Veiled to Express: Uncovering the Effect of Mask-Wearing on Voice Behavior in the Workplace.

Since the outbreak of COVID-19, mask-wearing has become a widespread phenomenon. Even after the pandemic, people continue to maintain the habit of wearing masks in their daily lives. While existing research has explored how mask-wearing can influence wearers' behavior in everyday life, its effects in the workplace have received less attention. Drawing on self-perception theory, this study examined the positive effect of mask-wearing in the workplace on wearers' voice behavior via psychological safety. An online experiment (N = 291) using a within-subject manipulation of wearing masks supported our hypotheses. This study uncovered the positive psychological and behavioral consequences of mask-wearing beyond its benefits in people's health conditions and everyday life.

A negative feedback loop between TET2 and leptin in adipocyte regulates body weight.

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Adipose stem cells control obesity-induced T cell infiltration into adipose tissue.

T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.

A novel lncRNA TCONS_00071187 upregulated by activated GSK3ß promotes high glucose-induced mesangial cell proliferation in the diabetic nephropathy.

Inhibiting mesangial cell proliferation is one of the strategies to control the early progression of diabetic nephropathy (DN). GSK3ß is closely related to cell apoptosis as well as the development of DN, but whether it acts on the proliferation of mesangial cells is unclear. This study aimed to elucidate the role and mechanism of GSK3ß-mediated lncRNA in high glucose-induced mesangial cell proliferation. HBZY-1 cells were used to establish the cell model of DN. The automatic cell counter was applied to assess cell proliferation. Flow cytometry was used to detect cell apoptosis and intracellular ROS levels. High-throughput transcriptomics sequencing was performed to detect the different expressions of long noncoding RNAs (lncRNAs) in the cell model of DN after knocking down the expression of GSK3ß by the transfection of siRNA. The expression of RNA was detected by real-time PCR. In the cell model of DN using HBZY-1 cells, cell proliferation was enhanced accompanied by GSK3ß activation and elevated apoptosis rate and reactive oxygen species (ROS) levels. A panel of novel lncRNAs, which were differentially expressed after GSK3ß knockdown in the cell model of DN, were identified by high-throughput transcriptomics sequencing. Among them, the expression of TCONS_00071187 was upregulated under high glucose conditions while the knockdown of the GSK3ß expression led to the downregulation of TCONS_00071187. The knockdown of TCONS_00071187 resulted in reduced mesangial cell proliferation, and decreased apoptosis rates and ROS levels. In conclusion, GSK3ß promoted mesangial cell proliferation by upregulating TCONS_00071187, which led to enhanced ROS production under high glucose conditions in the cell model of DN. This study revealed the role of GSK3ß medicated lncRNAs in the development of DN.

The Diagnostic Value of Carnett's Test with Chronic Abdominal Pain: A Narrative Review.

PURPOSE OF REVIEW: Chronic abdominal wall pain is a poorly recognized cause of chronic abdominal pain, and patients frequently go misdiagnosed despite a battery of medical tests. The Carnett's test is a diagnostic tool used to distinguish between abdominal wall pain and visceral pain. This review synthesizes the current literature on the Carnett's test, merges the viewpoints of diverse writers, and evaluates and reports on the Carnett's test's applicability. RECENT FINDINGS: Several clinical investigations have established the usefulness of the Carnett's test in the diagnosis of chronic abdominal wall pain. Furthermore, the Carnett's test is quite useful in determining the depth of the mass and detecting psychogenic abdominal pain. However, its diagnostic use for acute abdominal pain is limited. The Carnett's test is a simple and safe point-of-care diagnostic technique, with several studies supporting its usefulness. Early detection of abdominal wall pain is critical for chronic abdominal wall pain therapy. Carnett's test is very useful in patients with chronic, unexplained local abdominal discomfort who are compliant and do not have a clear rationale for surgery.

Strong Exciton-Phonon Coupling as a Fingerprint of Magnetic Ordering in van der Waals Layered CrSBr.

The layered, air-stable van der Waals antiferromagnetic compound CrSBr exhibits pronounced coupling among its optical, electronic, and magnetic properties. As an example, exciton dynamics can be significantly influenced by lattice vibrations through exciton-phonon coupling. Using low-temperature photoluminescence spectroscopy, we demonstrate the effective coupling between excitons and phonons in nanometer-thick CrSBr. By careful analysis, we identify that the satellite peaks predominantly arise from the interaction between the exciton and an optical phonon with a frequency of 118 cm-1 (∼14.6 meV) due to the out-of-plane vibration of Br atoms. Power-dependent and temperature-dependent photoluminescence measurements support exciton-phonon coupling and indicate a coupling between magnetic and optical properties, suggesting the possibility of carrier localization in the material. The presence of strong coupling between the exciton and the lattice may have important implications for the design of light-matter interactions in magnetic semiconductors and provide insights into the exciton dynamics in CrSBr. This highlights the potential for exploiting exciton-phonon coupling to control the optical properties of layered antiferromagnetic materials.

Plants recruit insecticidal bacteria to defend against herbivore attacks.

Pest feeding affects the rhizobacteria community. The rhizomicrobiota activates salicylic acid and jasmonic acid signaling pathways to help plants deal with pest infestation. However, whether plants can recruit special pesticidal microorganisms to deal with attack from herbivores is unclear. A system composed of peanuts and first-instar larvae of Holotrichia parallela were used to analyze whether peanuts truly enrich the insecticidal bacteria after feeding by larvae, and whether inoculation of the enriched bacteria promotes the resistance of plants to herbivore. In this study, high-throughput sequencing of 16 S rRNA gene amplicons was used to demonstrate that infestation of the subterranean pest H. parallela quickly changed the rhizosphere bacterial community structure within 24 h, and the abundance of Enterobacteriaceae, especially Enterobacter, was manifestly enriched. Root feeding induced rhizobacteria to form a more complex co-occurrence network than the control. Rhizosphere bacteria were isolated, and 4 isolates with high toxicity against H. parallela larvae were obtained by random forest analysis. In a back-inoculation experiment using a split-root system, green fluorescent protein (GFP)-labeled Enterobacter sp. IPPBiotE33 was observed to be enriched in uneaten peanut roots. Additionally, supplementation with IPPBiotE33 alleviated the adverse effects of H. parallela on peanuts. Our findings indicated that herbivore infestation could induce plants to assemble bacteria with specific larvicidal activity to address threats.

Selenium Concentration Is Positively Associated with Triglyceride-Glucose Index and Triglyceride Glucose-Body Mass Index in Adults: Data from NHANES 2011-2018.

Compiling evidence supports that selenium plays a vital role in glucose metabolism. Triglyceride-glucose index (TyG) and triglyceride-glucose-body mass index (TyG-BMI) are commonly used in epidemiologic studies to evaluate insulin resistance and cardiovascular disease (CVD) risks. This study is aimed to investigate the association between whole blood selenium concentration and TyG and TyG-BMI. A total of 6290 participants (age ≥ 20 years) from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were included. Multiple linear regression models were used to examine the association between blood selenium quartiles and TyG and TyG-BMI. Subgroup analysis stratified by diabetes status was also performed. The adjusted model showed a positive association between TyG and blood selenium concentration (ß [95%CI] = 0.099 [0.063, 0.134], p < 0.001) and TyG-BMI (ß [95%CI] = 3.185 [2.102, 4.268], p < 0.001). The association persisted after stratification by diabetes status (p < 0.001). Participants were stratified into four quartiles based on selenium concentration (Q1: 1.08-2.24 µmol/L, Q2: 2.25-2.42 µmol/L, Q3: 2.43-2.62 µmol/L, Q4: 2.63-8.08). Compared with the Q1 group, TyG in the Q3 and Q4 groups was significantly higher (ß = 0.075 [95%CI 0.039 to 0.112] and ß = 0.140 [95%CI 0.103 to 0.176], respectively). Additionally, TyG-BMI in the Q2, Q3, and Q4 groups was higher than that in the Q1 group (ß = 1.189 [95%CI 0.065 to 2.314], ß = 2.325 [95%CI 1.204 to 3.446], and ß = 4.322 [95%CI 3.210 to 5.435], respectively). Blood level of selenium was positively associated with TyG and TyG-BMI, indicating that excessive blood selenium may be associated with impaired insulin sensitivity and increased risk of cardiovascular disease.

The relationship between alterations in plasma metabolites and treatment responses in antipsychotic-naïve female patients with schizophrenia.

This study aimed to explore the relationship between alterations in plasma metabolites and treatment responses amongst antipsychotic-naïve female patients with schizophrenia. A total of 38 antipsychotic-naïve female schizophrenia patients (ANS) and 19 healthy female controls (HC) were recruited. Plasma samples were obtained from all participants, and targeted metabolomics were measured with FIA-MS/MS and LC-MS/MS. The positive and negative syndrome scale (PANSS) was used to assess the severity of psychotic symptoms before and after eight weeks of treatment. Receiver operator characteristics (ROC) curves were used to predict diagnostic and therapeutic responses. A total of 186 metabolites passed quality control procedures and were used in statistical analysis to identify potential biomarkers. Before treatment, the ANS patients had lower levels of γ -Aminobutyric Acid (GABA) and higher levels of Cholesteryl esters (CE) (20:3), Cholic Acid (CA) and Glycocholic Acid (GCA) compared to the HCs. These four differential metabonomic markers were synthesised into a combinatorial biomarker panel. This panel significantly distinguished ANS from HC. Moreover, this biomarker panel was able to effectively predict therapeutic responses. Our results suggest that plasma CE (20:3), CA, GCA, and GABA levels may be useful for diagnosing and predicting antipsychotic efficacy amongst female schizophrenia patients.

Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis.

While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1ß (IL-1ß) production in bone-marrow-derived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1ß secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.

Autophagy markers, cognitive deficits and depressive symptoms in Parkinson's disease.

Depressive symptoms are common in Parkinson's disease (PD). The relationships between autophagy and PD or depression have been documented. However, no studies explored the role of autophagy markers associated with depressive symptoms in PD. Our study aimed to investigate the relationships between autophagy markers, cognitive impairments and depressive symptoms in PD patients. A total of 163 PD patients aged 50-80 years were recruited. Plasma concentrations of autophagy markers (LC3-I, LC3-II and p62/SQSTM1) and glycolipid parameters were measured. Depressive symptoms, cognitive impairments, and motor function were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MoCA), and the Movement Disorders Society Unified Parkinson's Rating Scale Part III (MDS-UPDRS-III), respectively. There were no significant differences between depressed and non-depressed PD patients for LC3-I, LC3-II, LC3-II/LC3-I and p62/SQSTM1. After controlling confounding variables, LC3-II/LC3-I showed an independent relationship with depressive symptoms in PD patients (Beta = 10.082, t = 2.483, p = 0.014). Moreover, in depressive PD patients, p62/SQSTM1 was associated with MoCA score (Beta = - 0.002, t = - 2.380, p = 0.020); Further, p62/SQSTM1 was related to naming ability; in addition, p62/SQSTM1 was independently associated with delayed recall (Beta = - 0.001, t = - 2.452, p = 0.017). LC3-II/LC3-I was related to depressive symptoms in PD patients. In depressive PD patients, p62/SQSTM1 was associated with cognitive function, especially naming ability and delayed recall.

EEG synchronized left prefrontal transcranial magnetic stimulation (TMS) for treatment resistant depression is feasible and produces an entrainment dependent clinical response: A randomized controlled double blind clinical trial.

BACKGROUND: Synchronizing a TMS pulse with a person's underlying EEG rhythm can modify the brain's response. It is unclear if synchronizing rTMS trains might boost the antidepressant effect of TMS. In this first-in-human trial, we demonstrated that a single TMS pulse over the prefrontal cortex produces larger effects in the anterior cingulate depending on when it is fired relative to the individual's EEG alpha phase. OBJECTIVE/HYPOTHESES: We had three hypotheses. 1) It is feasible to synchronize repetitive TMS (rTMS) delivery to a person's preferred prefrontal alpha phase in each train of every session during a 30-visit TMS depression treatment course. 2) EEG-synchronized rTMS would produce progressive entrainment greater than unsynchronized (UNSYNC) rTMS. And 3) SYNC TMS would have better antidepressant effects than UNSYNC (remission, final Hamilton Depression Rating <10). METHODS: We enrolled (n = 34) and treated (n = 28) adults with treatment resistant depression (TRD) and randomized them to receive six weeks (30 treatments) of left prefrontal rTMS at their individual alpha frequency (IAF) (range 6-13 Hz). Prior to starting the clinical trial, all patients had an interleaved fMRI-EEG-TMS (fET) scan to determine which phase of their alpha rhythm would produce the largest BOLD response in their dorsal anterior cingulate. Our clinical EEG-rTMS system then delivered the first TMS pulse in each train time-locked to this patient-specific 'preferred phase' of each patient's left prefrontal alpha oscillation. We randomized patients (1:1) to SYNC or UNSYNC, and all were treated at their IAF. Only the SYNC patients had the first pulse of each train for all sessions synchronized to their individualized preferred alpha phase (75 trains/session ×30 sessions, 2250 synchronizations per patient over six weeks). The UNSYNC group used a random firing with respect to the alpha wave. All other TMS parameters were balanced between the two groups. The system interfaced with a MagStim Horizon air-cooled Fig. 8 TMS coil. All patients were treated at their IAF, coil in the F3 position, 120 % MT, frequency 6-13 Hz, 40 pulses per train, average 15-s inter-train interval, 3000 pulses per session. All patients, raters, and treaters were blinded. RESULTS: In the intent to treat (ITT) sample, both groups had significant clinical improvement from baseline with no significant between-group differences, with the USYNC group having mathematically more remitters but fewer responders. (ITT -15 SYNC; 13 UNSYNC, response 5 (33 %), 1 (7 %), remission 2 (13 %), 6 (46 %). The same was true with the completer sample - 12 SYNC; 12 UNSYNC, response 4, 4 (both 30 %), remission 2 (17 %), 3 (25 %)). The clinical EEG phase synchronization system performed well with no failures. The average treatment session was approximately 90 min, with 30 min for placing the EEG cap and the actual TMS treatment for 45 min (which included gathering 10 min of resting EEG). Four subjects (1 SYNC) withdrew before six weeks of treatment. All 24 completer patients were treated for six weeks despite the trial occurring during the COVID pandemic. SYNC patients exhibited increased post-stimulation EEG entrainment over the six weeks. A detailed secondary analysis of entrainment data in the SYNC group showed that responders and non-responders in this group could be cleanly separated based on the total number of sessions with entrainment and the session-to-session precision of the entrained phase. For the SYNC group only, depression improvement was greater when more sessions were entrained at similar phases. CONCLUSIONS: Synchronizing prefrontal TMS with a patient's prefrontal alpha frequency in a blinded clinical trial is possible and produces progressive EEG entrainment in synchronized patients only. There was no difference in overall clinical response in this small clinical trial. A secondary analysis showed that the consistency of the entrained phase across sessions was significantly associated with response outcome only in the SYNC group. These effects may not simply be due to how the stimulation is delivered but also whether the patient's brain can reliably entrain to a precise phase. EEG-synchronized clinical delivery of TMS is feasible and requires further study to determine the best method for determining the phase for synchronization.

Biomarkers predict the efficacy of closed-loop rTMS treatment for refractory depression.

Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients (i.e., less than 50%). Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders.

Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression.

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.

Identification of Plasma Biomarkers in Drug-Naïve Schizophrenia Using Targeted Metabolomics.

OBJECTIVE: Schizophrenia (SCZ) is a severe psychiatric disorder with unknown etiology and lacking specific biomarkers. Herein, we aimed to explore plasma biomarkers relevant to SCZ using targeted metabolomics. METHODS: Sixty drug-naïve SCZ patients and 36 healthy controls were recruited. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. We analyzed the levels of 271 metabolites in plasma samples from all subjects using targeted metabolomics, and identified metabolites that differed significantly between the two groups. Then we evaluated the diagnostic power of the metabolites based on receiver operating characteristic curves, and explored metabolites associated with the psychotic symptoms in SCZ patients. RESULTS: Twenty-six metabolites showed significant differences between SCZ patients and healthy controls. Among them, 12 metabolites were phosphatidylcholines and cortisol, ceramide (d18:1/22:0), acetylcarnitine, and γ-aminobutyric acid, which could significantly distinguish SCZ from healthy controls with the area under the curve (AUC) above 0.7. Further, a panel consisting of the above 4 metabolites had an excellent performance with an AUC of 0.867. In SCZ patients, phosphatidylcholines were positively related with positive symptoms, and cholic acid was positively associated with negative symptoms. CONCLUSION: Our study provides insights into the metabolite alterations associated with SCZ and potential biomarkers for its diagnosis and symptom severity assessment.

The relationship between inflammatory markers, clinical characteristics, and cognitive performance in drug-naïve patients with schizophrenia.

Increasing evidence implicates that inflammatory factors do play a crucial role in the pathophysiology of schizophrenia. However, the association between inflammatory markers and different symptom dimensions and cognitive function of schizophrenia remains unclear. A total of 140 drug-naïve patients with schizophrenia and 69 healthy controls matched for age and gender were enrolled. Peripheral blood plasma concentrations of S-100 calcium-binding protein B (S100B), neutrophil gelatinase-associated lipocalin (NGAL), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Compared with healthy controls, patients with schizophrenia had significantly worse cognitive function and lower levels of NGAL and IFN-γ (P < 0.001). In schizophrenia, plasma NGAL and IFN-γ levels negatively correlated with positive symptom scores (all P < 0.05). There was a positive correlation between plasma levels of NGAL and IFN-γ with visual learning, neurocognition, and MCCB total score (all P < 0.05). We found that NGAL levels (ß = 0.352, t = 5.553, 95% CI 0.228-0.477, P < 0.001) and negative symptoms subscale scores (ß = - 0.321, OR = 0.725, 95% CI 648-0.811, P < 0.001) were independently associated with the MCCB total score. Further, binary logistic regression analysis indicated that the concentrations of NGAL (ß = - 0.246, OR = 0.782, 95% CI 0.651-0.939, P = 0.008) were independently associated with the diagnosis of schizophrenia. There was a positive correlation between NGAL and IFN-γ levels and MCCB total score in schizophrenia. NGAL level was an independent protective factor for cognitive function and an independent risk factor for the diagnosis of schizophrenia.

A non-canonical striatopallidal Go pathway that supports motor control.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons.

Bile acids ameliorates lipopolysaccharide-induced endometritis in mice by inhibiting NLRP3 inflammasome activation.

AIMS: Endometritis is a common inflammatory disorder affecting the reproductive health in both humans and livestock. The NLR family pyrin domain containing 3 (NLRP3) inflammasome has recently been identified as a possible therapeutic target for several inflammatory disorders. Bile acids (BAs) have been shown to possess anti-inflammatory properties by inhibiting the activation of the NLRP3 inflammasome. However, whether BAs ameliorate endometritis by targeting NLRP3 inflammasome remain poorly understood. MAIN METHODS: Female NLRP3+/+ and NLRP3-/- mice were subjected to uterine perfusion with lipopolysaccharide (LPS) to establish the endometritis model. For BAs pre-treatment, wild-type mice were administered oral gavage of BAs for seven days followed by uterine perfusion with LPS. All mice were euthanized and the uterine tissues were collected for analysis. KEY FINDINGS: The abundances of NLRP3 and interleukin-1 beta (IL-1ß) were significantly upregulated in the uterine tissues of endometritis mice. NLRP3 deficiency led to a reduction in the inflammatory response, neutrophil infiltration, and myeloperoxidase (MPO) activity in the uterus, as well as an inhibition of IL-1ß secretion. Moreover, BAs pre-treatment successfully decreased LPS-induced upregulation of NLRP3, ASC, and Caspase1, lessened histopathological alteration in the uterus, and notably reduced MPO activity and secretion of IL-1ß. SIGNIFICANCE: NLRP3 inflammasome is a promising target for endometritis treatment and BAs exhibit anti-inflammatory properties by repressing NLRP3 inflammasome activation, making them a possible novel therapeutic strategy for endometritis.

Efficacy and safety of ciprofol for long-term sedation in patients receiving mechanical ventilation in ICUs: a prospective, single-center, double-blind, randomized controlled protocol.

Introduction: Critically ill patients who receive mechanical ventilation after endotracheal intubation commonly experience discomfort and pressure. The major sedative drugs that are currently used in clinical practice present with many complications, such as hypotension, bradycardia, and respiratory depression. Ciprofol (HSK3486), which is a newly developed structural analog of propofol, is a short-acting gamma-aminobutyric acid (GABA) receptor agonist, and its mechanism of action is sedation or anesthesia by enhancing GABA-mediated chloride influx. The high efficacy of ciprofol for short-term sedation is comparable to that of propofol, and it has a relatively low incidence of adverse effects and high level of safety, which has been confirmed by multiple clinical studies. However, few studies have examined its safety and efficacy for long-term sedation. The purpose of the study is to evaluate the efficacy and safety of ciprofol for long-term sedation in mechanically ventilated patients. Methods: A prospective, single-center, double-blind, randomized, propofol-controlled, non-inferiority trial is proposed. The study will enroll 112 mechanically ventilated patients hospitalized in the intensive care unit (ICU) of the Shanghai Fourth People's Hospital affiliated with Tongji University based on the inclusion and exclusion criteria of the study, and randomly assign them to a group sedated with either ciprofol or propofol. The primary outcome is the percentage of time spent under target sedation, and secondary outcomes include drug dose, number of cases requiring additional dextrometropine, incidence of systolic blood pressure <80 or >180 mmHg, incidence of diastolic blood pressure <50 or >100 mmHg, incidence of heart rate <50 beats per minute (bpm) or >120 bpm, inflammatory indicators, blood lipid levels, liver and kidney functions, nutritional indicators, ventilator-free days within the 7-day period after enrollment, 28-day mortality, ICU stay duration, and hospitalization costs. Discussion: We hypothesize that the efficacy and safety of ciprofol for long-term sedation in mechanically ventilated ICU patients will not be inferior to that of propofol. Trial registration: Chinese Clinical Trials Registry identifier ChiCTR2200066951.