Left Bundle Branch Area Pacing With or Without Conduction System Capture in Heart Failure Models.

BACKGROUND: Left bundle branch area pacing includes left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP), which is effective in patients with dyssynchronous heart failure (DHF). However, the basic mechanisms are unknown. OBJECTIVES: This study aimed to compare LBBP with LVSP and explore potential mechanisms underlying the better clinical outcomes of LBBP. METHODS: A total of 24 beagles were assigned to the following groups: 1) control group; 2) DHF group, left bundle branch ablation followed by 6 weeks of AOO pacing at 200 ppm; 3) LBBP group, DHF for 3 weeks followed by 3 weeks of DOO pacing at 200 ppm; and 4) LVSP with the same interventions in the LBBP group. Metrics of electrocardiogram, echocardiography, hemodynamics, and expression of left ventricular proteins were evaluated. RESULTS: Compared with LVSP, LBBP had better peak strain dispersion (44.67 ± 1.75 ms vs 55.50 ± 4.85 ms; P < 0.001) and hemodynamic effect (dP/dtmax improvement: 27.16% ± 7.79% vs 11.37% ± 4.73%; P < 0.001), whereas no significant differences in cardiac function were shown. The altered expressions of proteins in the lateral wall vs septum in the DHF group were partially reversed by LBBP and LVSP, which was associated with the contraction and adhesion process, separately. CONCLUSIONS: The animal study demonstrated that LBBP offered better mechanical synchrony and improved hemodynamics than LVSP, which might be explained by the reversed expression of contraction proteins. These results supported the potential superiority of left bundle branch area pacing with the capture of the conduction system in DHF model.

Slipped capital femoral epiphysis in an adolescent with congenital adrenal hyperplasia: A case report.

In previous reports, hypothyroidism, hypopituitrism, and hypogonadism were common endocrine causes of SCFE, but this is the first time that congenital adrenal hyperplasia has been observed. As such, patients who have undergone long-term endocrine treatment for congenital adrenal hyperplasia could potentially be subjected to a higher risk for SCFE.

The role of transforming growth factor-ß (TGF-ß) in the formation of exhausted CD8 + T cells.

CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-ß (TGF-ß) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-ß is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-ß in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy.

BACKGROUND: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Overall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

Safety assessments of recombinant DTaP vaccines developed in South Korea.

Purpose: Pertussis bacteria have many pathogenic and virulent antigens and severe adverse reactions have occurred when using inactivated whole-cell pertussis vaccines. Therefore, inactivated acellular pertussis (aP) vaccines and genetically detoxified recombinant pertussis (rP) vaccines are being developed. The aim of this study was to assess the safety profile of a novel rP vaccine under development in comparison to commercial diphtheria-tetanus-acellular pertussis (DTaP) vaccines. Materials and Methods: The two positive control DTaP vaccines (two- and tri-components aP vaccines) and two experimental recombinant DTaP (rDTaP) vaccine (two- and tri-components aP vaccines adsorbed to either aluminum hydroxide or purified oat beta-glucan) were used. Temperature histamine sensitization test (HIST), indirect Chinese hamster ovary (CHO) cell cluster assay, mouse-weight-gain (MWG) test, leukocytosis promoting (LP) test, and intramuscular inflammatory cytokine assay of the injection site performed for safety assessments. Results: HIST results showed absence of residual pertussis toxin (PTx) in both control and experimental DTaP vaccine groups, whereas in groups immunized with tri-components vaccines, the experimental tri-components rDTaP absorbed to alum showed an ultra-small amount of 0.0066 IU/mL. CHO cell clustering was observed from 4 IU/mL in all groups. LP tests showed that neutrophils and lymphocytes were in the normal range in all groups immunized with the two components vaccine. However, in the tri-components control DTaP vaccine group, as well as two- and tri-components rDTaP with beta-glucan group, a higher monocyte count was observed 3 days after vaccination, although less than 2 times the normal range. In the MWG test, both groups showed changes less than 20% in body temperature and body weight before the after the final immunizations. Inflammatory cytokines within the muscle at the injection site on day 3 after intramuscular injection revealed no significant response in all groups. Conclusion: There were no findings associated with residual PTx, and no significant differences in both local and systemic adverse reactions in the novel rDTaP vaccine compared to existing available DTaP vaccines. The results suggest that the novel rDTaP vaccine is safe.

Classical and novel properties of Holliday junction resolvase SynRuvC from Synechocystis sp. PCC6803.

Cyanobacteria, which have a photoautotrophic lifestyle, are threatened by ultraviolet solar rays and the reactive oxygen species generated during photosynthesis. They can adapt to environmental conditions primarily because of their DNA damage response and repair mechanisms, notably an efficient homologous recombination repair system. However, research on double-strand break (DSB) repair pathways, including the Holliday junction (HJ) resolution process, in Synechocystis sp. PCC6803 is limited. Here, we report that SynRuvC from cyanobacteria Synechocystis sp. PCC6803 has classical HJ resolution activity. We investigated the structural specificity, sequence preference, and biochemical properties of SynRuvC. SynRuvC strongly preferred Mn2+ as a cofactor, and its cleavage site predominantly resides within the 5'-TG↓(G/A)-3' sequence. Interestingly, novel flap endonuclease and replication fork intermediate cleavage activities of SynRuvC were also determined, which distinguish it from other reported RuvCs. To explore the effect of SynRuvC on cell viability, we constructed a knockdown mutant and an overexpression strain of Synechocystis sp. PCC6803 (synruvCKD and synruvCOE) and assessed their survival under a variety of conditions. Knockdown of synruvC increased the sensitivity of cells to MMS, HU, and H2O2. The findings suggest that a novel RuvC family HJ resolvase SynRuvC is important in a variety of DNA repair processes and stress resistance in Synechocystis sp. PCC6803.

Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype.

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

Drug repositioning for immunotherapy in breast cancer using single-cell analysis.

Immunomodulatory peptides, while exhibiting potential antimicrobial, antifungal, and/or antiviral properties, can play a role in stimulating or suppressing the immune system, especially in pathological conditions like breast cancer (BC). Thus, deregulation of these peptides may serve as an immunotherapeutic strategy to enhance the immune response. In this meta-analysis, we utilized single-cell RNA sequencing data and known therapeutic peptides to investigate the deregulation of these peptides in malignant versus normal human breast epithelial cells. We corroborated our findings at the chromatin level using ATAC-seq. Additionally, we assessed the protein levels in various BC cell lines. Moreover, our in-house drug repositioning approach was employed to identify potential drugs that could positively impact the relapse-free survival of BC patients. Considering significantly deregulated therapeutic peptides and their role in BC pathology, our approach aims to downregulate B2M and SLPI, while upregulating PIGR, DEFB1, LTF, CLU, S100A7, and SCGB2A1 in BC epithelial cells through our drug repositioning pipeline. Leveraging the LINCS L1000 database, we propose BRD-A06641369 for B2M downregulation and ST-4070043 and BRD-K97926541 for SLPI downregulation without negatively affecting the MHC complex as a significantly correlated pathway with these two genes. Furthermore, we have compiled a comprehensive list of drugs for the upregulation of other selected immunomodulatory peptides. Employing an immunotherapeutic approach by integrating our drug repositioning pipeline with single-cell analysis, we proposed potential drugs and drug targets to fortify the immune system against BC.

Superconductivity in Ca-intercalated bilayer graphene: C2CaC2.

The deposition and intercalation of metal atoms can induce superconductivity in monolayer and bilayer graphenes. For example, it has been experimentally proved that Li-deposited graphene is a superconductor with critical temperature Tc of 5.9 K, Ca-intercalated bilayer graphene C6CaC6 and K-intercalated epitaxial bilayer graphene C8KC8 are superconductors with Tc of 2-4 K and 3.6 K, respectively. However, the Tc of them are relatively low. To obtain higher Tc in graphene-based superconductors, here we predict a new Ca-intercalated bilayer graphene C2CaC2, which shows higher Ca concentration than the C6CaC6. It is proved to be thermodynamically and dynamically stable. The electronic structure, electron-phonon coupling (EPC) and superconductivity of C2CaC2 are investigated based on first-principles calculations. The EPC of C2CaC2 mainly comes from the coupling between the electrons of C-pz orbital and the high- and low-frequency vibration modes of C atoms. The calculated EPC constant λ of C2CaC2 is 0.75, and the superconducting Tc is 18.9 K, which is much higher than other metal-intercalated bilayer graphenes. By further applying -4% biaxial compressive strain to C2CaC2, the Tc can be boosted to 26.6 K. Thus, the predicted C2CaC2 provides a new platform for realizing superconductivity with the highest Tc in bilayer graphenes.

Neuropilin-1high monocytes protect against neonatal inflammation.

Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, yet the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1 (Nrp1), termed Nrp1high monocytes. Compared with their Nrp1low counterparts, Nrp1high monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, by binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates.

Enhanced acetone gas-sensing characteristics of Pd-NiO nanorods/SnO2 nanowires sensors.

Acetone is a well-known volatile organic compound that is widely used in different industrial and domestic areas, but it can cause dangerous effects on human health. Thus, the fabrication of highly sensitive and selective sensors for recognition of acetone is incredibly important. Here, we prepared the SnO2/Pd-NiO (SPN) nanowires-based gas sensor for the detection of acetone, in which, the amount of Pd nanoparticles were varied to enhance the performance of the devices. We demonstrated that the acetone gas sensing performance of the SPN device was significantly enhanced, showing increases of 3.72 and 6.53 folds compared to pristine SnO2 and NiO sensors, respectively. The Pd-NiO 0.01% wt Pd SPN sensor (SPN-1) exhibited an excellent response (Ra/Rg = 14.88) toward 500 ppm acetone gas. The SPN-1 sensor also showed a fast gas response time of 11/150 seconds with 500 ppm Acetone at 450 °C, while the recovery time was 468/526 seconds. Additionally, the sensor showed good selectivity toward acetone over other reducing gases, such as NH3, CH4, and VOCs. With those results, the SPN-1 sensor shows superiority compared to sensors based on pure materials.

Durvalumab Consolidation After Chemoradiotherapy in Elderly Patients With Unresectable Stage III NSCLC: A Real-World Multicenter Study.

BACKGROUND: The PACIFIC trial demonstrated survival benefit of durvalumab after concurrent chemoradiotherapy (CCRT) in unresectable stage III non-small-cell lung cancer. Data on the effectiveness and safety of durvalumab in elderly patients is lacking. METHODS: This retrospective study was conducted between September 2017 and September 2022. Progression-free survival (PFS), overall survival (OS), recurrence patterns, first subsequent treatment after recurrence, factors associated with survival outcomes, and adverse events (AEs) were compared. RESULTS: Of the 286 patients, 120 (42.0%) were ≥ 70 years and 166 (58.0%) were < 70 years. The median PFS (17.7 vs. 19.4 months; P = .43) and median OS (35.7 months vs. not reached; P = .13) were similar between 2 groups. Proportion of patients who completed durvalumab was lower in elderly patients (27.5% vs. 39.2%; P = .040). In elderly patients, ECOG PS 0 or 1 was associated with better PFS, and being male and having received a cisplatin-based regimen during CCRT were factors associated with better and worse OS, respectively. In patients aged < 70 years, a PD-L1 ≥ 50% was associated with improved PFS and OS. Elderly patients experienced more treatment-related AEs, grade 3/4 AEs, permanent discontinuation of durvalumab, and treatment-related deaths. Among the AEs leading to permanent discontinuation or death, pulmonary AE was significantly more common in elderly patients. CONCLUSION: Durvalumab demonstrated similar outcomes in elderly compared to younger patients. However, AEs were more common in elderly patients. Thus, judicious selection of patients and chemotherapy regimens, coupled with careful AE monitoring, are important factors for ensuring optimal durvalumab treatment.

Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development.

Family with sequence similarity 20 member C (FAM20C) is a Golgi casein kinase that phosphorylates extracellularly-secreted regulatory proteins involved in bone development and mineralization, but its specific role in bone development is still largely unknown. In this study, to examine the specific mechanisms that FAM20C influences bone development, we cross-bred Osx-Cre with FAM20Cflox/flox mice to establish a Osx-Cre; FAM20Cflox/flox knockout (oKO) mouse model; FAM20C was KO in pre-osteoblasts. oKO development was examined at 1-10 weeks, in which compared to control FAM20Cflox/flox, they had lower body weights and bone tissue mineralization. Furthermore, oKO had lower bone volume fractions, thickness, and trabecular numbers, along with higher degrees of trabecular separation. These mice also had decreased femoral metaphyseal cartilage proliferation layer, along with thickened hypertrophic layer and increased apoptotic cell counts. Transcriptomic analysis found that differentially-expressed genes in oKO were concentrated in the osteoclast differentiation pathway, in line with increased osteoclast presence. Additionally, up-regulation of osteoclast-related, and down-regulation of osteogenesis-related genes, were identified, in which the most up-regulated genes were signal regulatory protein ß-1 family (Sirpb1a-c) and mitogen-activated protein kinase 13. Overall, FAM20C KO in pre-osteoblasts leads to abnormal long bone development, likely due to subsequent up-regulation of osteoclast differentiation-associated genes.

Comparative biomechanical analysis of reconstruction and cephalomedullary nails in the treatment of osteoporotic subtrochanteric fractures.

INTRODUCTION: This study aimed to compare the biomechanical properties of two types of intramedullary nails - reconstruction nails (RCN) and cephalomedullary nails (CMN) - each with different proximal fixations, in a model of an osteoporotic subtrochanteric femoral fracture. This study focused on assessing stiffness and load to failure of RCN and CMN nails to provide insight into their clinical applications in osteoporotic fracture treatments. MATERIALS AND METHODS: Ten synthetic osteoporotic femoral models were used to generate a comminuted subtrochanteric fracture model. Five femurs were fixed using an RCN, and the remaining five were fixed using a CMN. The constructs were subjected to axial compression to measure their structural stiffness, load to failure, and failure modes. RESULTS: The CMN group demonstrated a slightly higher load to failure (mean, 2250 N) than the RCN group (mean, 2100 N), which was statistically significant (p = 0.008). However, the stiffness in both groups was statistically similar (RCN, 250 N/mm; CMN, 255 N/mm; p = 0.69). Both groups showed a load to failure exceeding 1500 N, a typically exerted load on the femoral head by a 75 kg individual. The failure patterns differed, with CMN failures starting at the nail insertion area and RCN failures starting at the reconstruction screw area. CONCLUSION: The RCN offers stiffness comparable to that of the CMN; although its load to failure is slightly lower than that of the CMN, it still exceeds the physiological tolerance limit. These findings suggest that the RCN is a viable alternative for treating osteoporotic subtrochanteric fractures.

Lifestyle intervention in children with obesity and nonalcoholic fatty liver disease (NAFLD): study protocol for a randomized controlled trial in Ningbo city (the SCIENT study).

BACKGROUND: The increasing prevalence of childhood obesity has become an urgent public health problem, evidence showed that intervention for childhood obesity bring enormous health benefits. However, an effective individualized intervention strategy remains to be developed, and the accompanying remission of related complications, such as nonalcoholic fatty liver disease (NAFLD), needs to be assessed. This study aimed to develop an m-Health-assisted lifestyle intervention program targeting overweight/obese children and assess its effectiveness on indicators of adiposity and NAFLD. METHODS: This is a cluster-randomized controlled trial that conducted in children with overweight/obesity in Ningbo city, Zhejiang Province, China. Students in Grade 3 (8-10 years old) were recruited from six primary schools, with three be randomized to intervention group and three to usual practice group. The intervention program will last for one academic year and consists of health education, dietary guidance, and physical activity reinforcement. This program is characterized by encouraging four stakeholders, including School, Clinic, famIly, and studENT (SCIENT), to participate in controlling childhood obesity, assisted by m-Health technology. Assessments will be conducted at baseline and 3 months, 9 months, 24 months, and 36 months after baseline. The primary outcome will be the differences between the two groups in students' body mass index and fatty liver index at the end of the intervention (9 months after baseline). During the implementation process, quality control methods will be adopted. DISCUSSION: The program will test the effectiveness of the m-Health-assisted lifestyle intervention on children with obesity and NAFLD. The results of this study will provide evidence for establishing effective lifestyle intervention strategy aimed at childhood obesity and NAFLD and may help develop guidelines for the treatment of obesity and NAFLD in Chinese children. TRIAL REGISTRATION: Clinicaltrials.gov NCT05482191. Registered on July 2022.

Functional versatility of Zur in metal homeostasis, motility, biofilm formation, and stress resistance in Yersinia pseudotuberculosis.

Zur (zinc uptake regulator) is a significant member of the Fur (ferric uptake regulator) superfamily, which is widely distributed in bacteria. Zur plays crucial roles in zinc homeostasis and influences cell development and environmental adaptation in various species. Yersinia pseudotuberculosis is a Gram-negative enteric that pathogen usually serves as a model organism in pathogenicity studies. The regulatory effects of Zur on the zinc transporter ZnuABC and the protein secretion system T6SS have been documented in Y. pseudotuberculosis. In this study, a comparative transcriptomics analysis between a ∆zur mutant and the wild-type (WT) strain of Y. pseudotuberculosis was conducted using RNA-seq. This analysis revealed global regulation by Zur across multiple functional categories, including membrane transport, cell motility, and molecular and energy metabolism. Additionally, Zur mediates the homeostasis not only of zinc but also ferric and magnesium in vivo. There was a notable decrease in 35 flagellar biosynthesis and assembly-related genes, leading to reduced swimming motility in the ∆zur mutant strain. Furthermore, Zur upregulated multiple simple sugar and oligopeptide transport system genes by directly binding to their promoters. The absence of Zur inhibited biofilm formation as well as reduced resistance to chloramphenicol and acidic stress. This study illustrates the comprehensive regulatory functions of Zur, emphasizing its importance in stress resistance and pathogenicity in Y. pseudotuberculosis. IMPORTANCE: Bacteria encounter diverse stresses in the environment and possess essential regulators to modulate the expression of genes in responding to the stresses for better fitness and survival. Zur (zinc uptake regulator) plays a vital role in zinc homeostasis. Studies of Zur from multiple species reviewed that it influences cell development, stress resistance, and virulence of bacteria. Y. pseudotuberculosis is an enteric pathogen that serves a model organism in the study of pathogenicity, virulence factors, and mechanism of environmental adaptation. In this study, transcriptomics analysis of Zur's regulons was conducted in Y. pseudotuberculosis. The functions of Zur as a global regulator in metal homeostasis, motility, nutrient acquisition, glycan metabolism, and nucleotide metabolism, in turn, increasing the biofilm formation, stress resistance, and virulence were reviewed. The importance of Zur in environmental adaptation and pathogenicity of Y. pseudotuberculosis was emphasized.

Realization of Large Low-Stress Elastocaloric Effect in TiZrNbAl Alloy.

Seeking novel high-performance elastocaloric materials with low critical stress plays a crucial role in advancing the development of elastocaloric refrigeration technology. Here, as a first attempt, the elastocaloric effect of TiZrNbAl shape memory alloy at both room temperature and finite temperatures ranging from 245 K to 405 K, is studied systematically. Composition optimization shows that Ti-19Zr-14Nb-1Al (at.%), possessing excellent room-temperature superelasticity with a critical stress of around 100 MPa and a small stress hysteresis of around 70 MPa and outstanding fracture resistance with a compressive strain of 20% and stress of 1.7 GPa, demonstrates a substantial advantage as an elastocaloric refrigerant. At room temperature, a large adiabatic temperature change (ΔTad) of -6.7 K is detected, which is comparable to the highest value reported in the Ti-based alloys. A high elastocaloric cyclic stability, with almost no degradation of ΔTad after 4000 cycles, is observed. Furthermore, the sizeable elastocaloric effect can be steadily expanded from 255 K to 395 K with a temperature window of as large as 140 K. A maximum ΔTad of -7.9 K appears at 355 K. The present work demonstrates a promising potential of TiZrNbAl as a low critical stress and low hysteresis elastocaloric refrigerant.

The global distribution of special needs dentistry across dental school curricula.

INTRODUCTION: Special needs dentistry (SND) is an emerging dental specialty, with ongoing developments in education and clinical practice focused towards the tailored management of individuals with special needs (SN). Patients with SN have a higher prevalence of oral diseases and unmet dental needs compared to the general population. Although inadequate training and experience in managing patients with SN has been highlighted as a significant barrier to accessing care, there is limited data about the extent of SND teaching at the entry-to-practice or higher levels. METHODS: This work is the first to map SND curricula globally, across 180 countries and 1265 dental schools. RESULTS: Although 74.62% of dental schools were found in developing economies, the distribution of programs that reported SND in their courses was highly skewed towards developed countries. In terms of advanced degrees, beyond basic entry-to-practice training, the USA delivered 60% of the SND programs, followed by Canada (15.56%), UK (13.33%), and Australia (8.89%). The term SND appeared in 33.95% of entry-to-practice level program curricula and was less commonly used in transitioning economies. Only 112 SND-specialized practitioners enter the workforce globally each year from developed economies, and all but three advanced degrees are found in G7 countries. CONCLUSION: By exploring the impact of economic status on its distribution, this paper highlighted the lack of SND representation in dental curricula, especially amongst programs in transitioning or developing economies. Education of both general dentists and specialists is critical as a collaborative effort is needed to manage the growing population of patients with SN.

Identification of a gene network driving the attenuated response to lipopolysaccharide of monocytes from hypertensive coronary artery disease patients.

Introduction: The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes-a pivotal cell type in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus. Methods: We conducted a comparative analysis of monocyte gene expression profiles from the CTMM - CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database. Results: Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10-80). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response. Conclusions: Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined.