The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Additive-free oxychlorination of unsaturated C-C bonds with tert-butyl hypochlorite and water.

Herein we report an additive-free protocol for the facile synthesis of α,α-dichloroketones and α-chlorohydrins from various aryl terminal, diaryl internal, and aliphatic terminal alkynes and alkenes, respectively. The commercially available tert-butyl hypochlorite (tBuOCl) was employed as a suitable chlorinating reagent, being accompanied by the less harmful tBuOH as the by-product. In addition, the oxygen atoms in the products came from water rather than molecular oxygen, based on the 18O-labelling experiments. Meanwhile, the diastereoselectivity of the Z- and the corresponding E-alkenes has been compared and rationalized. Using a group of control experiments, the possible mechanisms have been proposed as the initial electrophilic chlorination of unsaturated C-C bonds in a Markovnikov-addition manner in general followed by a nucleophilic addition with water. This work simplified the oxychlorination method with a mild chlorine source and a green oxygen source under ambient conditions.

Interictal interleukin-6 and tumor necrosis factor α levels are associated with seizure recurrence in adults with epilepsy.

BACKGROUND: Although there are models predicting epilepsy recurrence under different clinical conditions, few studies have examined blood biomarkers. Inflammation plays a crucial role in the occurrence and development of epilepsy. We analyzed inflammatory mediators in a regional hospital-based epilepsy cohort and investigated their relationship with subsequent epilepsy recurrence. METHODS: Interictal inflammatory mediators were measured in 128 patients diagnosed with epilepsy participating in a prospective study. Inflammatory mediators were compared during the follow-up period between patients who experienced epilepsy recurrence and those who did not. We also assessed the correlation between inflammatory mediators and the time interval until the next recurrence. RESULTS: Over a median 4-month follow-up period, 41 patients experienced seizure recurrence. Differences in interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were observed between seizure recurrence and non-recurrence groups. After adjusting for covariates through multivariate Cox regression analysis, the patients in the third IL-6 tertile (>2.31 pg/mL; HR: 2.49; 95 % CI: 1.00-6.16; P = 0.049) and in the third TNF-α tertile (>0.74 pg/mL; HR: 2.80; 95 % CI: 1.13-6.92; P = 0.026) had higher risk of seizure recurrence. The time until the next recurrence was negatively correlated with IL-6 level (ρ =  - 0.392, P = 0.011). CONCLUSION: High levels of IL-6 and TNF-α are associated with a higher possibility of seizure recurrence. Future predictive models should also include inflammatory mediators in addition to clinical variables.

Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.

Bronchial thermoplasty (BT), an effective treatment for severe asthma, requires heat to reach the airway to reduce the mass of airway smooth muscle cells (ASMCs). Autophagy is involved in the pathological process of airway remodeling in patients with asthma. However, it remains unclear whether autophagy participates in controlling airway remodeling induced by BT. In this study, we aim to elucidate the autophagy-mediated molecular mechanisms in BT. Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin (α-SMA) fluorescence are significantly decreased in airway biopsy tissues after BT. As the temperature increased, BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells (HASMCs). Furthermore, increase in temperature significantly downregulates cellular autophagy, autophagosome accumulation, the LC3II/LC3I ratio, and Beclin-1 expression, upregulates p62 expression, and inhibits the AMPK/mTOR pathway. Furthermore, cotreatment with AICAR (an AMPK agonist) or RAPA (an mTOR antagonist) abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect. Therefore, we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.

Unraveling a Small Secreted Peptide SUBPEP3 That Positively Regulates Salt-Stress Tolerance in Pyrus betulifolia.

Small secreted peptides (SSPs) play important roles in regulating plants' growth and development in response to external stimulus, but the genes and functions of SSPs in many species are still unknown. Therefore, it is particularly significant to characterize and annotate SSP genes in plant genomes. As a widely used stock of pears, Pyrus betulifolia has strong resistance to biotic and abiotic stresses. In this study, we analyzed the SSPs genes in the genome of P. betulifolia according to their characteristics and homology. A total of 1195 SSP genes were identified, and most of them are signaling molecules. Among these, we identified a new SSP, subtilase peptide 3 (SUBPEP3), which derived from the PA region of preSUBPEP3, increasing the expression level under salt stress. Both adding synthetic peptide SUBPEP3 to the culture medium of pears and the overexpression of SUBPEP3 in tobacco can improve the salt tolerance of plants. In summary, we annotated the SSP genes in the P. betulifolia genome and identified a small secreted peptide SUBPEP3 that regulates the salt tolerance of P. betulifolia, which provides an important theoretical basis for further revealing the function of SSPs.

Modulating the Gut Microbiota and Metabolites with Traditional Chinese Medicines: An Emerging Therapy for Type 2 Diabetes Mellitus and Its Complications.

Currently, an estimated 537 million individuals are affected by type 2 diabetes mellitus (T2DM), the occurrence of which is invariably associated with complications. Glucose-lowering therapy remains the main treatment for alleviating T2DM. However, conventional antidiabetic agents are fraught with numerous adverse effects, notably elevations in blood pressure and lipid levels. Recently, the use of traditional Chinese medicines (TCMs) and their constituents has emerged as a preferred management strategy aimed at curtailing the progression of diabetes and its associated complications with fewer adverse effects. Increasing evidence indicates that gut microbiome disturbances are involved in the development of T2DM and its complications. This regulation depends on various metabolites produced by gut microbes and their interactions with host organs. TCMs' interventions have demonstrated the ability to modulate the intestinal bacterial microbiota, thereby restoring host homeostasis and ameliorating metabolic disorders. This review delves into the alterations in the gut microbiota and metabolites in T2DM patients and how TCMs treatment regulates the gut microbiota, facilitating the management of T2DM and its complications. Additionally, we also discuss prospective avenues for research on natural products to advance diabetes therapy.

CrMP-Sol database: classification, bioinformatic analyses and comparison of cancer-related membrane proteins and their water-soluble variant designs.

Membrane proteins are critical mediators for tumor progression and present enormous therapeutic potentials. Although gene profiling can identify their cancer-specific signatures, systematic correlations between protein functions and tumor-related mechanisms are still unclear. We present here the CrMP-Sol database ( https://bio-gateway.aigene.org.cn/g/CrMP ), which aims to breach the gap between the two. Machine learning was used to extract key functional descriptions for protein visualization in the 3D-space, where spatial distributions provide function-based predictive connections between proteins and cancer types. CrMP-Sol also presents QTY-enabled water-soluble designs to facilitate native membrane protein studies despite natural hydrophobicity. Five examples with varying transmembrane helices in different categories were used to demonstrate the feasibility. Native and redesigned proteins exhibited highly similar characteristics, predicted structures and binding pockets, and slightly different docking poses against known ligands, although task-specific designs are still required for proteins more susceptible to internal hydrogen bond formations. The database can accelerate therapeutic developments and biotechnological applications of cancer-related membrane proteins.

Single-cell analysis reveals distinct functional heterogeneity of CD34+ cells in anagen wound and diabetic wound.

Wound healing is a complex biological process involving multiple cell types with their critical functions. The diabetic wounds show delayed wound healing, while the anagen wounds display accelerated wound closure. However, the mechanisms underlying the effect of cellular heterogeneity on wound healing are still unclear. CD34+ cells exhibit high heterogeneity in wound skins and improve wound healing. Herein, we investigated the phenotypic and functional heterogeneity of CD34+ cells in normal, anagen, and diabetic wounds. We obtained CD34 lineage tracing mice, constructed distinct wound models, collected CD34+ cells from wound edges, and performed single-cell RNA sequencing. We identified 10 cell clusters and 6 cell types of CD34+ cells, including endothelial cells, fibroblasts, keratinocytes, neutrophils, macrophages, and T cells. 5 subclusters were defined as fibroblasts. The CD34+ fibroblasts C2 highly expressed papillary fibroblastic markers took up the largest proportion in anagen wounds and were associated with inflammation and extracellular matrix. Increased CD34+ endothelial cells, fibroblasts C4, and neutrophils as well as decreased fibroblasts C1 were discovered in diabetic wounds. We also filtered out differentially expressed genes (DEGs) of each cell cluster in anagen wounds and diabetic wounds. Functional enrichment analysis was performed on these DEGs to figure out the enriched pathways and items for each cell cluster. Pseudotime analysis of CD34+ fibroblasts was next carried out indicating fibroblast C4 mainly with low differentiation. Our results have important implications for understanding CD34+ cell type-specific roles in anagen and diabetic wounds, provide the possible mechanisms of wound healing from a new perspective, and uncover potential therapeutic approaches to treating wounds.

GLRaV-2 protein p24 suppresses host defenses by interaction with a RAV transcription factor from grapevine.

Grapevine leafroll-associated virus 2 (GLRaV-2) is a prevalent virus associated with grapevine leafroll disease, but the molecular mechanism underlying GLRaV-2 infection is largely unclear. Here, we report that 24-kDa protein (p24), an RNA-silencing suppressor (RSS) encoded by GLRaV-2, promotes GLRaV-2 accumulation via interaction with the B3 DNA-binding domain of grapevine (Vitis vinifera) RELATED TO ABSCISIC ACID INSENSITIVE3/VIVIPAROUS1 (VvRAV1), a transcription factor belonging to the APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) superfamily. Salicylic acid-inducible VvRAV1 positively regulates the grapevine pathogenesis-related protein 1 (VvPR1) gene by directly binding its promoter, indicating that VvRAV1 may function in the regulation of host basal defense responses. p24 hijacks VvRAV1 to the cytoplasm and employs the protein to sequester 21-nt double-stranded siRNA together, thereby enhancing its own RSS activity. Moreover, p24 enters the nucleus via interaction with VvRAV1 and weakens the latter's binding affinity to the VvPR1 promoter, leading to decreased expression of VvPR1. Our results provide a mechanism by which a viral RSS interferes with both the antiviral RNA silencing and the AP2/ERF-mediated defense responses via the targeting of one specific host factor.

Synthesis, Characterization and Singlet Fission Behaviors of Heteroatom-Doped Polycyclic Aromatic Hydrocarbons with (ß, ß) Connected Furan/Thiophene Ring.

Singlet fission (SF) has been proven to be an effective strategy to overcome the Shockley-Queisser limit of photovoltaics. However, the materials suitable for SF are relatively rare due to the strict requirements for the occurrence of this process. In the present study, we report the first preparation of two heteroatoms (O and S)-doped polycyclic aromatic hydrocarbons (PAHs) molecules with (ß, ß) connected furan/thiophene ring. The optical and physiochemical properties of both compounds are investigated by a variety of spectroscopies, including UV-vis absorption, photoluminescence and cyclic voltammetry. In addition, their ultrafast excited state dynamics are studied by femtosecond transient absorption. Experimental data showed that the singlet fission efficiency was improved by 2 times when replacing oxygen with sulfur atom, which could provide some guidelines in designing singlet fission materials with better efficiency.

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer.

OBJECTIVE: Although the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC. SUBJECTS AND METHODS: This was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC). RESULTS: The median follow-up was 5.2 years. Compared with instillation for 1-2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3-6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27-12.41;0.26-9.28;0.07-0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC. CONCLUSIONS: In our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

Changes in seizure frequency and anti-seizure medication therapy during pregnancy and one year postpregnancy.

Seizure control in women with epilepsy (WWE) during pregnancy is a vital concern. The aim of this study was to compare changes in seizure frequency and anti-seizure medication (ASM ) therapy in WWE in a real-world setting over three epochs (prepregnancy, pregnancy, and postpregnancy). We screened WWE who were pregnant between 1 January 2010 and 31 December 2020 from the epilepsy follow-up registry database of a tertiary hospital in China. We reviewed and collected follow-up data for the following time periods: 12 months before pregnancy (epoch 1), throughout pregnancy and the first 6 weeks postpartum (epoch 2), and from 6 weeks to 12 months postpartum (epoch 3). Seizures were classified into two categories: tonic‒clonic/focal to bilateral tonic‒clonic seizures and non-tonic‒clonic seizures. The main indicator was the seizure-free rate over the three epochs. Using epoch 1 as a reference, we also compared the percentage of women with an increased seizure frequency, as well as changes in ASM treatment, in epochs 2 and 3. Ultimately, 271 eligible pregnancies in 249 women were included. The seizure-free rates in epoch 1, epoch 2, and epoch 3 were 38.4%, 34.7%, and 43.9%, respectively (P = 0.09). The top three ASMs used in the three epochs were lamotrigine, levetiracetam, and oxcarbazepine. Using epoch 1 as a reference, the percentages of women with increased frequencies of tonic‒clonic/focal to bilateral tonic‒clonic seizures in epoch 2 and epoch 3 were 17.0% and 14.8%, respectively, while the percentages of women with an increased frequency of non-tonic‒clonic seizures in epoch 2 and epoch 3 were 31.0% and 21.8% (P = 0.02). The percentage of women whose ASM dosages were increased in epoch 2 was higher than that in epoch 3 (35.8% vs. 27.3%, P = 0.03). The seizure frequency during pregnancy may not differ significantly from that during prepregnancy and postpregnancy if WWE are treated according to the guidelines.

Design, synthesis and evaluation of monoketene compounds as novel potential Parkinson's disease agents by suppressing ER stress via AKT.

Curcumin is identified that it has the potential to treat Parkinson's disease (PD), but its instability limits its further application in clinic. The mono-carbonyl analogs of curcumin (MACs) with diketene structure can effectively improve its stability, but it is highly toxic. In the present study, a less cytotoxic and more stable monoketene MACs skeleton S2 was obtained, and a series of monoketene MACs were synthesized by combining 4-hydroxy-3­methoxy groups of curcumin. In the 6-OHDA-induced PD's model in-vitro, some compounds exhibited significant neurotherapeutic effect. The quantitative structure-activity relationship (QSAR) model established by the random forest algorithm (RF) for the cell viability rate of above compounds showed that the statistical results are good (R2 = 0.883507), with strong reliability. Among all compounds, the most active compound A4 played an important role in neuroprotection in the PD models both in vitro and in vivo by activating AKT pathway, and then inhibiting the apoptosis of cells caused by endoplasmic reticulum (ER) stress. In the PD model in-vivo, compound A4 significantly improved survival of dopaminergic neurons and the contents of neurotransmitters. It also enhanced the retention of nigrostriatal function which was better than the effect in the mice treated by Madopar, a classical clinical drug for PD. In summary, we screened out the compound A4 with high stability, less cytotoxic monoketene compounds. And these founding provide evidence that the compound A4 can protect dopaminergic neurons via activating AKT and subsequently suppressing ER stress in PD.

A mutant R70V/E166A of short manganese peroxidase showing Mn2+-independent dye decolorization.

Il-MnP1, a short-type manganese peroxidase from Irpex lacteus F17, can oxidize some substrates in the absence of Mn2+, but the catalysis was much lower than in the presence of Mn2+. Here, we report a mutant R70V/E166A of Il-MnP1 with some unique properties, which possessed clearly higher catalysis for the decolorization of anthraquinone and azo dyes in the absence of Mn2+ than that of Il-MnP1. Importantly, the optimum pH of R70V/E166A for decolorization of anthraquinone dyes (Reactive Blue 19, RB19) was 6.5, and the mutant achieved high decolorization activities in the range of pH 4.0-7.0, whereas Il-MnP1 only showed decolorization for RB19 at pH 3.5-4.0. In addition, the optimum H2O2 concentration of R70V/E166A for RB19 decolorization was eight times that of Il-MnP1 and the H2O2 stability has improved 1.4 times compared with Il-MnP1. Furthermore, Mn2+ competitively inhibited the oxidation of RB19 by R70V/E166A, explaining the higher catalytic activity of the mutant R70V/E166A in the absence of Mn2+. Molecular docking results suggested that RB19 binds to the distal side of the heme plane in mutant R70V/E166A, which extended from the heme δ-side to the heme γ-side, and close to the mutated residues of R70V and E166A, whereas RB19 could not access the heme pocket of Il-MnP1 due to the steric hindrance of the side-chain group of Arg 70. Thus, this study constructed a useful mutant R70V/E166A and analyzed its higher Mn2+-independent activity, which is very important for better understanding the Mn2+-independent catalytic mechanism for short manganese peroxidases. KEY POINTS: • The mutant R70V/E166A of atypical MnP1 of I. lacteus F17 shows unique catalytic properties. • At pH 6.5, the R70V/E166A had a strong ability to decolorize anthraquinone dyes in the absence of Mn2+. • The binding sites of Reactive Blue 19 in mutant R70V/E166A were elucidated.

COVID-19 vaccine attitudes among a majority black sample in the Southern US: public health implications from a qualitative study.

BACKGROUND: The COVID-19 pandemic continues to have high caseloads in the US, with vaccines a critical component of the response. Disparities in COVID-19 morbidity and mortality have been identified across states and racial/ethnic groups, which are likely in part due to disparities in COVID-19 vaccine uptake. This study aims to better understand and contextualize COVID-19 vaccine hesitancy among persons from under-represented racial/ethnic populations in the Southern US. METHODS: We conducted 29 in-depth interviews with a sample of households in Atlanta, GA that were selected from an address-based sampling frame. We purposively approached households, from February 6 to June 27, 2021, that declined participation in a national COVID-19 serosurvey to gain perspectives of people who are often under-represented in research. Interviews were conducted in-person or over phone calls for participants with that preference. Thematic analysis was used to identify barriers and facilitators of COVID-19 vaccination, and to contextualize drivers of vaccine hesitancy. RESULTS: Decision-making about vaccination was described as dynamic, and was compared to the feeling of being on a roller coaster. The predominant reported sources of information were mass media and social media. Facilitators of vaccination included altruism, positive communication from trusted community members and workplace colleagues, and local vaccine provision sites. Driving reasons for vaccine hesitancy included limited trust in the government and concerns about COVID-19 vaccine safety, which one participant compared to jumping off a cliff without a tested rope. Among a subset of participants, beliefs regarding perceived intent to harm the Black community were prevalent. Opportunities to optimally address vaccine hesitancy included countering negative social media messages with positive messaging that matches the community's vivid ways of discussing vaccines, collaborating with community stakeholders on vaccine promotion efforts, and offering workplace-based vaccine promotion efforts. CONCLUSIONS: This study presents data that indicate it may be optimal to more broadly define 'community' in COVID-19 vaccine promotion efforts to include social media and workplace venues. To optimize vaccine and vaccine booster uptake and equity, public health must address historic racism and other concerns by using outreach that is grounded in communities.

The ß-1,3-Glucanase Degrades Callose at Plasmodesmata to Facilitate the Transport of the Ribonucleoprotein Complex in Pyrus betulaefolia.

Grafting is widely used to improve the stress tolerance and the fruit yield of horticultural crops. Ribonucleoprotein complexes formed by mRNAs and proteins play critical roles in the communication between scions and stocks of grafted plants. In Pyrus betulaefolia, ankyrin was identified previously to promote the long-distance movement of the ribonucleoprotein complex(PbWoxT1-PbPTB3) by facilitating callose degradation at plasmodesmata. However, the mechanism of the ankyrin-mediated callose degradation remains elusive. In this study, we discovered a ß-1,3-glucanase (EC 3.2.1.39, PbPDBG) using ankyrin as a bait from plasmodesmata by co-immunoprecipitation and mass spectrometry. Ankyrin was required for the plasmodesmata-localization of PbPDBG. The grafting and bombardment experiments indicated that overexpressing PbPDBG resulted in decreased callose content at plasmodesmata, and thereby promoting the long-distance transport of the ribonucleoprotein complex. Altogether, our findings revealed that PbPDBG was the key factor in ankyrin-mediated callose degradation at plasmodesmata.

11ß-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice.

BACKGROUND: Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied. METHODS: We first investigated the expression of 11ß-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11ß-HSD1 on the excitability of primary cultured neurons in vitro using whole-cell patch clamp recordings. Further, we assessed the effects of adeno-associated virus (AAV)-induced hippocampal 11ß-HSD1 knockdown in the PTZ model, conducting behavioural observations of seizures, assessment of spatial learning and memory using the Morris water maze, and biochemical and histopathological analyses. RESULTS: We found that 11ß-HSD1 was primarily expressed in neurons but not astrocytes, and its expression was significantly (p < 0.05) increased in the hippocampus of PTZ epilepsy mice compared to sham controls. Whole-cell patch clamp recordings showed that overexpression of 11ß-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11ß-HSD1 significantly reduced the severity score of PTZ seizures and increased the latent period required to reach the fully kindled state compared to control knockdown. Knockdown of 11ß-HSD1 also significantly mitigated the impairment of spatial learning and memory, attenuated hippocampal neuronal damage and increased the ratio of Bcl-2/Bax, while decreasing the expression of cleaved caspase-3. CONCLUSIONS: 11ß-HSD1 participates in the pathogenesis of both epilepsy and the associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and subsequent hippocampal neuronal damage. Inhibition of 11ß-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity.

Enoxacin Up-Regulates MicroRNA Biogenesis and Down-Regulates Cytotoxic CD8 T-Cell Function in Autoimmune Cholangitis.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is a prototypical organ-specific autoimmune disease that is mediated by autoreactive T-cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune-directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune diseases. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC). In the dominant-negative TGF-ß receptor type II (dnTGFßRII) mouse model of PBC, autoreactive CD8 T cells play a major pathogenic role and demonstrate a striking pattern of miRNA down-regulation. Enoxacin is a small molecule fluoroquinolone that enhances miRNA biogenesis, partly by stabilizing the interaction of transactivation response RNA-binding protein with Argonaute (Ago) 2. APPROACH AND RESULTS: We hypothesized that correcting aberrant T-cell miRNA expression with enoxacin in dnTGFßRII mice could modulate autoreactive T-cell function and prevent PBC. Here, we show that liver-infiltrating dnTGFßRII CD8 T cells have significantly decreased levels of the miRNA biogenesis molecules prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and Ago2 along with significantly increased levels of granzyme B and perforin. Enoxacin treatment significantly up-regulated miRNAs in dnTGFßRII CD8 T cells and effectively treated autoimmune cholangitis in dnTGFßRII mice. Enoxacin treatment directly altered T cells both ex vivo and in vitro, resulting in altered memory subset numbers, decreased proliferation, and decreased interferon-γ production. Enoxacin significantly decreased CD8 T-cell expression of the transcription factor, Runx3, and significantly decreased perforin expression at both the mRNA and protein levels. CONCLUSIONS: Enoxacin increases miRNA expression in dnTGFßRII CD8 T cells, reduces CD8 T-cell pathogenicity, and effectively halted progression of autoimmune biliary disease. Targeting the miRNA pathway is a therapeutic approach to autoimmunity that corrects pathological miRNA abnormalities in autoreactive T cells.

Development of a Psychometric Tool to Measure Community Solidarity Among Sexual Minorities: Evidence From a Pay-it-Forward Randomized Controlled Trial.

BACKGROUND: Community solidarity is increasingly important in public health. However, few studies have examined solidarity in relation to health outcomes. The purpose of this study was to develop a psychometric tool to measure solidarity among Chinese men who have sex with men (MSM) and assess whether community solidarity relates to differences in sexually transmitted infection testing. METHODS: We used data from the pay-it-forward randomized controlled trial of 301 men from Beijing and Guangzhou, China. Men who have sex with men were randomized into pay-it-forward (participants receive free gonorrhea/chlamydia testing as gifts and choose to donate toward subsequent MSM's tests), pay-what you-want, and standard payment arms. After testing decision, participants completed a cross-sectional questionnaire to assess community solidarity. Factor analysis was conducted to identify dimensions of solidarity. The solidarity factors were compared across study arms and assessed against gonorrhea/chlamydia test uptake in multivariable logistic regression. RESULTS: Two hundred eighty-eight participants responded to the survey. We identified 3 latent community solidarity factors: engagement, social network support, and sense of belonging. Several items related to belonging were significantly greater among participants in the pay-it-forward scenario compared with those assigned to other scenarios. Higher sense of belonging was associated with higher odds of gonorrhea and chlamydia test uptake. CONCLUSIONS: Community solidarity among MSM in China can be characterized by 3 factors: engagement, social network support, and sense of belonging. Sense of belonging was higher in the pay-it-forward intervention arm and may be associated with the uptake of gonorrhea/chlamydia test. Future studies are warranted to confirm the psychometric structure of community solidarity and further investigate behavioral mechanisms of pay it forward.

From declining PrEP to PrEP initiation as "first nature" - what changes PrEP initiation decisions among young, Black MSM.

Young Black men who have sex with men (YBMSM) bear a disproportionate burden of HIV, and HIV pre-exposure prophylaxis (PrEP) uptake has been slow. Decisions regarding PrEP initiation change in different life contexts over time. Our YBMSM cohort study found about 1/3 of those who initially declined PrEP subsequently changed and initiated PrEP care. This study explores the process of their PrEP decision changes. The study interviewed participants who initially voiced strong and clear reservations about PrEP, but subsequently started PrEP 1-14 months later. In "review/renew" follow-up interviews, participants reviewed their past statements from a time they declined PrEP, and renew their understanding regarding perspective and behavioral change. Analyzing the data with a positive deviance framework, we found that shifting the decisional balance in favor of PrEP initiation only required change in some areas. There were not consistent factors that prevented or facilitated PrEP uptake. Instead, YBMSM initiated PrEP while maintaining an array of substantial reservations. PrEP initiation discussions should be viewed by health practitioners as a longitudinal process, and routine PrEP offers should be made over time. To optimally facilitate PrEP use among YBMSM, the diverse benefits of PrEP should be emphasized rather than focusing on allaying all concerns.