Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens.

Defense against attaching-and-effacing bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. Although CD4(+) and NKp46(+) innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete mice of specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the attaching-and-effacing pathogen Citrobacter rodentium. We found that the signaling receptor Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b(+) cDCs were an obligate source of IL-23 required for survival after infection with C. rodentium, but CD103(+) cDCs dependent on the transcription factor Batf3 were not. Our results demonstrate a nonredundant function for CD11b(+) cDCs in the response to pathogens in vivo.

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

BACKGROUND: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. METHODS: This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. RESULTS: The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p < .0001). CONCLUSIONS: ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

Self-Flipping Solar Seesaw Evaporators Leverage Scaling to De-Scale.

Salt scaling poses a significant obstacle to the practical implementation of solar-driven evaporation for desalination. Attempts to mitigate scaling by enhancing mass transfer often lead to a compromise in evaporation efficiency due to associated heat loss. In the present work, a novel seesaw evaporator with a Janus structure to harness scaling for periodic self-descaling is reported. The seesaw evaporators are facilely fabricated by delignifying balsa wood and subsequently single-sided spray-coating it with soot and polydimethylsiloxane (PDMS). This unique Janus structure enables the evaporator to float on the brine while ensuring an ample supply of solution for evaporation. During evaporation, salt ions are transported directionally toward the cocked end of the evaporator to form scaling, triggering the seesaw evaporator to flip once a threshold is reached. The accumulated salts re-dissolve back into the solution. By adjusting the tilt angle, the evaporator can achieve an impressive evaporation rate of up to 2.65 kg m-2 h-1 when evaporating an 8 wt.% NaCl solution. Remarkably, these evaporators maintain a stable evaporation rate during prolonged 120 h operation and produce ≈3.93-6.35 L m⁻2·day⁻¹ of freshwater from simulated brines when assembled into an evaporation device.

Functional characterization of genes related to triterpene and flavonoid biosynthesis in Cyclocarya paliurus.

MAIN CONCLUSION: The oxidosqualene cyclases (OSCs) generating triterpenoid skeletons in Cyclocarya paliurus were identified for the first time, and two uridine diphosphate (UDP)-glycosyltransferases (UGTs) catalyzing the glycosylation of flavonoids were characterized. Cyclocarya paliurus, a native rare dicotyledonous plant in China, contains an abundance of triterpenoid saponins and flavonoid glycosides that exhibit valuable pharmaceutical effects in preventing hypertension, hyperlipidemia, and diabetes. However, the molecular mechanism explaining the biosynthesis of triterpenoid saponin and flavonoid glycoside in C. paliurus remains unclear. In this study, the triterpene content in different tissues and the expression pattern of genes encoding the key enzymes associated with triterpenoid saponin and flavonoid glycoside biosynthesis were studied using transcriptome and metabolome analysis. The eight upstream oxidosqualene cyclases (OSCs) involved in triterpenoid saponin biosynthesis were functionally characterized, among them CpalOSC6 catalyzed 2,3;22,23-dioxidosqualene to form 3-epicabraleadiol; CpalOSC8 cyclized 2,3-oxidosqualene to generate dammarenediol-II; CpalOSC2 and CpalOSC3 produced ß-amyrin and CpalOSC4 produced cycloartenol, while CpalOSC2-CpalOSC5, CpalOSC7, and CpalOSC8 all produced lanosterol. However, no catalytic product was detected for CpalOSC1. Moreover, two downstream flavonoid uridine diphosphate (UDP)-glycosyltransferases (UGTs) (CpalUGT015 and CpalUGT100) that catalyze the last step of flavonoid glycoside biosynthesis were functionally elucidated. These results uncovered the key genes involved in the biosynthesis of triterpenoid saponins and flavonoid glycosides in C. paliurus that could be applied to produce flavonoid glycosides and key triterpenoid saponins in the future via a synthetic strategy.

Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Associations between trauma exposure and irritability within the family unit: a network approach.

BACKGROUND: Pediatric irritability is a pervasive psychiatric symptom, yet its etiology remains elusive. While trauma exposure may contribute to the development of irritability, empirical research is limited. This study examined the prevalence of irritability among trauma-exposed children, identified factors that differentiate trauma-exposed children with and without irritability, and employed a network analysis to uncover associations between irritability and trauma exposure in the family unit. METHODS: Sample included 676 children (56.3% male, mean age = 9.67 ± 3.7 years) and their parents referred by the Connecticut Department of Children and Families to Fathers for Change - a psychotherapy intervention designed to reduce intimate partner violence (IPV) and child maltreatment. Child's trauma exposure, post-traumatic stress disorder (PTSD) symptoms, and irritability were assessed pre-intervention using self- and caregiver-report. Parents self-reported their childhood and adulthood trauma exposures, PTSD symptoms, irritability, psychopathology, and IPV. RESULTS: Across caregiver- and child-reports, 16%-17% of children exhibited irritability. Irritable children experienced greater trauma exposure, interpersonal violence, emotional abuse, and PTSD severity. They had caregivers, particularly mothers, with greater trauma histories, IPV, and psychopathology. Network analysis revealed 10 nodes directly correlated to child's irritability including child's PTSD severity, parental IPV (specifically psychological violence), and parental psychopathology. CONCLUSIONS: Results provide initial empirical evidence that pediatric irritability is linked to trauma exposure, suggesting trauma histories be considered in the diagnosis and treatment of irritability. Interventions addressing caregiver trauma, IPV, and psychopathology may ameliorate pediatric irritability. Future studies could benefit from adopting network approaches with longitudinal or time series data to elucidate causality and points of intervention.

An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion.

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

Factors influencing sexual interest in postmenopausal Asian women.

BACKGROUND: The sexual interest of postmenopausal women is a crucial aspect of their overall well-being. Despite its importance, factors influencing postmenopausal sexual interest, particularly in Asian women, remain understudied and poorly understood. AIMS: To investigate the various factors influencing sexual interest in postmenopausal women in Malaysia. METHODS: A cross-sectional study was conducted of postmenopausal women attending a gynecology or primary care clinic in a teaching hospital in Malaysia. OUTCOMES: We investigated how interpersonal dynamics and cultural norms-including the physical and mental health of women and their partners, as well as their sexual values-affect menopausal sexual interest as measured by the Menopausal Sexual Interest Questionnaire. RESULTS: Women in the study reported an average sexual interest, with a mean score of 32.8 (SD, 9.4) out of 70 on the Menopausal Sexual Interest Questionnaire. Multivariable analysis results showed that higher personal sexual values (odds ratio [OR], 2.65; 95% CI, 1.26-5.61) and spousal sexual values (OR, 2.68; 95% CI, 1.22-5.86) were significantly associated with higher menopausal sexual interest. There was a positive correlation between the physical fitness of spouses and menopausal sexual interest, with women who rated their spouses as very fit or fit (OR, 3.22; 95% CI, 1.15-9.00) or moderately fit (OR, 2.63; 95% CI, 1.05-6.63) showing higher menopausal sexual interest as compared with those whose spouses were very unfit or unfit. Women with normal stress levels (OR, 5.89; 95% CI, 1.03-33.62) and mild to moderate stress levels (OR, 8.13; 95% CI, 1.53-43.22) reported higher menopausal sexual interest. CLINICAL IMPLICATIONS: This study emphasizes a holistic approach to postmenopausal sexual health, highlighting the significance of promoting positive sexual values, improving physical fitness, and managing stress. Health care providers should educate, counsel, and collaborate interdisciplinarily, ensuring culturally sensitive care tailored to individual needs. STRENGTH AND LIMITATIONS: The study's strength lies in its provision of valuable insights into factors affecting sexual interest among postmenopausal Asian women, enhancing comprehension of holistic sexual health approaches. However, reliance on self-assessments may introduce response bias influenced by social desirability, and limited generalizability stems from single-site data collection. CONCLUSION: Our study highlights the significance of adopting a holistic approach to addressing sexual health in postmenopausal women, which includes promoting positive sexual values, improving physical fitness, and managing stress.

Poly(N,N-diethylacrylamide)-endowed spontaneous emulsification during the breath figure process and the formation of membranes with hierarchical pores.

The spontaneous emulsification for the formation of water-in-oil (W/O) or oil-in-water (O/W) emulsions needs the help of at least one kind of the third component (surfactant or cosolvent) to stabilize the oil-water interface. Herein, with the water/CS2-soluble polymer poly(N,N-diethylacrylamide) (PDEAM) as a surfactant, the spontaneous formation of water-in-PDEAM/CS2 emulsions is reported for the first time. The strong affinity between PDEAM and water or the increase of PDEAM concentration will accelerate the emulsification process with high dispersed phase content. It is demonstrated that the spontaneous emulsification of condensed water droplets into the PDEAM/CS2 solution occurs during the breath figure process, resulting in porous films with two levels of pore sizes (i.e., micron and submicron). The emulsification degree and the amounts of submicron-sized pores increase with PDEAM concentration and solidifying time of the solution. This work brings about incremental interest in spontaneous emulsification that may happen during the breath figure process. The combination of these two simultaneous processes provides us with an option to build hierarchically porous structures with condensed and emulsified water droplets as templates. Such porous membranes may have great potential in fields such as separation, cell culture, and biosensing.

Modulations of ocean-atmosphere interactions on squid abundance over Southwest Atlantic.

Anthropogenic shifts in seas are reshaping fishing trends, with significant implications for aquatic food sources throughout this century. Examining a 21-year abundance dataset of Argentine shortfin squids Illex argentinus paired with a regional oceanic analysis, we noted strong correlations between squid annual abundance and sea surface temperature (SST) in January and February and eddy kinetic energy (EKE) from March to May in the Southwest Atlantic. A deeper analysis revealed combined ocean-atmosphere interactions, pinpointed as the primary mode in a rotated empirical orthogonal function analysis of SST. This pattern produced colder SST and amplified EKE in the surrounding seas, factors crucial for the unique life stages of squids. Future projections from the CMIP6 archive indicated that this ocean-atmosphere pattern, referred to as the Atlantic symmetric pattern, would persist in its cold SST phase, promoting increased squid abundance. However, rising SSTs due to global warming might counteract the abundance gains. Our findings uncover a previously unrecognized link between squids and specific environmental conditions governed by broader ocean-atmosphere interactions in the Southwest Atlantic. Integrating these insights with seasonal and decadal projections can offer invaluable information to stakeholders in squid fisheries and marine conservation under a changing climate.

Pre-scan state anxiety is associated with greater right amygdala-hippocampal response to fearful versus happy faces among trait-anxious Latina girls.

BACKGROUND: Unfamiliarity with academic research may contribute to higher levels of anticipatory state anxiety about affective neuroimaging tasks. Children with high trait anxiety display differences in brain response to fearful facial affect compared to non-anxious youth, but little is known about the influence of state anxiety on this association. Because reduced engagement in scientific research and greater mistrust among minoritized groups may lead to systematic differences in pre-scan state anxiety, it is crucial to understand the neural correlates of state anxiety during emotion processing so as to disambiguate sources of individual differences. METHODS: The present study probed the interactive effects of pre-scan state anxiety, trait anxiety, and emotional valence (fearful vs. happy faces) on neural activation during implicit emotion processing in a community sample of 46 preadolescent Latina girls (8-13 years). RESULTS: Among girls with mean and high levels of trait anxiety, pre-scan state anxiety was associated with greater right amygdala-hippocampal and left inferior parietal lobe response to fearful faces relative to happy faces. CONCLUSIONS: Anticipatory state anxiety in the scanning context may cause children with moderate and high trait anxiety to be hypervigilant to threats, further compounding the effects of trait anxiety. Neuroimaging researchers should control for state anxiety so that systematic differences in brain activation resulting from MRI apprehension are not misleadingly attributed to demographic or environmental characteristics.

Protective Effects of Coptis chinensis Rhizome Extract and Its Constituents (Berberine, Coptisine, and Palmatine) against α-Synuclein Neurotoxicity in Dopaminergic SH-SY5Y Cells.

Parkinson's disease (PD) is a common neurodegenerative disease with progressive loss of dopaminergic neurons in substantia nigra and the presence of α-synuclein-immunoreactive inclusions. Gaucher's disease is caused by homozygous mutations in ß-glucocerebrosidase gene (GBA). GBA mutation carriers have an increased risk of PD. Coptis chinensis (C. chinensis) rhizome extract is a major herb widely used to treat human diseases. This study examined the association of GBA L444P mutation with Taiwanese PD in 1016 cases and 539 controls. In addition, the protective effects of C. chinensis rhizome extract and its active constituents (berberine, coptisine, and palmatine) against PD were assayed using GBA reporter cells, LC3 reporter cells, and cells expressing mutated (A53T) α-synuclein. Case-control study revealed that GBA L444P carriers had a 3.93-fold increased risk of PD (95% confidence interval (CI): 1.37-11.24, p = 0.006) compared to normal controls. Both C. chinensis rhizome extract and its constituents exhibited chemical chaperone activity to reduce α-synuclein aggregation. Promoter reporter and endogenous GBA protein analyses revealed that C. chinensis rhizome extract and its constituents upregulated GBA expression in 293 cells. In addition, C. chinensis rhizome extract and its constituents induced autophagy in DsRed-LC3-expressing 293 cells. In SH-SY5Y cells expressing A53T α-synuclein, C. chinensis rhizome extract and its constituents reduced α-synuclein aggregation and associated neurotoxicity by upregulating GBA expression and activating autophagy. The results of reducing α-synuclein aggregation, enhancing GBA expression and autophagy, and protecting against α-synuclein neurotoxicity open up the therapeutic potentials of C. chinensis rhizome extract and constituents for PD.

Application of time series analysis in predicting postpartum depression: integrating data from the hospitalization period and early postpartum weeks.

PURPOSE: This study aimed to explore the dynamic changes in postpartum depressive symptoms from the hospitalization period to 4-8 weeks postpartum using time series analysis techniques. By integrating depressive scores from the hospital stay and the early postpartum weeks, we sought to develop a predictive model to enhance early identification and intervention strategies for Postpartum Depression (PPD). METHODS: A longitudinal design was employed, analyzing Edinburgh Postnatal Depression Scale (EPDS) scores from 1,287 postpartum women during hospitalization and at 4, 6, and 8 weeks postpartum. Descriptive statistics summarized demographic characteristics. Time Series Analysis using the Auto-Regressive Integrated Moving Average (ARIMA) model explored temporal trends and seasonal variations in EPDS scores. Correlation analysis examined the relationships between EPDS scores and demographic characteristics. Model validation was conducted using a separate dataset. RESULTS: EPDS scores significantly increased from the hospitalization period to 4-8 weeks postpartum (p < .001). The ARIMA model revealed seasonal and trend variations, with higher depressive scores in the winter months. The model's fit indices (AIC = 765.47; BIC = 774.58) indicated a good fit. The Moving Average (MA) coefficient was - 0.69 (p < .001), suggesting significant negative impacts from previous periods' errors. CONCLUSIONS: Monitoring postpartum depressive symptoms dynamically was crucial, particularly during the 4-8 weeks postpartum. The seasonal trend of higher depressive scores in winter underscored the need for tailored interventions. Further research using longitudinal and multi-center designs was warranted to validate and extend these findings. Our predictive model aimed to enhance early identification and intervention strategies, contributing to better maternal and infant health outcomes.

An investigation into the present status and influencing factors of nurse retention in grade-a tertiary general hospitals in Shanxi Province within the framework of the magnet hospital concept.

BACKGROUND: The attrition of nursing staff significantly contributes to the shortage of healthcare professionals. This study entailed an examination of the propensity of nurses to sustain employment within Grade-A tertiary general hospitals and the various influencing factors. METHODS: A total of 2,457 nurses from three grade-A tertiary general hospitals were surveyed. The survey instruments included a general information questionnaire, a scale measuring their willingness to continue working, and a Chinese version of the Magnet Hospital Factor scale. RESULTS: The scores of the willingness to continue working scale and the Magnet Hospital Factor scale were 21.53 ± 4.52 and 145.46 ± 25.82, respectively. There were statistically significant differences in the scores of willingness of nurses to continue working across various factors, including the department, age, marital status, family location, length of service as nurses, professional title, position, and employment type, upon comparison (P < 0.001). The correlation analysis showed that there was a positive correlation between the willingness of nurses to continue working and the magnet hospital factors, with a correlation coefficient of 0.523 (P < 0.01). Regression analysis showed that department, length of service as nurses, professional title, position, average monthly income, number of night shifts, medical care relationship, educational support, and nursing manager support among the magnet hospital factors were important predictors of willingness to continue working (P < 0.001). CONCLUSION: The willingness of nurses to continue working in grade-A tertiary general hospitals in Shanxi Province was determined to be at an upper-middle level. The magnet status of grade-A tertiary general hospitals needs to be improved, and there are many factors that influenced willingness of nurses to continue working. To cultivate a more favorable environment and bolster nurse recruitment and retention, all healthcare institutions should strive to establish a magnet nursing environment, thereby fostering the robust development of the nursing team.

Screening of polysaccharides from the differently processed products of Angelica sinensis with the best liver protection effect on chicken and the intervention mechanism study based on tandem mass tag proteomics and multiple reaction monitoring approach.

The incidence of colibacillosis in poultry is on the rise, significantly affecting the chicken industry. Ceftiofur sodium (CS) is frequently employed to treat this disease, resulting in lipopolysaccharide (LPS) buildup. Processing plays a vital role in traditional Chinese veterinary medicine. The potential intervention in liver injury by polysaccharides from the differently processed products of Angelica sinensis (PDPPAS) induced by combined CS and LPS remains unclear. This study aims to investigate the protective effect of PDPPAS on chicken liver injury caused by CS combined with LPS buildup and further identify the polysaccharides with the highest hepatoprotective activity in chickens. Furthermore, the study elucidates polysaccharides' intervention mechanism using tandem mass tag (TMT) proteomics and multiple reaction monitoring (MRM) methods. A total of 190 1-day-old layer chickens were randomly assigned into 12 groups, of which 14 chickens were in the control group and 16 in other groups, for a 10-day trial. The screening results showed that charred A. sinensis polysaccharide (CASP) had the most effective and the best hepatoprotective effect at 48 h. TMT proteomics and MRM validation results demonstrated that the intervention mechanism of the CASP high-dose (CASPH) intervention group was closely related to the protein expressions of FCER2, TBXAS1, CD34, AGXT, GCAT, COX7A2L, and CYP2AC1. Conclusively, the intervention mechanism of CASPH had multitarget, multicenter regulatory features.

Neurological manifestations of SARS-CoV-2 infection in children in Taiwan: A cross-section, multicenter study.

BACKGROUND: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry. METHODS: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry. RESULTS: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement. In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients. CONCLUSION: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM.

Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3.

Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q75 folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q75 aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q75, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q75-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q75 and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q75-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases.

How are irritability and anhedonia symptoms linked? A network approach.

BACKGROUND: Anhedonia and irritability are two prevalent symptoms of major depressive disorder (MDD) that predict greater depression severity and poor outcomes, including suicidality. Although both symptoms have been proposed to result from paradoxical reward processing dysfunctions, the interactions between these symptoms remain unclear. Anhedonia is a multifaceted symptom reflecting impairments in multiple dimensions of reward processing (e.g., pleasure, desire, motivation, and effort) across distinct reward types (e.g., food, sensory experiences, social activities, hobbies) that may differentially interact with irritability. This study investigated the complex associations between anhedonia and irritability using network analysis. METHOD: Participants (N = 448, Mage = 33.29, SD = 14.58) reported their symptoms of irritability on the Brief Irritability Test (Holtzman et al., 2015) and anhedonia (i.e., pleasure, desire, motivation, and effort dimensions across four reward types) on the Dimensional Anhedonia Rating Scale (Rizvi et al., 2015). A regularized Gaussian Graphical Model was built to estimate the network structure between items. RESULTS: Irritability was negatively related to willingness to expand effort to obtain food/drinks (estimate = -0.18), social activities (-0.13), and hobbies (-0.12) rewards. Irritability was positively associated with a desire for food/drinks (0.12). LIMITATIONS: Only a small proportion (5.8%) of our sample was clinical and the study design was cross-sectional. CONCLUSION: A specific link between irritability and the effort dimension of the hedonic response across three reward types was identified. Investigating effort expenditure deficits with experimental paradigms may help us understand the mechanisms underlying the comorbidity between irritability and anhedonia in the context of MDD.

Combined Mindfulness-Based Stress Reduction and Exercise Intervention for Improving Psychological Well-Being in Patients With Non-Small Cell Lung Cancer.

OBJECTIVE: This study aims to assess the clinical effectiveness of combining mindfulness-based stress reduction (MBSR) with exercise intervention in improving anxiety, depression, sleep quality and mood regulation in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 60 patients with NSCLC who had not received surgical treatment were selected using convenience sampling and divided into an intervention group and control group, with 30 patients in each group. The control group received conventional psychological nursing care, whereas the intervention group received a combination of MBwSR and exercise therapy. Before the intervention, a questionnaire was completed to collect the basic data of the two groups. Further questionnaires were administered at 6 and 8 weeks after treatment to assess anxiety, depression, sleep quality and other items included in the five-item Brief Symptom Rating Scale (BSRS-5). RESULTS: No significant differences between the intervention and control groups were identified in terms of personal and clinical characteristics (p > 0.05). No significant differences were determined in the BSRS-5, Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) or Pittsburgh Sleep Quality Index (PSQI) scores between the intervention and control groups before the intervention. However, 6 and 8 weeks after the intervention, scores were significantly lower in both groups (p < 0.001). Significant differences in the BSRS-5, SAS, SDS and PSQI scores were identified between the two groups at different time points (p < 0.001). CONCLUSION: The combination of MBSR and exercise intervention demonstrated improvements in anxiety, depression, sleep quality and BSRS-5 scores in patients with NSCLC.