the administration has complete evidence of claims of behavioural violations. It does not have the right to accuse the employee of deviating from his job mandate without evidence. The employee is also entitled to present evidence refuting such claims. Thus, it falls to investigation committees to search for the necessary evidence to clarify the truth. Methods: this study adopts a descriptive and analytical approach that compares the Jordanian, Egyptian and Emirati legislation concerning the rules of evidence. Results and Conclusions: the paper concludes by with the following results such as: Jordanian Civil Service Law fails to organise the means of evidence and administrative papers, as the legislator did not explicitly grant the Administrative Investigation Committee the authority to review documents related to the violation. In contrast, they were expressly formulated in the Egyptian and Emirati legislations. As well as, the Jordanian legislator did not deal with the method of inspection before the administrative investigation committee in the Civil Service Law, unlike the Egyptian legislator who regulated that method in the law and provided instructions to the Administrative Prosecution. Such was also the case for the UAE federal legislator within the framework of the executive regulations of the human resources law in the federal government. [ABSTRACT FROM AUTHOR]

TMD pain and dysfunction were observed in up to 66 % and 41 % of patients seeking orthodontic treatment. Evidence-based knowledge of TMD etiology, detection, and management is thus paramount in contemporary orthodontic practice. This analytical review aims to introduce the biopsychosocial model, scrutinize the psychosocial construct, propose psychosocial screening tools, and clarify the effectiveness of psychological interventions for TMDs. The biopsychosocial model specifies that TMDs are the consequence of dynamic interactions between biological, psychological, and social factors across time. As the frequency of moderate-to-severe psychological distress and somatization/somatic symptoms burden is high in individuals with TMDs, prospective orthodontic patients should be screened for TMDs/psychosocial impairments to circumvent treatment and medico-legal complications. Among the available screening tools, an amalgamation of the quintessential 5 TMD symptoms (5Ts) of the DC/TMD, Physical Symptom Scale-8 (PSS-8), and Patient Health Questionnaire-4 (PHQ-4) provides an efficient way of identifying TMD, somatic, and psychological symptoms synchronously. For prospective orthodontic patients with considerable TMD pain/dysfunction and distress, tailored multimodal and multidisciplinary treatments incorporating psychosocial interventions, including counseling/self-management, cognitive-behavioral therapy, and behavior modification, may be warranted. Complementary positive psychological interventions could also be valuable in TMD management and the paradigm shift from "reactive" to "proactive" TMD care. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Craniopharyngiomas (CPG) have complex treatment challenges due to their proximity to vital structures, surgical and radiotherapeutic complexities, and the tendency for recurrence. The aim of this study was to identify the prevalence of endocrine and metabolic comorbidities observed during initial diagnosis and long-term follow-up in a nationwide cohort of pediatric CPG patients. A further aim was to highlight the difficulties associated with CPG management. METHODS: Sixteen centers entered CPG patients into the ÇEDD NET data system. The clinical and laboratory characteristics at presentation, administered treatments, accompanying endocrine, metabolic, and other system involvements, and the patient’s follow-up features were evaluated. RESULTS: Of the 152 evaluated patients, 64 (42.1%) were female. At presentation, the mean age was 9.1±3.67, ranging from 1.46 to 16.92, years. The most common complaints at presentation were headache (68.4%), vision problems (42%), short stature (15%), and nausea and vomiting (7%). The surgical procedures were gross total resection (GTR) in 97 (63.8%) and subtotal resection in 55 (36.2%). Radiotherapy (RT) was initiated in 11.8% of the patients. Histopathological examination reported 92% were adamantinamatous type and 8% were papillary type. Postoperatively, hormone abnormalities consisted of thyroid-stimulating hormone (92.1%), adrenocorticotropic hormone (81%), antidiuretic hormone (79%), growth hormone (65.1%), and gonadotropin (43.4%) deficiencies. Recombinant growth hormone treatment (rhGH) was initiated in 27 (17.8%). The study showed hesitancy among physicians regarding rhGH. The median survival without relapse was 2.2 years. Median (range) time of relapse was 1.82 (0.13-10.35) years. Relapse was related to longer followups and reduced GTR rates. The median follow-up time was 3.13 years. Among the last follow-up visits, the prevalence of obesity was 38%, but of these, 46.5% were already obese at diagnosis. However, 20% who were not obese at baseline became obese on follow-up. Permanent visual impairment was observed in 26 (17.1%), neurological deficits in 13 (8.5%) and diabetes mellitus in 5 (3.3%) patients. DISCUSSION AND CONCLUSION: Recurrence was predominantly due to incomplete resection and the low rate of postoperative RT. Challenges emerged for multidisciplinary regular follow ups. It is suggested that early interventions, such as dietary restrictions and increased exercise to prevent obesity, be implemented.

Abstract Background Male infertility presents global challenges, as current drug-based treatments demonstrate limited effectiveness due to an incomplete understanding of dysfunctions within the reproductive system. However, there is growing optimism surrounding natural products, particularly flavonoids, which offer promising therapeutic options. Extensive research has unveiled the positive impact of flavonoids on testicular structure, spermatogenesis, and sperm quality. Main body Flavonoids have diverse functions such as immune-stimulating, anti-inflammatory, and antioxidative effects. These properties make them potential inhibitors of male reproductive system problems. This narrative review aims to evaluate the effects of different flavonoids on male reproductive disorders by examining the phytochemical ingredients, traditional applications, potential pharmacological actions, documented effects, and therapeutic applications of flavonoids in functional abnormalities of the male reproductive system. Conclusion This review elaborates on the scientific study findings of flavonoids and recommends their use in male infertility.

Background: Carrying backpacks is believed to contribute to the musculoskeletal problems in school children. Studies on the use of backpacks by Nigerian school children are scanty. Objectives: To evaluate the use of backpack and associated problems among primary school children. Methods: A cross-sectional descriptive study was carried out on 813 children in six primary schools in Ado-Ekiti. Information about backpack use and associated problems were obtained. Results: 788 (96.9%) children carried backpacks daily. The backpacks were all double strapped and 85% pupils wore them on both shoulders. The backpacks of 64.1% of the pupils contained educational materials. In 79.1% of cases, the backpacks exceeded 10% of their body weights. Pain and loss of sporting time were associated with carrying backpacks in 23.2% and 8.2% respectively, 15.3% took analgesic and 5.5% had medical consultations because of backpack injuries. No pupil missed school and none was hospitalised for backpack injury. Complaint of pain was significantly associated with older subjects, carrying heavier backpack and longer period of carrying packs (p

Introduction There is limited knowledge on cognitive performance in Behçet’s disease (BD), the majority of which come from patients with neuro-Behçet’s disease. However, the influence of BD on cognitive function in patients without neurological involvement is still not well understood. The aim of the study was to determine the frequency of cognitive involvement in BD patients without evident neuropsychiatric symptoms and to identify associated clinical variables in those patients. Material and methods Forty BD patients who fulfilled the diagnostic International Criteria for Behçet ‘s Disease (ICBD) without obvious neuropsychiatric manifestations were studied and compared with forty healthy controls matched for age, sex, and education. A comprehensive medical history, rheumatological, neurological, psychiatric, and psychometric assessment were applied for all patients. Behçet’s disease Current Activity Form (BDCAF) was used to assess disease activity. For patients as well as controls, validated Arabic versions of the Wechsler Adult Intelligence Scale-Revised and Wechsler Memory Scale-Revised were used for assessment of cognitive function. Anxiety and depression were additionally assessed for both groups using the anxiety and depression subdivisions of the Arabic Version of Symptom Checklist 90 Revised. Results Cognitive impairment was identified in 37.5% of BD patients compared to none of the controls. Memory represents the cognitive domain most frequently affected. Cognitive involvement was significantly associated with current corticosteroid use and depression as measured by SCL-90-R. On the other hand, neither the activity of the disease nor the level of anxiety was associated with cognitive involvement. Conclusions Cognitive dysfunction is reported in BD patients distinctly and independently of clinically overt neurologic involvement. Prevalence of cognitive impairment in patients with BD is strikingly high at 37.5%, whereas the control group exhibited no such signs. Psychological assessment should be performed for every BD patient to reveal any cognitive involvement. It is highly recommended to encourage psychological intervention to prevent any further deterioration, especially in patients who are experiencing depression or currently using corticosteroids.

BACKGROUND: Percutaneous vertebroplasty has become the main treatment method for osteoporotic vertebral compression fractures due to its advantages of convenient operation and low trauma. However, the optimal bone cement-vertebral volume ratio has not been determined. OBJECTIVE: To investigate the effect of bone cement-vertebral volume ratio on percutaneous vertebroplasty for osteoporotic vertebral compression fractures. METHODS: The clinical data of 100 patients with single-stage osteoporotic vertebral compression fractures admitted to Xinjiang Bazhou People’s Hospital from July 2019 to July 2022 were retrospectively analyzed. All patients received percutaneous vertebroplasty. According to the bone cement-vertebral volume ratio, they were divided into the low volume group (15% ≤ ratio ≤ 20%) and the high volume group (20% < ratio ≤ 25%) with 50 cases in each group. The visual analog scale score, Oswestry disability index, vertebral anterior margin height, Cobb angle of injured vertebra, bone cement distribution pattern, and bone cement leakage rate were analyzed before surgery, 3 days and 1 year after surgery. RESULTS AND CONCLUSION: (1) Compared with the preoperative results, the visual analog scale scores, vertebral anterior margin height, Cobb angle of injured vertebra at 3 days and 1 year after surgery, and Oswestry disability index at 1 year after surgery were significantly improved in 100 patients (P < 0.05). There were no significant differences in visual analog scale scores at 3 days and 1 year after surgery and Oswestry disability index at 1 year after surgery between the low volume group and the high volume group (P > 0.05). The vertebral anterior margin height in the low volume group was lower than that in the high volume group at 3 days and 1 year after surgery (P < 0.05). The Cobb angle of the injured vertebrae in the low volume group was higher than that in the high volume group at 3 days and 1 year after surgery (P < 0.05). (2) There were 10 H-type and 40 O-type bone cement distributions in the low volume group. There were 36 H-type and 14 O-type bone cement distributions in the high volume group, and there was no significant difference in bone cement distributions between the two groups (P < 0.05). The bone cement leakage rate in the high volume group and low volume group was 10% and 6%, respectively. (3) It is indicated that both low and high bone cement-vertebral volume ratios can improve postoperative pain and functional dysfunction, but high bone cement-vertebral volume ratio can improve the morphological recovery of injured vertebral, which may be related to the fact that the distribution of bone cement in this group is more H-type. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing b-cells, recent studies indicate that b-cell apoptosis rates are relatively low in diabetes. Instead, b-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to b-cell failure. The underlying mechanisms driving b-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing b-cell dedifferentiation in T2D. This review explores the proposed drivers of b-cell dedifferentiation leading to b-cell failure, and discusses current interventions capable of reversing this process, thus restoring b-cell identity and function. [ABSTRACT FROM AUTHOR]

Endothelial cells play a critical role in maintaining vascular function and kinetic homeostasis, but excessive accumulation of palmitic acid (PA) may lead to endoplasmic reticulum stress and trigger endothelial cell dysfunction. Baicalin (BCL), a natural plant extract, has received widespread attention for its biological activities in anti-inflammation and anti-oxidative stress. However, the mechanism of BCL on PA-induced endothelial cell dysfunction is unclear. Therefore, the aim of this study was to investigate whether BCL could inhibit PA-induced endoplasmic reticulum stress and thus attenuate endothelial cell dysfunction.Human umbilical vein endothelial cells (HUVECs) were divided into Control, PA, PA + BCL-10 μM, PA + BCL-20 μM, and PA + BCL-50 μM groups. The PA group was treated with PA (200 μM), while the PA + BCL groups were co-treated with different concentrations of BCL (10 μM, 20 μM, 50 μM) for 24 hours. Cell viability was detected by MTT. Cell migration ability was determined by Transwell assay, apoptosis level by flow cytometry, and tube formation ability by tube formation assay. Finally, the levels of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-3) and angiogenesis-related proteins (VEGFA and FGF2) were detected by western blot, MMP-9, as well as the protein levels of endoplasmic reticulum stress biomarkers (GRP78, CHOP, PERK, and ATF4).The results at the cellular level showed that cell viability, migration ability and tube formation ability of PA-induced HUVECs were significantly reduced, while apoptosis level was significantly increased. However, administration of different concentrations of BCL significantly enhanced PA-induced cell viability, migration ability and tube formation ability of HUVECs while inhibiting apoptosis. The results of protein levels showed that the protein levels of Bax and cleaved caspase-3 were observably up-regulated in the cells of the PA group, while the protein level of Bcl-2 was significantly down-regulated; compared with the PA group, the protein levels of Bax and cleaved caspase-3 were much lower and the Bcl-2 protein level was much higher in the PA + BCL group. Additionally, the protein levels of VEGFA, FGF2 and MMP-9 were raised and those of GRP78, CHOP, PERK and ATF4 were lowered in the PA + BCL group of cells in a concentration-dependent manner.BCL significantly attenuates PA-induced endothelial cell dysfunction by inhibiting endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Functioning describes how well a person handles life, but the constituents of functioning and its measurement remain subjects of debate among researchers. However, approaches investigating how the concept of functioning is understood among laypeople and practitioners have received less attention. The present study uses a bottom‐up approach to explore the concept of functioning among laypeople and mental health professionals in a Scandinavian context. Participants were asked to describe a person doing well in life and a person not doing well in life, resulting in a total of 2,345 statements from 128 laypeople and 78 mental health professionals. Initially, statements were rated according to the meta‐concepts of Agency and Communion. This analysis revealed a dominant prevalence of Agency across groups, with laypeople demonstrating a heightened emphasis on Agency when characterizing an individual not doing well in life, suggesting an intensified focus on personal responsibility and achievement when describing dysfunction. Next, an independent semantic domain analysis was used to elucidate and identify distinctive features of functioning within the statements. This revealed a shared conceptualization of functioning among both laypeople and mental health professionals based on three main domains: (1) thriving; (2) daily activities and social roles; and (3) personality features. The findings underscore the importance of considering subjective experiences of thriving, efficacy in managing daily tasks and roles, and personality traits in attaining a comprehensive understanding of functioning levels. [ABSTRACT FROM AUTHOR]

Metaphysical realism about mental disorder is the thesis that mental disorder exists mind-independently. There are two ways to challenge metaphysical realism about mental disorder. The first is by denying that mental disorder exists. The second is by denying that mental disorder exists mind-independently. Or, differently put, by arguing that mental disorder is mind-dependent. The aim of this paper is three-fold: (a) to examine three ways in which mental disorder can be said to be mind-dependent (namely, by being causally dependent on the human mind, by being weakly dependent on human attitudes, and by being strongly dependent on human attitudes), (b) to clarify their differences, and (c) to discuss their implications regarding metaphysical realism about mental disorder. I argue that mental disorder being mind-dependent in the first two senses is compatible with metaphysical realism about mental disorder, whereas mental disorder being mind-dependent in the third sense is not. [ABSTRACT FROM AUTHOR]

Background: To investigate the differences in pelvic floor muscle (PFM) electromyography (EMG) parameters between women with or without sexual dysfunction (FSD) and their correlations. Methods: Women who voluntarily participated in a questionnaire-based survey on sexual function and underwent PFM EMG in Weifang People's Hospital during the period from March 2021 to December 2021 were retrospectively enrolled. The female sexual (dys)function was measured using the Female Sexual Function Index. Glazer PFM EMG was performed using a Melander instrument (MLD A2 Deluxe). The differences in PFM EMG parameters between women with or without FSD were compared, and the relationships between PFM EMG parameters and FSD were analysed using multiple linear regression models. Results: A total of 305 women were enrolled, with 163 in the FSD group and 142 in the non-FSD group. Comparisons of PFM EMG parameters between these two groups revealed that the FSD group had significantly higher peak EMG amplitude during the phasic (flick) contractions and shorter recovery latency during the tonic contractions than the non-FSD group (both P < 0.05). Multivariate linear regression suggested that the peak EMG amplitude during the phasic (flick) contractions was 5.39 μV higher in the FSD group than in the non-FSD group, whereas the recovery latency during the tonic contractions was 0.29 s shorter (both P < 0.05). Conclusions: The results of the pelvic floor EMG in this study suggest that the pelvic floor muscles of women with FSD may be more susceptible to fatigue, and may have poorer coordination of their pelvic floor muscles. Female sexual dysfunction brings great trouble to women. Evidence suggests that women with greater pelvic floor muscle (PFM) strength have better sexual function. Sexually active women have better PFM endurance than inactive women. However, it has also been reported that PFM strength is not correlated with sexual function. Here, we assessed female PFM function with electromyography, and explored the relationships between electromyography parameters and sexual dysfunction, in an attempt to provide an objective basis for sexual dysfunction diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Alpha-methyl acyl-CoA racemase deficiency (AMACRD) is a rare peroxisomal disorder that results in the accumulation of pristanic acid and 16 cases have been reported in the literature. Here, we present three additional patients, two confirmed by genomic study and one suspected. Three siblings who were born to healthy unrelated parents developed recurrent episodes of encephalopathy, seizures, and behavioral disturbances. In all 3, brain MRI showed lesions in the thalami, cerebral peduncles, and mesencephalic tegmentum, as well as brain volume loss. In addition, one patient had a chronic hemispheric infarct and an acute contralateral infarct, and another had a subacute infarct involving multiple vascular territories without abnormalities on MR angiography. [ABSTRACT FROM AUTHOR]

Central 5-hydroxytryptaminergic dorsal raphe nucleus (5-HTDRN)-bed nucleus of stria terminalis (BNST) neural circuit dysfunction is one of the important neurobiological basis of anxiety and fear disorders. Under stress, 5-hydroxytryptamine (5-HT) neurons act on BNST receptors to attenuate anxiety and fear responses or enhance anxiety and fear. In BNST, corticotropin releasing factor neurons play a role in regulating emotions by reversely regulating excitatory or inhibitory 5-HT neurons. The composition of 5-HTDRNBNST neural circuit, the pathological changes of 5-HTDRN-BNST neural circuit function damage under stress, and the effects of 5-HTDRN-BNST neural circuit on anxiety disorder, panic disorder and post-traumatic stress disorder were analyzed and are summarized in this paper. The characteristics of functional changes of the neural circuit and its effects on brain functional activities provide a basis and ideas for the treatment of anxiety and fear disorders through the regulation of 5-HTDRN-BNST neural circuit, and they also provide a new perspective for understanding the pathological mechanism of such diseases. [ABSTRACT FROM AUTHOR]

Introduction: fluctuation in serum levels of thyroid hormones or thyroid-associated dysfunction can negatively affect the sexual behaviors or performance, and disruption in couples' relationship or satisfaction. Thus, this systematic review and meta-analysis study was aimed to investigate the global prevalence of sexual dysfunction in men with thyroid gland disorders (TGD). Methods: this systematic review and meta-analysis study conducted based on PRISMA statement criteria regarding the available evidences representing the prevalence of sexual dysfunction in men with TGD. The initial searching process was applied on July, 2023. In this era, the main keywords of "Prevalence", "Sexual disorders", "Sexual disorder", "Sexual dysfunction", "Male sexual dysfunction", "Erectile dysfunction", "Males", "Men", "Thyroid disorders", "Thyroid diseases", "Hyperthyroidism", "Thyroid", and "Thyroiditis" were hired. Also, "AND" and "OR" operators were used for keywords combination. All intended studies were searched using the databases of Web of Science, Google Scholar, Scopus, ScienceDirect, PubMed, and Embase. Random effects model was used to perform the analysis and the heterogeneity of the studies was assessed through I2 index. Data analysis was applied with CMA software (v.2). Results: following the assessment of 17 eligible studies with a sample size of 501 individuals, the global prevalence of male sexual dysfunction with TGD was found 51.5% (95% CI:38.7–64). Also, the prevalence of male sexual dysfunction in hypothyroidism and hyperthyroidism cases was 59.1% (95% CI:37.2–77.8) and 41.5% (95% CI:25.9–59.1), respectively. The meta-regression analysis showed that following incremental trend in sample size, the global prevalence of male sexual dysfunction with TGD decreases. This assessment also revealed that the prevalence of male sexual dysfunction increases with the year of study conduction, significantly (p < 0.05). Conclusion: the global prevalence of sexual dysfunction in men with TGD was found relatively high. also, the highest prevalence of sexual disorders was reported in hypothyroid cases. Thus, health policymakers are suggested to inform the individuals prone to this pathology regarding the negative effects of TGD on sexual dysfunction. Besides, TGD-affected cases can prevent sexual disorders and unpleasant consequences through timely medical treatments. [ABSTRACT FROM AUTHOR]

Purpose: Neuromuscular deficits and atrophy after anterior cruciate ligament reconstruction (ACLR) may be accompanied by changes in muscle composition and poor quadriceps muscle quality (QMQ). Quadriceps atrophy occurs after ACLR but improves within the first three postoperative months, yet this hypertrophy could be attributable to increases in noncontractile tissue (i.e., poor QMQ). The purposes of this study were to evaluate changes in QMQ after ACLR and to determine if changes in QMQ and cross-sectional area (CSA) occur in parallel or independently. Methods: A longitudinal prospective cohort design was implemented to evaluate QMQ and CSA in 20 individuals with ACLR and 12 healthy controls. Participants completed three testing sessions (baseline/presurgery, 1 month, and 3 months) during which ultrasound images were obtained from the vastus lateralis (VL) and rectus femoris (RF). QMQ was calculated as the echo intensity (EI) of each image, with high EI representing poorer QMQ. Anatomical CSA was also obtained from each image. Results: RF and VL EI were greater at 1 and 3 months in the ACLR limb compared with baseline and the contralateral limb and did not change between 1 and 3 months. VL and RF CSA in the ACLR limb were smaller at 1 and 3 months compared with the contralateral limb and controls (VL only) but increased from 1 to 3 months. Changes in QMQ and CSA were not correlated. Conclusions: QMQ declines within the first month after ACLR and does not improve by 3 months although hypertrophy occurs, suggesting that these morphological characteristics change independently after ACLR. Poorer QMQ represents greater concentration of noncontractile tissues within the muscle and potentially contributes to chronic quadriceps dysfunction observed after ACLR. [ABSTRACT FROM AUTHOR]

Early evaluation of β-cell dysfunction of hyperglycemic patients in asymptomatic adults would be valuable for timely prevention of the diabetes. This study aimed to evaluate functional changes in the pancreas using intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and determine whether it could be used as a non-invasive method of assessing β-cell dysfunction. This prospective cohort study was conducted from August 2022 to November 2022 in Jinan University Affiliated Guangdong Second General Hospital. Three groups were enrolled and underwent IVIM-DWI: confirmed patients with type 2 diabetes (T2DM); hyperglycemic patients in asymptomatic adults; and the volunteers with normal glucose tolerance (NGT). Imaging parameters were obtained: apparent diffusion coefficient (ADC), the true diffusion coefficient (D t), the pseudo-diffusion coefficient (D p), and the perfusion fraction (f). The β-cell function indexes were calculated from blood examinations: composite insulin sensitivity index (ISI), 60-min insulinogenic index (IGI60), and the disposition index (DI). We compared imaging parameters among three groups, calculated the diagnostic performance of them for differentiating different groups, and the reproducibility of them was evaluated using intraclass correlation coefficient (ICC). The imaging parameters except f gradually decreased among the groups with significant differences for ADC (p < 0.0001), D t (p < 0.0001), and D p (p = 0.013). D t demonstrated the best diagnostic performance for differentiating asymptomatic patients from NGT (Area Under Curve [AUC] = 0.815, p < 0.0001). IVIM-DWI parameters correlated with composite ISI and DI, of which, D t has the highest correlation with DI (Pearson correlation coefficient [r] = 0.546, p < 0.0001). The ICC of IVIM-DWI parameters was very good, D t was highest (Interobserver ICC = 0.938, 95% Confidence Interval [CI], 0.899–0.963; Intraobserver ICC = 0.941, 95% CI, 0.904–0.965). IVIM-DWI is a non-invasive quantitative method that can identify β-cell dysfunction in the pancreas. [ABSTRACT FROM AUTHOR]

Introduction: There is limited knowledge on cognitive performance in Behçet’s disease (BD), the majority of which come from patients with neuro-Behçet’s disease. However, the influence of BD on cognitive function in patients without neurological involvement is still not well understood. The aim of the study was to determine the frequency of cognitive involvement in BD patients without evident neuropsychiatric symptoms and to identify associated clinical variables in those patients. Material and methods: Forty BD patients who fulfilled the diagnostic International Criteria for Behçet ‘s Disease (ICBD) without obvious neuropsychiatric manifestations were studied and compared with forty healthy controls matched for age, sex, and education. A comprehensive medical history, rheumatological, neurological, psychiatric, and psychometric assessment were applied for all patients. Behçet’s disease Current Activity Form (BDCAF) was used to assess disease activity. For patients as well as controls, validated Arabic versions of the Wechsler Adult Intelligence Scale-Revised and Wechsler Memory Scale-Revised were used for assessment of cognitive function. Anxiety and depression were additionally assessed for both groups using the anxiety and depression subdivisions of the Arabic Version of Symptom Checklist 90 Revised. Results: Cognitive impairment was identified in 37.5% of BD patients compared to none of the controls. Memory represents the cognitive domain most frequently affected. Cognitive involvement was significantly associated with current corticosteroid use and depression as measured by SCL-90-R. On the other hand, neither the activity of the disease nor the level of anxiety was associated with cognitive involvement. Conclusions: Cognitive dysfunction is reported in BD patients distinctly and independently of clinically overt neurologic involvement. Prevalence of cognitive impairment in patients with BD is strikingly high at 37.5%, whereas the control group exhibited no such signs. Psychological assessment should be performed for every BD patient to reveal any cognitive involvement. It is highly recommended to encourage psychological intervention to prevent any further deterioration, especially in patients who are experiencing depression or currently using corticosteroids. [ABSTRACT FROM AUTHOR]

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How do people understand the concepts of mental health and disorder? The objective of this paper is to examine the impact of several factors on people’s judgments about whether a condition constitutes a mental disorder or a healthy state. Specifically, this study examines the impact of the source of the condition, its outcome, individual valuation (i.e., the value the individual attaches to the condition), and group valuation (i.e., the value the relevant group attaches to the condition). While we find that people’s health and disorder judgments are driven by perceived dysfunction, we also find that health and disorder judgments are impacted differently by these factors. Health judgements are impacted by outcome and individual valuation, and disorder judgments are impacted by condition source. These results suggest that the folk concept of mental health is positive (i.e., mental health is more than the absence of mental disorder) and normativist (i.e., value judgments play a significant role in determining whether a condition counts as healthy), while the concept of mental disorder aligns with a naturalist perspective, at least to the extent that dysfunction plays an important role in categorizing a condition as a disorder. However, our finding that people’s dysfunction judgments are influenced by individual valuation and outcomes poses a strong challenge to naturalist accounts. [ABSTRACT FROM AUTHOR]

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed. [ABSTRACT FROM AUTHOR]

Trauma and stressor-related behavioral health conditions are prevalent in military populations and have become a major public health concern in recent years. Individuals who commonly report suicidal ideation often have comorbid mental health diagnoses (i.e., posttraumatic stress disorder; PTSD). However, the mechanisms associated with stress, suicidal ideation, and PTSD are unclear. The present study examined the moderating role of dysfunctional and recovery cognitions between (i) PTSD and suicidal ideation, and (ii) stress and suicidal ideation in two distinct samples. Sample 1 was composed of civilians and military personnel (N = 322). Sample 2 was composed of (N = 377) student service members and veterans (SSM/Vs). In Study 1, we found that low recovery cognitions at higher and moderate levels of PTSD symptoms were significantly associated with increased suicidal ideation. High dysfunctional cognitions were significantly associated with suicidal ideation at higher levels of PTSD symptoms. In Study 2, we found no differences in any level of recovery cognitions at low and moderate stress levels with suicidal ideation. Higher levels of stress were associated with high dysfunctional cognitions and suicidal ideation. Promoting higher levels of recovery cognitions and reducing dysfunctional cognitions are important in addressing stress, suicidal ideation, and comorbid conditions such as PTSD. Future research should focus on examining the clinical utility of the Dispositional Recovery and Dysfunction Inventory (DRDI) in other populations (i.e., firefighters and paramedics). This could contribute to efforts of suicide prevention and the promotion of the well-being of individuals experiencing suicidal ideation. Promoting recovery cognitions may serve as a protective factor against stress. Dysfunctional cognitions contribute to worsening behavioral health conditions. Suicide prevention efforts should target dysfunctional and recovery cognitions. [ABSTRACT FROM AUTHOR]

I argue that despite the merits of Jefferson's account of a brain disorder, which are many, the notion of function she deploys is unsuitable to the overall goals of that account. In particular, Jefferson accepts Cummins' causal role theory of function and dysfunction. As the causal role view, in its standard elaborations, is wedded to human interests, goals, and values, it cannot serve as a value-neutral anchor for her hybrid "harm-dysfunction" account of disorder. I argue that the selected effects theory, or some comparably value-neutral account, would serve her purposes better. [ABSTRACT FROM AUTHOR]

In her book "Are Mental Disorders Brain Disorders?" (2022), Anneli Jefferson proposes that brain processes that always realize mental dysfunctions are brain dysfunctions. This paper explores possible interpretations of two underdeveloped aspects of this thesis. First, it argues that "realization" should be interpreted as partial rather than full realization. Second, it argues that the "always" should only quantify over biologically normal situations. Taken together, these changes can account for the fact that some psychological dysfunctions are partially realized by functional mechanisms, for the existence of psychological dysfunctions due to mismatches rather than brain dysfunctions, and for the fact that brain dysfunctions do not cease to be brain dysfunctions just because they can be compensated. [ABSTRACT FROM AUTHOR]

In an important and timely book, Anneli Jefferson outlines a view according to which a given mental disorder is a brain disorder if it is a (harmful) mental dysfunction realised by a brain dysfunction. Prima facie, Jefferson's book is a study in the metaphysics of dysfunction: how does mental dysfunction relate to brain dysfunction, and what does this imply for the status of mental disorders and brain disorders? In what follows, I shall argue that Jefferson's contribution to this debate is better understood as a conceptual explication of how psychiatrists, some philosophers, scientists and clinicians in the field (broadly construed) think of the label 'brain disorder'. I infer this on the basis that Jefferson's thesis would not follow from any serious, well-worked out theory of proper function. Despite initial appearances, Jefferson's book about brain dysfunction is not about function at all. [ABSTRACT FROM AUTHOR]

Suboptimal CD4+ T cell activation leads to a hyporesponsive state in mice characterized by incomplete differentiation, limited cytokine production, and changes in T helper (Th) subsets. Together, these factors impair CD4+ T cell trafficking to the tumor and enable the immune evasion of tumor cells. Sustained inflammation, antigen stimulation, and suppressive factors induce CD4+ T cell dysfunctions during tumor progression in murine models. Despite sharing some phenotypic similarities with CD8+ T cells in mouse and human, CD4+ T cell dysfunctions are distinct and should be viewed through the lens of Th subset differentiation. Since CD4+ T cells can help multiple parameters of the innate and adaptive immune response, reinvigorating CD4+ T cells holds great potential in enhancing various immunotherapies, including immune checkpoint blockade, cancer vaccines, and the use of CAR T cells. CD4+ T cells are crucial for enhancing the functions of antigen-presenting cells, increasing CD8+ T cell effector differentiation, driving B cell activation and antibody affinity maturation, and temporally sustaining immune efficacy during cancer progression. As a result, CD4+ T cells serve as a central nexus that directs the initiation and coordination of an immune response. Thus, a deeper understanding of the nature, impact, and restorability of CD4+ T cell dysfunction holds vast potential in guiding therapeutic strategies to effectively harness the potential of these cells in cancer treatments. CD4+ T cells are crucial in generating and sustaining immune responses. They orchestrate and fine-tune mammalian innate and adaptive immunity through cell-based interactions and the release of cytokines. The role of these cells in contributing to the efficacy of antitumor immunity and immunotherapy has just started to be uncovered. Yet, many aspects of the CD4+ T cell response are still unclear, including the differentiation pathways controlling such cells during cancer progression, the external signals that program them, and how the combination of these factors direct ensuing immune responses or immune-restorative therapies. In this review, we focus on recent advances in understanding CD4+ T cell regulation during cancer progression and the importance of CD4+ T cells in immunotherapies. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study was to analyze objective and subjective olfactory/gustatory function in post‐COVID‐19 infection (PCI). Materials and Methods: Patients with past PCR‐confirmed COVID‐19 infection and persistent olfactory/gustatory complaints were investigated. Olfactory threshold and identification, gustatory detection, identification, and magnitude scaling were tested. Results: A total of 42 PCI subjects were compared to 41 age‐ and gender‐matched controls with no COVID‐19 history. All PCI tested had mild COVID‐19 disease. Mean interval between COVID‐19 confirmations to testing was 7.4 ± 3.1 months. PCI subjects complained of combined dysfunction in 85.7%, isolated olfactory or gustatory dysfunction in 7.1% each. Combined complaints were significantly higher in PCI (p < 0.001). Objective testing showed significantly higher prevalence of dysfunction in PCI versus controls for hyposmia (73.8%, 12.2%), anosmia (11.9%, 0%), odor identification (68.5%, 83.0%), hypogeusia (23% and 2.4%, respectively), and impaired magnitude scaling, (p < 0.05). All PCI subjects with hypogeusia had abnormal gustatory magnitude scaling. Conclusions: While most PCI subjects complained of combined gustatory and olfactory dysfunction, objective testing showed in the majority an isolated single sense dysfunction, with a low level of agreement between subjective and objective findings. Abnormal objective results for all olfactory and gustatory functions tested may suggest a central rather than peripheral mechanism, although concomitant mechanisms cannot be excluded. [ABSTRACT FROM AUTHOR]

Malocclusions have a continuously increasing prevalence from one generation to another as a result of climate change, soil, atmosphere, and water pollution. All of these aspects have unfavorable consequences for the nutritional scheme. Thus, nutrition, together with other etiopathogenic factors, contributes to complex alterations in the somatic development of the entire organism and, implicitly, of the cephalic extremity. The study group included 4147 children from randomly selected schools from Vâlcea County, Romania. The aim of this study is to determine the prevalence of malocclusions in schoolchildren in Vâlcea County, Romania, according to the three main classes of malocclusions (according to Angle's classification), age groups (from 6 to 10 years old and from 11 to 14 years old), gender (male and female), and place of origin (rural and urban). For Angle class I malocclusions, we recorded the highest prevalence (48.78% of the total number of schoolchildren with malocclusions), followed by Angle class II malocclusions (45.85% of the total number of schoolchildren with malocclusions), and for Angle class III malocclusions we found the lowest prevalence (5.37% of the total number of schoolchildren with malocclusions). According to gender, we found the highest prevalence in the female gender (29.90% of the total number of female subjects), while in the male gender, we recorded a prevalence of 27.70% of the total number of male subjects. Regarding the place of origin, there is a higher prevalence of malocclusions in urban areas (29.16%). The study subgroup included 140 children randomly selected from the total number of subjects in the study group. They were included in a more advanced study. The aim is to find potential associations between the presence of malocclusions and various oral variables. Categorical variables were expressed as numerical values and percentages, and their association was evaluated with either the Chi-square test of association or homogeneity, or the Fisher Exact test. The acquired data were incorporated into a binomial logistic regression model to assess the likelihood of developing malocclusions in relation to the following variables: defective phonation, bruxism, frequency of teeth brushing, onychophagia, oral respiration, infantile deglutition, placing objects between the maxillaries, thumb sucking, and salivary aspects. It is also aimed at comparing the results obtained with similar ones from the specialized literature. [ABSTRACT FROM AUTHOR]

The N 6-methyladenosine (m6A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in Gng4 expression via m6A modifications. Our findings provide functional insight into the correlation between circHECW2 and m6A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment. Increased expression of circHECW2 stimulated ubiquitin-mediated degradation of WTAP, resulting in the decreased methylation of Gng4 with a concomitant decrease in Gng4 mRNA stability and expression, and subsequent astrocyte dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is located at the interface between the vascular system and the brain parenchyma, and is responsible for communication with systemic circulation and peripheral tissues. During life, the BBB can be subjected to a wide range of perturbations or stresses that may be endogenous or exogenous, pathological or therapeutic, or intended or unintended. The risk factors for many diseases of the brain are multifactorial and involve perturbations that may occur simultaneously (e.g., two-hit model for Alzheimer's disease) and result in different outcomes. Therefore, it is important to understand the influence of individual perturbations on BBB function in isolation. Here we review the effects of eight perturbations: mechanical forces, temperature, electromagnetic radiation, hypoxia, endogenous factors, exogenous factors, chemical factors, and pathogens. While some perturbations may result in acute or chronic BBB disruption, many are also exploited for diagnostic or therapeutic purposes. The resultant outcome on BBB function depends on the dose (or magnitude) and duration of the perturbation. Homeostasis may be restored by self-repair, for example, via processes such as proliferation of affected cells or angiogenesis to create new vasculature. Transient or sustained BBB dysfunction may result in acute or pathological symptoms, for example, microhemorrhages or hypoperfusion. In more extreme cases, perturbations may lead to cytotoxicity and cell death, for example, through exposure to cytotoxic plaques. [ABSTRACT FROM AUTHOR]

Abstract Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1‐deficient mice are resistant to metastasis and further protected by combined immune‐checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF‐β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK‐target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.