Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior.

Females may display dramatically different behavior depending on their state of ovulation. This is thought to occur through sex-specific hormones acting on behavioral centers in the brain. Whether incoming sensory activity also differs across the ovulation cycle to alter behavior has not been investigated. Here, we show that female mouse vomeronasal sensory neurons (VSNs) are temporarily and specifically rendered "blind" to a subset of male-emitted pheromone ligands during diestrus yet fully detect and respond to the same ligands during estrus. VSN silencing occurs through the action of the female sex-steroid progesterone. Not all VSNs are targeted for silencing; those detecting cat ligands remain continuously active irrespective of the estrous state. We identify the signaling components that account for the capacity of progesterone to target specific subsets of male-pheromone responsive neurons for inactivation. These findings indicate that internal physiology can selectively and directly modulate sensory input to produce state-specific behavior. PAPERCLIP.

Direct interaction of ß-catenin with nuclear ESM1 supports stemness of metastatic prostate cancer.

Wnt/ß-catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/ß-catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here, we report that the expression of endothelial cell-specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated with prostate cancer stemness and progression by promoting Wnt/ß-catenin signaling. Elevated ESM1 expression correlates with poor overall survival and metastasis. Accumulation of nuclear ESM1, instead of cytosolic or secretory ESM1, supports prostate cancer stemness by interacting with the ARM domain of ß-catenin to stabilize ß-catenin-TCF4 complex and facilitate the transactivation of Wnt/ß-catenin signaling targets. Accordingly, activated ß-catenin in turn mediates the nuclear entry of ESM1. Our results establish the significance of mislocalized ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/ß-catenin pathway, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.

MAOB expression correlates with a favourable prognosis in prostate cancer, and its genetic variants are associated with the metastasis of the disease.

Monoamine oxidase B (MAOB), a neurotransmitter-degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single-nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A-allele exhibited an increased risk of having a high initial prostate-specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A-allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G-allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A-allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G-allele expressed lower MAOB levels than those carrying the A-allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.

Effect of Cold Versus Hot Snare Polypectomy on Colon Postpolypectomy Bleeding in Patients with End-Stage Renal Disease: A Retrospective Cohort Study.

BACKGROUND: Patients with end-stage renal disease (ESRD) who undergo polypectomy may experience postpolypectomy bleeding. To reduce the risk of delayed postpolypectomy bleeding among the general population, cold snare polypectomy (CSP) is recommended for removing colon polyps smaller than 1 cm. Nevertheless, only few studies have examined the effect of CSP on patients with ESRD. METHODS: We retrospectively analyzed the data of patients with ESRD who underwent colonoscopic polypectomy for polyps larger than 5 mm at a Taiwanese university hospital from January 2014 to January 2023. The main outcome was delayed postpolypectomy bleeding within 30 days. Multivariate analysis was conducted to adjust for major confounders. RESULTS: A total of 557 patients with ESRD underwent colonoscopic polypectomy during the study period: 201 underwent CSP and 356 underwent hot snare polypectomy (HSP). Delayed postpolypectomy bleeding occurred in 27 patients (4.8%). The rate of delayed postpolypectomy bleeding was lower in patients with ESRD who underwent CSP than in those who underwent HSP (1.9% vs. 6.4%, P = 0.022). The percentage of patients who did not experience postpolypectomy bleeding within 30 days after CSP remained lower than that observed after HSP (P = 0.019, log-rank test). Multivariate analysis demonstrated immediate postpolypectomy bleeding and HSP to be independent risk factors for delayed postpolypectomy bleeding. A nomogram prognostic model was used to predict the potential of delayed postpolypectomy bleeding within 30 days in patients with ESRD. CONCLUSIONS: Compared with HSP, CSP is more effective in mitigating the risk of delayed postpolypectomy bleeding in patients with ESRD.

Upper Gastrointestinal Involvement in Crohn's Disease as an Independent Predictor of New-Onset Strictures: Insights from an Extensive Retrospective Cohort Analysis.

BACKGROUND/AIMS: Crohn's Disease (CD) can affect the entire gastrointestinal tract, including the upper sections (UGI), which is often overlooked, especially in Asian populations. There's a notable gap in research regarding the impact of UGI involvement on the intricate landscape of ensuing complications. This study aims to address this gap. METHODS: Conducting a retrospective study at Chang Gung Memorial Hospital from January 2001 to September 2023, we compared CD patients with UGI (Montreal L4) involvement against non-L4 counterparts, focusing on baseline characteristics, post-diagnosis complications, and overall outcomes. Routine UGI endoscopy was performed around the time of diagnosis in all patients followed in our inflammatory bowel disease (IBD) center, and all CD patients with adequate follow-up were included in this study. RESULTS: The study included 212 CD patients, 111 in the L4 group and 101 in the non-L4 group, with an average follow-up of 40.8 ± 15.1 months. At baseline, individuals in the L4 category demonstrated elevated smoking rates, increased Crohn's Disease Activity Index scores, a higher prevalence of strictures, and a more prevalent usage of biologics and proton pump inhibitors. Moreover, this group was characterized by reduced albumin levels. Upon concluding the follow-up, those with L4 involvement continued to show escalated CDAI scores and hospitalization frequencies, alongside heightened C-reactive protein levels and diminished albumin concentrations. Additionally, the occurrence of UGI involvement, stricturing disease at the time of diagnosis, and a younger age at the onset of CD were pinpointed as independent predictors for the development of new-onset strictures. CONCLUSIONS: CD patients with UGI involvement exhibit elevated disease activity and serve as independent predictors for the development of intestinal strictures. Thorough UGI evaluations at the time of diagnosis, coupled with assertive treatment strategies, are essential for managing these patients effectively.

Is the Epworth Sleepiness scale a valid outcome measure to evaluate the effectiveness of positive airway pressure treatments on daytime sleepiness? Psychometric insights from measurement invariance and response shifts.

PURPOSE: Although the validity of the Epworth Sleepiness Scale (ESS) as an effectiveness measure for sleep apnea treatments such as continuous positive airway pressure (CPAP) has been supported by multiple studies, some researchers continue to challenge it. They suggest that in addition to its impact on relieving patients' daytime sleepiness, CPAP also alters the internal standards patients use to evaluate their sleepiness (i.e., response shift; RS), confounding the meaning of the difference in the ESS scores. We believe an issue yet to be addressed in this debate is that all existing evidence of RS has been obtained through the then-test approach, a retrospective method sensitive to various cognitive mechanisms. Thus, in the current study, we re-examined this issue using the structural equation modeling (SEM) approach, a method that can be directly applied to randomized clinical trial (RCT) data without retrospective measures. METHODS: With the ESS data from two independent RCTs, we conducted cross-sectional and longitudinal measure invariance tests in SEM to examine whether CPAP would lead to RS. RESULTS: The ESS demonstrated cross-sectional and longitudinal scalar invariance against CPAP treatments. Its factorial pattern, loadings, and thresholds were invariant between the treatment and control groups and pre- and post-treatment, supporting the comparability of the observed mean ESS scores across time and groups. CONCLUSION: Our results support the validity of the average difference scores of the ESS for quantifying the effectiveness of CPAP on group-level daytime sleepiness in RCTs with relatively large sample sizes.

Outcomes of coronary artery bypass grafting (CABG) in patients with OSA-COPD overlap syndrome versus COPD alone: an analysis of US Nationwide Inpatient Sample.

BACKGROUND: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are associated with unfavorable outcomes following coronary artery bypass grafting (CABG). The purpose of this study was to compare in-hospital outcomes of patients with COPD alone versus OSA-COPD overlap after CABG. METHODS: Data of adults ≥ 18 years old with COPD who received elective CABG between 2005 and 2018 were extracted from the US Nationwide Inpatient Sample (NIS). Patients were divided into two groups: with OSA-COPD overlap and COPD alone. Propensity score matching (PSM) was employed to balance the between-group characteristics. Logistic and linear regression analyses determined the associations between study variables and inpatient outcomes. RESULTS: After PSM, data of 2,439 patients with OSA-COPD overlap and 9,756 with COPD alone were analyzed. After adjustment, OSA-COPD overlap was associated with a significantly increased risk of overall postoperative complications (adjusted odd ratio [aOR] = 1.12, 95% confidence interval [CI]: 95% CI: 1.01-1.24), respiratory failure/prolonged mechanical ventilation (aOR = 1.27, 95%CI: 1.14-1.41), and non-routine discharge (aOR = 1.16, 95%CI: 1.03-1.29), and AKI (aOR = 1.14, 95% CI: 1.00-1.29). Patients with OSA-COPD overlap had a lower risk of in-hospital mortality (adjusted odd ratio [aOR] = 0.53, 95% CI: 0.35-0.81) than those with COPD only. Pneumonia or postoperative atrial fibrillation (AF) risks were not significantly different between the 2 groups. Stratified analyses revealed that, compared to COPD alone, OSA-COPD overlap was associated with increased respiratory failure/prolonged mechanical ventilation risks among patients ≥ 60 years, and both obese and non-obese subgroups. In addition, OSA-COPD overlap was associated with increased risk of AKI among the older and obese subgroups. CONCLUSION: In US adults who undergo CABG, compared to COPD alone, those with OSA-COPD are at higher risks of non-routine discharge, AKI, and respiratory failure/prolonged mechanical ventilation, but a lower in-hospital mortality. No increased risk of AF was noted.

Validation of the Korean version of the Sleep Hygiene Practice Scale in a Non-Clinical Population.

OBJECTIVES: This study aimed to validate the Korean version of the sleep hygiene practice scale (SHPS-K) and determine its effectiveness in screening poor sleepers with insomnia. METHODS: Online survey was conducted using translated SHPS in Korean, the Korean versions of the Pittsburgh Sleep Quality Index (PSQI-K), Insomnia Severity Index (ISI-K), and Epworth Sleepiness Scale (KESS) in a non-clinical population. The internal consistency and test-retest reliability of the SHPS-K were assessed using Cronbach's alpha and intraclass correlation coefficients (ICC), respectively. Construct validity was evaluated using correlation analyses with other questionnaires and confirmatory factor analysis. We determined the cutoff values that could identify poor sleepers with insomnia symptoms (PSQI-K > 5 and ISI-K ≥ 15) using receiver operating characteristic analysis. RESULTS: A total of 484 participants (242 women, mean age of 43.8 years) were enrolled. The average SHPS-K score was 71.2, with no significant sex differences. Women had poorer sleep scheduling and timing behaviors, and men had poorer eating and drinking behaviors. Good internal consistency (Cronbach's alpha = 0.88) and test-retest reliability (ICC = 0.80) were observed. The SHPS-K was positively correlated with the PSQI-K (r = 0.55), ISI-K (r = 0.54), and KESS (r = 0.42). A cutoff value of 73 identified poor sleepers with insomnia (area under the curve = 0.828). CONCLUSIONS: The SHPS-K is a reliable instrument for evaluating sleep hygiene in non-clinical Korean populations.

Delta/Jagged-mediated Notch signaling induces the differentiation of agr2-positive epidermal mucous cells in zebrafish embryos.

Teleosts live in aquatic habitats, where they encounter ionic and acid-base fluctuations as well as infectious pathogens. To protect from these external challenges, the teleost epidermis is composed of living cells, including keratinocytes and ionocytes that maintain body fluid ionic homeostasis, and mucous cells that secret mucus. While ionocyte progenitors are known to be specified by Delta-Notch-mediated lateral inhibition during late gastrulation and early segmentation, it remains unclear how epidermal mucous cells (EMCs) are differentiated and maintained. Here, we show that Delta/Jagged-mediated activation of Notch signaling induces the differentiation of agr2-positive (agr2+) EMCs in zebrafish embryos during segmentation. We demonstrated that agr2+ EMCs contain cytoplasmic secretory granules and express muc5.1 and muc5.2. Reductions in agr2+ EMC number were observed in mib mutants and notch3 MOs-injected notch1a mutants, while increases in agr2+ cell number were detected in notch1a- and X-Su(H)/ANK-overexpressing embryos. Treatment with γ-secretase inhibitors further revealed that Notch signaling is required during bud to 15 hpf for the differentiation of agr2+ EMCs. Increased agr2+ EMC numbers were also observed in jag1a-, jag1b-, jag2a- and dlc-overexpressing, but not jag2b-overexpressing embryos. Meanwhile, reductions in agr2+ EMC numbers were detected in jag1a morphants, jag1b mutants, jag2a mutants and dlc morphants, but not jag2b mutants. Reduced numbers of pvalb8-positive epidermal cells were also observed in mib or jag2a mutants and jag1a or jag1b morphants, while increased pvalb8-positive epidermal cell numbers were detected in notch1a-overexpressing, but not dlc-overexpressing embryos. BrdU labeling further revealed that the agr2+ EMC population is maintained by proliferation. Cell lineage experiments showed that agr2+ EMCs are derived from the same ectodermal precursors as keratinocytes or ionocytes. Together, our results indicate that specification of agr2+ EMCs in zebrafish embryos is induced by DeltaC/Jagged-dependent activation of Notch1a/3 signaling, and the cell population is maintained by proliferation.

Impact of completely histological remission on reducing flare-ups in moderate-to-severe, biologics-experienced ulcerative colitis patients with endoscopic remission.

BACKGROUND/PURPOSE: Endoscopic remission is presently recognized as the standard therapeutic target in the treatment of ulcerative colitis (UC). However, achieving histological remission is increasingly viewed as a pivotal objective. This study investigates the effects of attaining completely histological remission on the clinical outcomes for UC patients with a high disease burden who have already reached endoscopic remission. This is the inaugural study to concentrate on this specific patient demographic. METHODS: This retrospective cohort study enrolled moderate-to-severe, biologics-experienced UC patients with completely endoscopic remission (Mayo endoscopic subscore of 0) between June 2017 and October 2023 at Chang Gung Memorial Hospital, Linkou. Patients were classified into histological remission (HR) and non-histological remission (non-HR) groups based on the Nancy index (NI). HR was defined as an NI score of 0, with all other patients categorized as non-HR. The definition of flare-ups was based on both clinical and endoscopic evidence. Comparative analyses focused on baseline characteristics and clinical outcomes at follow-up. RESULTS: A total of 42 patients (HR group: 23, non-HR group: 19) were included. The average follow-up duration was 17.6 months. Baseline characteristics were comparable between the groups. At the end of follow-up, the HR group showed a significantly lower rate of acute flare-ups (26.1% vs. 68.4%, P = 0.006). Although not statistically significant, the HR group also experienced fewer emergency department visits and hospital admissions. CONCLUSIONS: For moderate-to-severe, biologics-experienced UC patients in endoscopic remission, achieving completely histological remission is associated with a substantial reduction in flare-ups, suggesting its potential as a valuable therapeutic target.

Development and validation of a Chinese version chronic wound health-related quality of life instrument: A methodological study.

AIMS AND OBJECTIVES: To develop a Chinese version of a chronic wound health-related quality of life (QoL) instrument and to examine the psychometric properties of this instrument. BACKGROUND: Existing QoL instruments are not tailored to the linguistic and cultural characteristics of Chinese-speaking patients; a version addressing this gap will increase clinical understanding of their healthcare experience and may help guide chronic wound care. DESIGN: A methodological study. METHODS: The method advanced by DeVellis (2017) was used to develop the instrument. An initial pool of 38 items was created. To optimize scale length and test reliability and validity, exploratory and confirmatory factor analyses were conducted. A total of 23 items formed the final pool. After two rounds of expert discussions, the average content validity index of the final 23 items was .89. RESULTS: A total of 226 patients completed the instrument and were divided into two groups for further analysis. Exploratory factor analysis revealed that 15 items remained in four factors (social activity restrictions, physical and psychological disturbance, wound burden and daily life limitation), which accounted for 64.87% of the variance. Confirmatory factor analysis revealed an acceptable fit of the hypothesized factor structure and the convergent and discriminant validities were achieved. Cronbach's α coefficients for each factor were .807, .773, .799 and .713, respectively. CONCLUSION: The Chinese version of a chronic wound health-related QoL instrument consists of 15 items in four subscales and demonstrates good reliability and validity. RELEVANCE TO CLINICAL PRACTICE: This instrument can be used intermittently or continuously to evaluate the treatment effect of chronic wounds by assessing health-related QoL. Scholars in Chinese-speaking regions may find this culturally compatible instrument useful when conducting studies related to chronic wounds. PATIENT OR PUBLIC CONTRIBUTION: Two hundred twenty-six participants provided their perspectives on health-related QoL.

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-ß1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Functional variants of the chitinase 3-like 1 gene are associated with clinicopathologic outcomes and progression of prostate cancer.

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well-studied genetic variations are single-nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (-1371, G>A), rs10399805 (-247, G>A) and rs4950928 (-131, C>G), and one non-synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression-free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.

Genetic variants of dipeptidyl peptidase IV are linked to the clinicopathologic development of prostate cancer.

CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell-surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour-promoting or -suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case-control study to evaluate whether single-nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062-2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092-2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression-free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.

Unraveling Metal-Ligand Bonding in an HNO-Evolving {FeNO}6 Complex with a Combined X-ray Spectroscopic Approach.

Photolytic delivery of nitric oxide and nitroxide has substantial biomedical and phototherapeutic applications. Here, we utilized hard X-ray spectroscopic methods to identify key geometric and electronic structural features of two photolabile {FeNO}6 complexes where the compounds differ in the presence of a pendant thiol in [Fe(NO)(TMSPS2)(TMSPS2H)] and thioether in [Fe(NO)(TMSPS2)(TMSPS2CH3)] with the former complex being the only transition metal system to photolytically generate HNO. Fe Kß XES identifies the photoreactant systems as essentially Fe(II)-NO+, while valence-to-core XES extracts a NO oxidation state of +0.5. Finally, the pre-edge of the Fe high-energy-resolution fluorescence detected (HERFD) XAS spectra is shown to be acutely sensitive to perturbation of the Fe-NO covalency enhanced by the 3d-4p orbital mixing dipole intensity contribution. Collectively, this X-ray spectroscopic approach enables future time-resolved insights in these systems and extensions to other challenging redox noninnocent {FeNO}x systems.

Few-cycle THz wave manipulation with a high degree of freedom via f-t modulation.

THz waves have been intensively applied in many fields, e.g., spectroscopy, imaging, and communications. However, owing to the rarity of available techniques for manipulating circularly polarized few-cycle THz waves on picosecond time scales, most of the current studies are conducted with linearly polarized THz waves. Here we demonstrate circularly polarized (CP) THz (dual) pulses generated by a polarization-twisting pulse/dual pulse (PTP/PTDP). The polarization-twisting optical dual pulses can be generated via a modified Michelson interferometer (MI) system, which provides the ability to control the frequency, helicity, and time interval of the dual pulses arbitrarily and individually. Such a novel, to the best of our knowledge, modulation technique shows huge potential for applications, not only in imaging and spectroscopy but also in next-generation communications.

Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain.

Mutations in the Kelch-like 3 (KLHL3) gene are the most common cause of inherited pseudohypoaldosteronism type II (PHAII) featuring thiazide-sensitive hypertension and hyperkalemic metabolic acidosis. Although Klhl3R528H/+ knock-in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense KLHL3 mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed Klhl3 KI mice harboring a nonsense W523X mutation (corresponding to the human KLHL3 W470X mutation). Both heterozygous and homozygous Klhl3W523X/+ KI mice exhibited typical PHAII with low-renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of Klhl3 mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1/4-Spak/Osr1-N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p-)Spak, total Ncc, and p-Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk-mediated Ncc pathway. In vitro studies showed that the human KLHL3 W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense Klhl3W523X/+ mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK-mediated Na+ -Cl- co-transporter reiterated the in vivo pathogenic role of nonsense KLHL3 mutations in PHAII.

The RNA-binding protein KSRP aggravates malignant progression of clear cell renal cell carcinoma through transcriptional inhibition and post-transcriptional destabilization of the NEDD4L ubiquitin ligase.

BACKGROUND: KH-type splicing regulatory protein (KHSRP, also called KSRP), a versatile RNA-binding protein, plays a critical role in various physiological and pathological conditions through modulating gene expressions at multiple levels. However, the role of KSRP in clear cell renal cell carcinoma (ccRCC) remains poorly understood. METHODS: KSRP expression was detected by a ccRCC tissue microarray and evaluated by an in silico analysis. Cell loss-of-function and gain-of-function, colony-formation, anoikis, and transwell assays, and an orthotopic bioluminescent xenograft model were conducted to determine the functional role of KRSP in ccRCC progression. Micro (mi)RNA and complementary (c)DNA microarrays were used to identify downstream targets of KSRP. Western blotting, quantitative real-time polymerase chain reaction, and promoter- and 3-untranslated region (3'UTR)-luciferase reporter assays were employed to validate the underlying mechanisms of KSRP which aggravate progression of ccRCC. RESULTS: Our results showed that dysregulated high levels of KSRP were correlated with advanced clinical stages, larger tumor sizes, recurrence, and poor prognoses of ccRCC. Neural precursor cell-expressed developmentally downregulated 4 like (NEDD4L) was identified as a novel target of KSRP, which can reverse the protumorigenic and prometastatic characteristics as well as epithelial-mesenchymal transition (EMT) promotion by KSRP in vitro and in vivo. Molecular studies revealed that KSRP can decrease NEDD4L messenger (m)RNA stability via inducing mir-629-5p upregulation and directly targeting the AU-rich elements (AREs) of the 3'UTR. Moreover, KSRP was shown to transcriptionally suppress NEDD4L via inducing the transcriptional repressor, Wilm's tumor 1 (WT1). In the clinic, ccRCC samples revealed a positive correlation between KSRP and mesenchymal-related genes, and patients expressing high KSRP and low NEDD4L had the worst prognoses. CONCLUSION: The current findings unveil novel mechanisms of KSRP which promote malignant progression of ccRCC through transcriptional inhibition and post-transcriptional destabilization of NEDD4L transcripts. Targeting KSRP and its pathways may be a novel pharmaceutical intervention for ccRCC.

Precise application of topical tranexamic acid to enhance endoscopic hemostasis for peptic ulcer bleeding: a randomized controlled study (with video).

BACKGROUND AND AIMS: Peptic ulcer recurrent bleeding occurs in 20% to 30% of patients after standard endoscopic hemostasis, particularly within 4 days after the procedure. The application of additional tranexamic acid (TXA) to the ulcer may enhance hemostasis. This study investigated the effectiveness of TXA powder application on bleeding ulcers during endoscopic hemostasis. METHODS: This study enrolled patients who had peptic ulcer bleeding between March 2022 and February 2023. After undergoing standard endoscopic therapy, the patients were randomly assigned to either the TXA group or the standard group. In the TXA group, an additional 1.25 g of TXA powder was sprayed endoscopically on the ulcer. Both groups then received 3 days of high-dose (8 mg/h) continuous infusion proton pump inhibitor therapy. Second-look endoscopy was conducted on days 3 to 4. The primary end point of early treatment failure was defined as ulcer recurrent bleeding within 4 days or major stigmata of recent hemorrhage on the second-look endoscopy. RESULTS: Sixty patients (30 in each group) with peptic ulcer bleeding and balanced baseline characteristics were randomly assigned to a treatment group. The early treatment failure rate was lower in the TXA group (6.7%) than in the standard group (30%) (P = .042). The freedom from treatment failure periods for 4 and 28 days was significantly longer in the TXA group than in the standard group (P = .023). No adverse events from TXA were recorded. CONCLUSIONS: The precise delivery of topical TXA alongside standard endoscopic hemostasis reduced the early treatment failure rate in patients with bleeding peptic ulcers. (Clinical trial registration number: NCT05248321.).

Comparison of two titration programmes for adding insulin detemir to oral antidiabetic drugs in patients with poorly controlled type 2 diabetes mellitus.

AIM: To explore the effect of active insulin titration versus usual titration on glycaemic control in patients with type 2 diabetes mellitus uncontrolled with oral antidiabetic drugs (OADs). METHODS: In a 24-week, prospective and randomized study, 172 patients with uncontrolled type 2 diabetes were randomly assigned to either active titration or usual titration. Efficacy and safety outcomes included changes in glycated haemoglobin (HbA1c) and fasting plasma glucose, percentage of individuals achieving HbA1c<53 mmol/mol, and hypoglycaemic events. RESULTS: At Week 24, change in HbA1c was -1.08% ± 1.60% in the active titration group and -0.95% ± 1.34% in the usual titration group (P = 0.569). The percentages of individuals achieving HbA1c<53 mmol/mol were 29.4% and 16.1% in the active and usual titration groups, respectively (P = 0.037). There was no significant difference in the incidence of hypoglycaemia between the two groups. Multivariate logistic regression indicated that, with active titration, baseline HbA1c levels and postprandial glucose excursion were significantly associated with achieving HbA1c<53 mmol/mol. CONCLUSION: Addition of basal insulin using active titration for 24 weeks provided a higher rate of HbA1c target achievement without significant hypoglycaemia compared to usual titration in individuals with uncontrolled type 2 diabetes.