The correlation of orthostatic hypotension in Parkinson disease with the disease course and severity and its impact on quality of life.

We investigated the correlation of orthostatic hypotension (OH) in Parkinson disease (PD) with the disease course and severity, and its possible impact on quality of life. 171 PD patients were recruited and divided into the PD-NOH (n = 91) and PD-OH groups (n = 80). Clinical data were collected. The severity and quality of life of PD patients were evaluated. The impact of disease severity was analyzed using logistic regression analysis. The ROC curve was plotted. There were significant differences (P < .05) between PD-NOH and PD-OH groups in terms of the disease course, non-motor symptoms (somnipathy), Hoehn&Yahr stage, LEDD score, RBDSQ score, PDQ-39 score, MMSE score, MoCA, MDS-UPDRS Part III scores during off- and on-periods, and NMSS score. Hoehn&Yahr stage (OR 4.950, 95% CI 1.516-16.157, P = .008) was closely associated with the risk of OH in PD. PDQ-39 score (OR 1.079, 95% CI 1.033-1.127, P = .001) in PD patients with OH further decreased. Patients with PD-OH experienced severe impairment in 4 dimensions of quality of life, including motor function, cognitive function, physical discomfort, and activities of daily living. Different clinical symptoms of PD-OH were positively correlated with PDQ39 subscales. The area under the ROC curve of the Hoehn&Yahr stage in predicting the occurrence of OH was 0.679 (95% CI 0.600-0.758), and that of the Hoehn&Yahr stage combined with levodopa equivalent dose, and MDS-UPDRS Part III score during off-period was 0.793 (95% CI 0.727-0.862). Higher Hoehn&Yahr stage is associated with increased risk of OH in PD patients, and deteriorated quality of life of PD patients. Patients with different OH symptoms are affected in different dimensions of their quality of life. The Hoehn & Yahr stage can independently predict the risk of OH in PD patients.

Diagnostic value and clinical significance of lncRNA LINC01123 combined with fibrinogen in acute cerebral infarction.

OBJECTIVE: To explore the diagnostic value and clinical significance of lncRNA LINC01123 (LINC01123) binding fibrinogen in acute cerebral infarction (ACI) by evaluating the expression and potential molecular mechanism of LINC01123 in patients with acute cerebral infarction. METHODS: The clinical data of all the volunteers were collected. The level of serum LINC01123 in ACI patients was detected by RT-qPCR. The relationship between LINC01123 and fibrinogen was studied via Pearson's correlation analysis. ROC curve was used to evaluate the diagnostic value of LINC01123 and fibrinogen for ACI. The risk factors of ACI were investigated by Binary Logistic regression analysis. And the targeting relationship between LINC01123 and downstream miR-361-3p was verified through luciferase activity assay. RESULTS: Serum LINC01123 and fibrinogen levels were upregulated in ACI patients compared with healthy controls (P < 0.001), and there was a positive correlation between them (r = 0.6537, P < 0.001). In predicting the occurrence of ACI, LINC01123 and fibrinogen have high diagnostic value, and the AUC of combined diagnosis was 0.961, and the sensitivity and specificity (92.54%, 85.82%) were more significant. Meanwhile, LINC01123 and fibrinogen were confirmed to be independent risk factors for ACI (P < 0.0001). Mechanistically, miR-361-3p is the target of LINC01123. The expression of miR-361-3p was low in the serum of ACI patients, which was negatively correlated with the LINC01123 expression (r = -0.6885, P < 0.0001). CONCLUSION: LINC01123 combined with fibrinogen may have important reference value in the diagnosis of ACI as serum markers, which may become clinical indicators to predict the occurrence of ACI.

Impact of Acute Ocular Hypertension on Retinal Ganglion Cell Loss in Mice.

Purpose: To assess the correlation between intraocular pressure (IOP) levels and retinal ganglion cell (RGC) loss across different fixed-duration episodes of acute ocular hypertension (AOH). Methods: AOH was induced in Thy1-YFP-H transgenic mice by inserting a needle connected to a saline solution container into the anterior chamber. Thirty-one groups were tested, each comprising three to five mice exposed to IOP levels ranging from 50 to 110 mm Hg in 5/10 mm Hg increments for 60/90/120 minutes and a sham control group. The YFP-expressing RGCs were quantified by confocal scanning laser ophthalmoscopy, whereas peripapillary ganglion cell complex thickness was measured using spectral-domain optical coherence tomography. Changes in RGC count and GCCT were determined from values measured 30 days after AOH relative to baseline (before AOH). Results: In the 60-minute AOH groups, RGC loss varied even when IOP was increased up to 110 mm Hg (36.8%-68.2%). However, for longer durations (90 and 120 minutes), a narrow range of IOP levels (60-70 mm Hg for 90-minute duration; 55-65 mm Hg for 120-minute duration) produced a significant difference in RGC loss, ranging from <25% to >90%. Additionally, loss of YFP-expressing RGCs was comparable to that of total RGCs in the same retinas. Conclusions: Reproducible RGC loss during AOH depends on precise durations and IOP thresholds. In the current study, the optimal choice is an AOH protocol set at 70 mm Hg for a duration of 90 minutes. Translational Relevance: This study can assist in determining the optimal duration and intensity of IOP for the effective utilization of AOH models.

The longitudinal relationship between leisure activities and depressive symptoms among older Chinese adults: an autoregressive cross-lagged analysis approach.

BACKGROUND: Existing studies have shown a correlation between leisure activities and depressive symptoms in older adults, but the direction of the longitudinal relationship is inconsistent. This study used an autoregressive cross-lagged model to examine the longitudinal relationship between leisure activity participation and geriatric depression. METHODS: A total of 7,138 participants aged 60 years or older from the 2nd to the 4th wave of the China Health and Retirement Longitudinal Study (CHARLS) were analysed. RESULTS: First, present depressive symptoms were significantly associated with future depressive symptoms (ß2013-2015 = .893, p < .001; ß2015-2018 = .946, p < .001), and the same rule applied to leisure activities (ß2013-2015 = .402, p < .001; ß2015-2018 = .404, p < .001). Second, current depressive symptoms negatively predicted future leisure activities (ß2013-2015 = -.071, p < .001; ß2015-2018 = -.085, p < .001), but the inverse relationship was not statistically significant (ß2013-2015 = -.003, p > .05; ß2015-2018 = -.003, p > .05). CONCLUSION: These findings underscore the importance of interventions targeting depressive symptoms to potentially enhance engagement in leisure activities among older adults. The results contribute to the understanding of the complex dynamics between mental health and lifestyle choices in older populations, highlighting the potential of proactive mental health interventions to improve overall well-being.

Risk perception, compliance with COVID-19 measures, and the role of social media after China's lockdown lift.

Introduction: Few studies have investigated people's reactions after a sudden lift. The transitional experiences of Chinese people at the end of 2022 serve as a valuable reference for pandemic management. Therefore, this study investigates Chinese people's perception of risks after the lifting, the influence of risk perception on their compliance with COVID-19 measures, and the moderating effect of social media on this influence. Methods: Initially, using a random sampling approach, we carried out an online questionnaire survey through Questionnaire Star, an online questionnaire platform. 417 (304 females, 13-64 years old) participants responded to questions on their perception of risks, compliance with COVID-19 measures, and trust in social media. Then, in the follow-up experiment, we observed another 60 (30 females, 18-22 years old) participants' actual behaviors to see how they comply with COVID-19 measures (for the peak of the confirmed cases, we chose to make do with this small size). We also asked them to complete a paper questionnaire on risk perception and trust in social media. Results: The initial survey indicated that, after the lifting, Chinese citizens perceived high risks (they reported a possibility of 61.04 out of 100 to be infected and threatened by COVID-19. The number was 54 in a previous study), showed a low degree of adherence to COVID-19 measures (on a scale of 1-5, they reported a score of 2.04 in private, and 1.89 in public), and social media positively moderated the relationship between risk perception and adherence (ΔR2 = 0.10, p < .01 for private behavior; ΔR2 = 0.13, p < .01 for public behavior). The follow-up experiment further confirmed these findings. Conclusion: This study suggests that, when lifting lockdowns on a national scale, the government should inform the public about the risks accurately, encourage healthy behaviors, and make full use of social media to promote adherence to COVID-19 measures. By using a hybrid approach that combines a questionnaire survey with actual behavior observation, this study expands earlier research into the understudied context of lockdown lifts. Finding effective strategies to support individuals through the transition period can facilitate global pandemic management.

The clinical and genetic characteristics of maternally inherited diabetes and deafness (MIDD) with mitochondrial m.3243A > G mutation: A 10-year follow-up observation study and literature review.

Maternally inherited diabetes and deafness (MIDD) is often caused by the m.3243A > G mutation in mitochondrial DNA. Unfortunately, the characteristics of MIDD, especially long-term outcomes and heteroplasmic changes, have not been well described previously. The purpose of this study was to describe the clinical and genetic features of a family with MIDD after 10 years of follow-up.A 33-year-old male patient with typical characteristics of MIDD, including early-onset diabetes, deafness, and low body mass index, was admitted to our department. Further investigation revealed that the vast majority of his maternal relatives suffered from diabetes with or without deafness. A detailed family history was then requested from the patient and a pedigree was constructed. The patient suspected of MIDD was screened for mutations using whole mitochondrial DNA sequencing. Candidate pathogenic variants were then validated in other family members through Sanger sequencing. The patient was diagnosed with MIDD, with inherited m.3243A > G mutation in the mitochondrially encoded tRNA leucine 1 (MT-TL1) gene, after 10 years of symptom onset. The patient was then treated with insulin and coenzyme Q10 to improve mitochondrial function. During the follow-up period, his fasting blood glucose and HbA1c levels were improved and the incidence of diabetic ketoacidosis was significantly reduced. Our findings indicate that whole mitochondrial DNA sequencing should be considered for patients suspected of MIDD to improve the efficiency of diagnosis and prognosis.

Nitrogen atom insertion into arenols to access benzazepines.

Advances in site-selective molecular editing have enabled structural modification on complex molecules. However, thus far, their applications have been restricted to C-H functionalization chemistry. The modification of the underlying molecular skeleton remains limited. Here, we describe a skeletal editing approach that provides access to benzazepine structures through direct nitrogen atom insertion into arenols. Using widely available arenols as benzazepine precursors, this alternative approach allowed the streamlined assembly of benzazepines with broad functional group tolerance. Experimental mechanistic studies support a reaction pathway involving dearomatizative azidation and then aryl migration. This study further highlights the potential for carbon-nitrogen transmutation sequences through combinations with oxidative carbon atom deletion, providing an alternative for the development of N-heteroarenes and demonstrating significant potential in materials chemistry.

The nearby atomic environment effect on an Fe-N-C catalyst for the oxygen reduction reaction: a density functional theory-based study.

Fe-N-C materials have emerged as highly promising non-noble metal catalysts for oxygen reduction reactions (ORRs) in polymer electrolyte membrane fuel cells. However, they still encounter several challenges that need to be addressed. One of these challenges is establishing an atomic environment near the Fe-N4 site, which can significantly affect catalyst activity. To investigate this, herein, we employed density functional theory (DFT). According to our computational analysis of the Gibbs free energy of the reaction based on the computational hydrogen electrode (CHE) model, we successfully determined two C-O-C structures near the Fe-N4 site (referred to as str-11) with the highest limiting potential (0.813 V). Specifically, in the case of O-doped structures, the neighboring eight carbon (C) atoms around nitrogen (N) can be categorized into two distinct types: four C atoms (type A) exhibiting high sensitivity to the limiting potential and the remaining four C atoms (type B) displaying inert behavior. Electronic structure analysis further elucidated that a structure will have strong activity if the valence band maximum (VBM) around its gamma point is mainly contributed by dxz, dyz or dz2 orbitals of Fe atoms. Constant-potential calculations showed that str-11 is suitable for the ORR under both acidic and alkaline conditions with a limiting potential of 0.695 V at pH = 1 and 0.926 V at pH = 14, respectively. Additionally, microkinetic simulations indicated the possibility of str-11 as the active site for the ORR under working potential at pH = 14.

Chiral Cpx Rhodium(III)-Catalyzed Enantioselective Aziridination of Unactivated Terminal Alkenes.

Chiral cyclopentadienyl-rhodium(III) Cpx Rh(III) catalysis has been demonstrated to be competent for catalyzing highly enantioselective aziridination of challenging unactivated terminal alkenes and nitrene sources. The chiral Cpx Rh(III) catalysis system exhibited outstanding catalytic performance and wide functional group tolerance, yielding synthetically important and highly valuable chiral aziridines with good to excellent yields and enantioselectivities (up to 99 % yield, 93 % ee). This protocol presents a novel and effective strategy for synthesizing enantioenriched aziridines from simple alkenes. Various transformations were performed on the aziridine products, illustrating the versatility and synthetic potential of this protocol for constructing highly functionalized compounds.

OTUB1 Targets CHK1 for Deubiquitination and Stabilization to Facilitate Lung Cancer Progression and Radioresistance.

PURPOSE: Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. Ovarian tumor domain ubiquitin aldehyde binding 1 (OTUB1) is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism, and cytokine secretion as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. METHODS AND MATERIALS: The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry. In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and Gene Ontology terms were analyzed based on RNA sequencing. RESULTS: Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiation therapy for lung adenocarcinoma. CONCLUSIONS: These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilization of the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiation therapy in lung cancer.

Enantioselective Glutamic Acid Discrimination and Nanobiological Imaging by Chiral Fluorescent Silicon Nanoparticles.

Enantioselective discrimination of chiral molecules is essential in chemistry, biology, and medical science due to the configuration-dependent activities of enantiomers. Therefore, identifying a specific amino acid and distinguishing it from its enantiomer by using nanomaterials with outstanding performance are of great significance. Herein, blue- and green-emitting chiral silicon nanoparticles named bSiNPs and gSiNPs, respectively, with excellent water solubility, salt resistance, pH stability, photobleaching resistance, biocompatibility, and ability to promote soybean germination, were fabricated in a facile one-step method. Especially, chiral gSiNPs presented excellent fluorescence recognition ability for glutamic acid enantiomers within 1 min, and the enantiomeric recognition difference factor was as high as 9.0. The mechanism for enantiomeric fluorescence recognition was systematically explored by combining the fluorescence spectra with density functional theory (DFT) calculation. Presumably, the different Gibbs free energy and hydrogen-bonding interaction of the chiral recognition module with glutamic acid enantiomers mainly contributed to the difference in the fluorescence signals. Most noteworthy was the fact that the chiral gSiNPs can showcase not only the ability to recognize l- and d-glutamic acids in living cells but also the test strips fabricated by soaking gSiNPs can be applied for d-glutamic acid visual detection. As a result, this study provided insights into the design of multifunctional chiral sensing nanoplatforms for enantiomeric detection and other applications.

In vivo functional immunoprotection correlates for vaccines against invasive bacteria.

Vaccination has significantly reduced the incidence of invasive infections caused by several bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. However, no vaccines are available for many other invasive pathogens. A major hurdle in vaccine development is the lack of functional markers to quantify vaccine immunity in eliminating pathogens during the process of infection. Based on our recent discovery of the liver as the major organ of vaccine-induced clearance of blood-borne virulent bacteria, we here describe a new vaccine evaluation system that quantitatively characterizes the key features of effective vaccines in shuffling virulent bacteria from the blood circulation to the liver resident macrophage Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) in mouse septic infection model. This system consists of three related correlates or assays: pathogen clearance from the bloodstream, pathogen trapping in the liver, and pathogen capture by KCs/LSECs. These readouts were consistently associated with the serotype-specific immunoprotection levels of the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against lethal infection of S. pneumoniae, a major invasive Gram-positive pathogen of community-acquired infections in humans. Furthermore, the reliability and sensitivity of these correlates in reflecting vaccine efficacy were verified with whole cell vaccines of Klebsiella pneumoniae and Escherichia coli, two major Gram-negative pathogens in hospital-acquired invasive infections. This system may be used as effective readouts to evaluate the immunoprotective potential of vaccine candidates in the preclinical phase by filling the current technical gap in vaccine evaluation between the conventional in vitro approaches (e.g. antibody production and pathogen neutralization/opsonophagocytosis) and survival of immunized animals.

Gut microbiota: A double-edged sword in immune checkpoint blockade immunotherapy against tumors.

Tumor cells can evade immune surveillance by expressing immune checkpoint molecule ligands, resulting in effective immune cell inactivation. Immune checkpoint blockades (ICBs) have dramatically improved survival of patients with multiple types of cancers. However, responses to ICB immunotherapy are heterogeneous with lower patient response rates. The advances have established that the gut microbiota can be as a promising target to overcome resistance to ICB immunotherapy. Furthermore, some bacterial species have shown to promote improved responses to ICBs. However, gut microbiota is critical in maintaining gut and systemic immune homeostasis. It not only promotes differentiation and function of immunosuppressive immune cells but also inhibits inflammatory cells via gut microbiota derived products such as short chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, which play an important role in tumor immunity. Since the gut microbiota can either inhibit or enhance immune against tumor, it should be a double-edged sword in ICBs against tumor. In this review, we discuss the effects of gut microbiota on immune cells and also tumor cells, especially enhances of gut microbiota on ICB immunotherapy. These discussions can hopefully promote the development of ICB immunotherapy.

IL-17A is involved in the hyperplasia of blood vessels in local lesions of psoriasis by inhibiting autophagy.

OBJECTIVE: Increased angiogenesis is a pathological feature of psoriasis, but the pathomechanisms of angiogenesis in psoriasis are not clear. Interleukin-17A (IL-17A) is the major effect factor in the pathogenesis of psoriasis. Our results showed that IL-17A can promote angiogenesis and cause endothelial cell inflammation. Autophagy plays an important role not only in regulating inflammation, but also in regulating angiogenesis. Whether angiogenesis in psoriasis is related to autophagy remains unclear. In this study, we treated human umbilical vein endothelial cells (HUVECs) with IL-17A to simulate increased angiogenesis to study whether increased angiogenesis in psoriasis is related to autophagy. METHODS AND RESULTS: Our results showed that treatment of HUVECs with IL-17A significantly increased angiogenesis and expression levels of mRNA for multiple proinflammatory cytokines (CCL20, IL-8, CCL2, IL-6, and IL-1ß) and, while decreasing intracellular levels of nitric oxide (NO) and NO synthase (NOS) activity. Moreover, IL-17A inhibited autophagy as shown that IL-17A significantly increased expression levels of LC3II and p62 proteins. Induction of autophagy ameliorated IL-17A-mediated inflammatory response and inhibited angiogenesis, accompanied by increased p-AMPKα(Thr172) and p-ULK1(Ser555) expression, and decreased p-mTOR(Ser2448) and p-ULK1(Ser757) expression. Furthermore, inhibition of either AMPK or lysosomal acidification completely overrode autophagy-induced changes in angiogenesis and NOS activity. Finally, induction of autophagy decreased apoptosis and caspase-3 activity in IL-17A-treated HUVECs. CONCLUSIONS: These results showed that IL-17A is involved in angiogenesis and inflammatory response by inhibiting autophagy through AMPK signaling pathway, suggesting that autophagy may be a new therapeutic target for psoriasis.

Attaining inhibition of sneak current and versatile logic operations in a singular halide perovskite memristive device by introducing appropriate interface barriers.

Emerging resistive switching devices hold the potential to realize densely packed passive nanocrossbar arrays, suitable for deployment as random access memory devices (ReRAMs) in both embedded and high-capacity storage applications. In this study, we have engineered ReRAMs comprising ITO/(UVO-treated) amorphous ZnO (a-ZnO)/MAPbI3/Ag which effectively mitigate cross-talk currents without additional components. Significantly, we successfully executed a comprehensive set of 12 distinct 2-input sequential logic functions in a single halide perovskite ReRAM unit for the first time. Furthermore, these logic functions are devoid of any dependency on external light sources, entail merely 1 or 2 logic steps, and showcase symmetrical operability. A superior resistive switching behavior was achieved by harmonizing the charge transport within the bulk MAPbI3 and the tunneling barriers at the interfaces. The outcomes indicate progress in mitigating cross-talk and executing multiple logic functions within a single halide perovskite ReRAM unit, offering a new perspective for the advancement of halide perovskite ReRAMs.

A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone.

PURPOSE: Disorders of sex development (DSD) have complex pathogenesis, and evidence suggests an association between MAMLD1 defects and DSD. MAMLD1 is expressed in gonadal tissues and affected males exhibit hypospadias, steroid hormone abnormalities, or gonadal underdevelopment. We performed genetic testing on a newborn patient with severe hypospadias and an elevation of 17-hydroxyprogesterone (17α-OH) for the diagnosis of DSD. METHODS: Genetic testing of the proband and parents was conducted using whole-exome and Sanger sequencing. The identified variant was transfected into HEK293T cells to assess mutant protein expression using western blot (WB) and into steroidogenic NCI-H295R cells to assess MAMLD1 and CYP17A1 transcript levels using qPCR. Molecular dynamics simulations were performed to construct a structural model and analyze potential biological implications. RESULTS: A novel heterozygous variant was identified in the proband's MAMLD1, NM_005491.5: c.1619_1637del (p.Gln540Alafs*72), inherited from the mother. In transfected cells, the wild-type and mutant proteins were 86.2 and 68.3 kDa, respectively, indicating the formation of a truncated protein. While MAMLD1 transcription was not affected, CYP17A1 transcription levels decreased with the variant compared to wild-type, suggesting an impact on the transactivation of CYP17A1. The truncated protein exhibited enhanced hydrophobicity, owing to the absence of the C-terminal structural portion, resulting in a looser protein structure. CONCLUSION: Severe hypospadias in the proband may be attributed to a novel MAMLD1 variant, whereas the 17α-OH elevation might be related to interference with CYP17A1 transcriptional activation. This study expands the spectrum of MAMLD1 variants and underscores the critical role of genetic testing in the diagnosis of DSD.

RAD54L2 counters TOP2-DNA adducts to promote genome stability.

The catalytic cycle of topoisomerase 2 (TOP2) enzymes proceeds via a transient DNA double-strand break (DSB) intermediate termed the TOP2 cleavage complex (TOP2cc), in which the TOP2 protein is covalently bound to DNA. Anticancer agents such as etoposide operate by stabilizing TOP2ccs, ultimately generating genotoxic TOP2-DNA protein cross-links that require processing and repair. Here, we identify RAD54 like 2 (RAD54L2) as a factor promoting TOP2cc resolution. We demonstrate that RAD54L2 acts through a novel mechanism together with zinc finger protein associated with tyrosyl-DNA phosphodiesterase 2 (TDP2) and TOP2 (ZATT/ZNF451) and independent of TDP2. Our work suggests a model wherein RAD54L2 recognizes sumoylated TOP2 and, using its ATPase activity, promotes TOP2cc resolution and prevents DSB exposure. These findings suggest RAD54L2-mediated TOP2cc resolution as a potential mechanism for cancer therapy resistance and highlight RAD54L2 as an attractive candidate for drug discovery.

Liver macrophages and sinusoidal endothelial cells execute vaccine-elicited capture of invasive bacteria.

Vaccination has substantially reduced the morbidity and mortality of bacterial diseases, but mechanisms of vaccine-elicited pathogen clearance remain largely undefined. We report that vaccine-elicited immunity against invasive bacteria mainly operates in the liver. In contrast to the current paradigm that migrating phagocytes execute vaccine-elicited immunity against blood-borne pathogens, we found that invasive bacteria are captured and killed in the liver of vaccinated host via various immune mechanisms that depend on the protective potency of the vaccine. Vaccines with relatively lower degrees of protection only activated liver-resident macrophage Kupffer cells (KCs) by inducing pathogen-binding immunoglobulin M (IgM) or low amounts of IgG. IgG-coated pathogens were directly captured by KCs via multiple IgG receptors FcγRs, whereas IgM-opsonized bacteria were indirectly bound to KCs via complement receptors of immunoglobulin superfamily (CRIg) and complement receptor 3 (CR3) after complement C3 activation at the bacterial surface. Conversely, the more potent vaccines engaged both KCs and liver sinusoidal endothelial cells by inducing higher titers of functional IgG antibodies. Endothelial cells (ECs) captured densely IgG-opsonized pathogens by the low-affinity IgG receptor FcγRIIB in a "zipper-like" manner and achieved bacterial killing predominantly in the extracellular milieu via an undefined mechanism. KC- and endothelial cell-based capture of antibody-opsonized bacteria also occurred in FcγR-humanized mice. These vaccine protection mechanisms in the liver not only provide a comprehensive explanation for vaccine-/antibody-boosted immunity against invasive bacteria but also may serve as in vivo functional readouts of vaccine efficacy.

Influence of biofertilizer on heavy metal bioremediation and enzyme activities in the soil to revealing the potential for sustainable soil restoration.

Overuse of chemical fertilizer and pesticides in agricultural activity is frequently damaging to soil health and can accumulate heavy metals in the soil environment, causing harm to plants, humans, and the ecosystem. This study was done to evaluate the effectiveness of biofertilizers in reducing heavy metal levels in contaminated soil and enhancing the activity of soil enzymes that are crucial to plant growth and development. Two bacteria strains, Pseudomonas aeruginosa. and Bacillus firmus, were chosen to develop biofertilizers based on molasses. The pot experiment was setup using a completely randomized design with four treatments and five levels; Bacillus firmus and Pseudomonas aeruginosa were used separately, and they were combined for the biofertilizer dose (20, 40, 60, 80, and 100 mL). Utilizing contaminated soils taken from a greenhouse farm the effect of biofertilizer on heavy metal bioremediation and soil enzyme activity was examined. Methods of soil agrochemical analysis were used to determine the soil physiochemical properties and the concentrations of heavy metals Cu, Fe, Zn, Cd, Mo, Mn, were determined by inductively coupled plasma-mass spectrometry ICP-MS, following DTPA extraction methods. In results, soil pH decreased from 8.28 to 7.39, Ec increased from 0.91 to 1.12, organic matter increased from 18.88 to 20.63 g/kg, N increased gradually from 16.7 to 24.4 mg/kg, and K increased from 145.25 to 201.4 mg/kg. The effect of biofertilizer treatment on soil physiochemical characteristics was significantly positive. Application of biofertilizer significantly increased the heavy metal bioavailability and the activities of soil enzymes. Soil pH were positively correlated with soil Zn (0.99819*), APK (0.95869*) activity and negatively correlated with Fe (0.96759*) also statistically significant at (p < 0.05). The soil Cu positively correlated with Fe (0.99645*), Cd (0.97866*), ß.D.GLU (0.99769*) and negatively correlated with PAK (- 0.9624*). Soil ARY had positive correlation with soil Mn (0.99683*), Cd (0.95695*), and negative correlation with PAK (- 0.99424*) at (p < 0.05). Soil enzyme activities were negatively correlated to heavy metals at a significant level. Collectively, the study highlights the potential of biofertilizers as a sustainable and effective approach to enhance soil health and remediate heavy metal-contaminated soils in greenhouses.

Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation.

Background: POLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved. Methods: The TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type. Results: The bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type. Conclusion: The infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.