The bacterial flagellar motor is a supramolecular protein machine that drives rotation of the flagellum for motility, which is essential for bacterial survival in different environments and a key ...determinant of pathogenicity. The detailed structure of the flagellar motor remains unknown. Here we present an atomic-resolution cryoelectron microscopy (cryo-EM) structure of the bacterial flagellar motor complexed with the hook, consisting of 175 subunits with a molecular mass of approximately 6.3 MDa. The structure reveals that 10 peptides protruding from the MS ring with the FlgB and FliE subunits mediate torque transmission from the MS ring to the rod and overcome the symmetry mismatch between the rotational and helical structures in the motor. The LP ring contacts the distal rod and applies electrostatic forces to support its rotation and torque transmission to the hook. This work provides detailed molecular insights into the structure, assembly, and torque transmission mechanisms of the flagellar motor.
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•Cryo-EM structure of the bacterial flagellar motor complexed with the hook•Each subunit in the rod interlocks with adjacent subunits•Ten peptides, FlgB, and FliE are adaptors that join the MS ring and the rod•The LP ring applies electrostatic forces to support rotation of the rod
The cryo-EM structure of the Salmonella flagellar motor complexed with the hook reveals how the flagellar motor is assembled and carries out torque transmission to drive rotation of the flagellum.
Organochlorine pesticides, with their environmental persistence and bioaccumulation potential, have gained significant attention. This study explores the impact of organochlorine pesticides on ...mortality and chronic diseases, investigates their link to inflammatory states, and examines the role of anti-inflammatory diets in mitigating adverse reactions to these pesticides.
This study, with 2,847 participants, used gas chromatography and mass spectrometry to measure organochlorine pesticide exposure in NHANES data. Conventional statistical methodologies, encompassing survival curves, Cox proportional hazards regression, regression analysis, and restricted quadratic spline analysis, were employed to investigate the association between pesticides and mortality, chronic ailments, and inflammation. Furthermore, machine learning techniques, comprising RF, AdaBoost, Extra-Trees, LightGBM, and BPNN, were leveraged to evaluate the impact of pesticides on chronic disease and mortality prognostication.
Organochlorine pesticides were significantly and positively correlated with increased mortality (p<0.05). Additionally, these pollutants were linked to the incidence of chronic diseases such as chronic kidney disease, diabetes, and hypertension (p< 0.05). Our study, utilizing various machine learning models, also showed a notable increase in the Area Under the Curve when incorporating organochlorine pesticide indicators into the model as opposed to excluding them. Furthermore, strong correlations were observed between serum c-reactive protein (CRP) and CRP to serum albumin ratio (CAR) concentrations with these substances, demonstrating their pro-inflammatory effects at specific concentrations. Interestingly, cutting down on dietary inflammation through changes in diet effectively reduced the risk of death at high organochlorine pesticide exposure levels, but the effect was less noticeable at low to moderate exposure levels.
Exposure to organochlorine pesticides was linked to a higher risk of mortality, likely due to an increased prevalence of chronic diseases. In this context, inflammation played a crucial role, and adopting an anti-inflammatory diet significantly reduced the mortality risk associated with these pesticides.
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•Currently, there is a notable lack of high-quality epidemiological research on the potential health impacts of organochlorine pesticides in relation to inflammation.•Our study demonstrates a considerable rise in mortality rates linked to organochlorine pesticides, which is most likely attributable to the emergence of various chronic diseases.•The exposure to these substances was found to be positively correlated with systemic inflammatory states, leading us to postulate that these substances may have a detrimental impact on health by activating inflammatory pathways.•Optimizing our dietary habits can effectively suppress the inflammatory reaction, resulting in a decreased likelihood of mortality and the adverse health consequences associated with these substances.
Assessing residual consciousness and cognitive abilities in unresponsive patients is a major clinical concern and a challenge for cognitive neuroscience. Although neuroimaging studies have ...demonstrated a potential for informing diagnosis and prognosis in unresponsive patients, these methods involve sophisticated brain imaging technologies, which limit their clinical application. In this study, we adopted a new language paradigm that elicited rhythmic brain responses tracking the single-word, phrase and sentence rhythms in speech, to examine whether bedside electroencephalography (EEG) recordings can help inform diagnosis and prognosis. EEG-derived neural signals, including both speech-tracking responses and temporal dynamics of global brain states, were associated with behavioral diagnosis of consciousness. Crucially, multiple EEG measures in the language paradigm were robust to predict future outcomes in individual patients. Thus, EEG-based language assessment provides a new and reliable approach to objectively characterize and predict states of consciousness and to longitudinally track individual patients' language processing abilities at the bedside.
•EEG resting-state shows a hierarchy of intrinsic neural timescales.•Sensory deficits as in disorders and alterations of consciousness lead to prolonged intrinsic neural timescales.•Clinical ...conditions with motor deficits do not show changes in intrinsic neural timescales.
The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioral states. We address these questions by investigating the brain's intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activity's intrinsic neural timescale is related to the neural capacity that specifically supports sensory rather than motor information processing in the healthy brain.
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It was reported that histopathologic lesions are risk factors for the progression of IgA Nephropathy (IgAN). The aim of this study was to investigate the relationships between mesangial deposition of ...C1q and renal outcomes in IgAN. 1071 patients with primary IgAN diagnosed by renal biopsy were enrolled in multiple study centers form January 2013 to January 2017. Patients were divided into two groups: C1q-positive and C1q-negative. Using a 1: 4 propensity score matching (PSM) method identifying age, gender, and treatment modality to minimize confounding factors, 580 matched (out of 926) C1q-negative patients were compared with 145 C1q-positive patients to evaluate severity of baseline clinicopathological features and renal outcome. Kaplan-Meier and Cox proportional hazards analyses were performed to determine whether mesangial C1q deposition is associated with renal outcomes in IgAN. During the follow-up period (41.89 ± 22.85 months), 54 (9.31%) patients in the C1q negative group and 23 (15.86%) patients in C1q positive group reached the endpoint (50% decline of eGFR and/or ESRD or death) respectively (p = 0.01) in the matched cohort. Significantly more patients in C1q negative group achieved complete or partial remission during the follow up period (P = 0.003) both before and after PSM. Three, 5 and 7-year renal survival rates in C1q-positive patients were significantly lower than C1q-negative patients in either unmatched cohort or matched cohort (all p < 0.05). Furthermore, multivariate Cox regression analysis showed that independent risk factors influencing renal survival included Scr, urinary protein, T1-T2 lesion and C1q deposition. Mesangial C1q deposition is a predictor of poor renal survival in IgA nephropathy.Trial registration TCTR, TCTR20140515001. Registered May 15, 2014, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=1074 .
This was an observational study based on the National Health and Nutrition Examination Survey (NHANES) and National Death Index (NDI) 2009-2014 which aimed to validate whether a proinflammatory diet ...may increase mortality risk in patients with diabetes mellitus. Dietary inflammatory potential was assessed by dietary inflammatory index (DII) based on 24 h dietary recall. Mortality follow-up information was accessed from NDI, which was then merged with NHANES data following the National Center for Health Statistics (NCHS) protocols. For 15,291 participants from the general population, the average DII was 0.37 ± 1.76 and the prevalence rate of diabetes was 13.26%. DII was positively associated with fasting glucose (β = 0.83, 95% CI: 0.30, 1.36,
= 0.0022), glycohemoglobin (β = 0.02, 95% CI: 0.01, 0.03,
= 0.0009), and the risk of diabetes (OR = 1.05, 95% CI: 1.01, 1.09,
= 0.0139). For 1904 participants with diabetes and a median follow-up of 45 person-months, a total of 178 participants with diabetes died from all causes (mortality rate = 9.34%). People with diabetes who adhered to a proinflammatory diet showed a higher risk of all-cause mortality (HR = 1.71, 95%CI: 1.13, 2.58,
= 0.0108). In summary, DII was positively associated with diabetes prevalence and a proinflammatory diet may increase mortality risk in patients with diabetes mellitus.
Ubiquitination is essential for numerous eukaryotic cellular processes. Here, we show that the type III effector CteC from Chromobacterium violaceum functions as an adenosine diphosphate ...(ADP)-ribosyltransferase that specifically modifies ubiquitin via threonine ADP-ribosylation on residue T66. The covalent modification prevents the transfer of ubiquitin from ubiquitin-activating enzyme E1 to ubiquitin-conjugating enzyme E2, which inhibits subsequent ubiquitin activation by E2 and E3 enzymes in the ubiquitination cascade and leads to the shutdown of polyubiquitin synthesis in host cells. This unique modification also causes dysfunction of polyubiquitin chains in cells, thereby blocking host ubiquitin signaling. The disruption of host ubiquitination by CteC plays a crucial role in C. violaceum colonization in mice during infection. CteC represents a family of effector proteins in pathogens of hosts from different kingdoms. All the members of this family specifically ADP-ribosylate ubiquitin. The action of CteC reveals a new mechanism for interfering with host ubiquitination by pathogens.
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•C. violaceum blocks host ubiquitination via the type III effector CteC•CteC is an ADP-ribosyltransferase that specifically modifies Ub on T66•Threonine ADP-ribosylation of Ub by CteC disrupts host ubiquitin signaling•CteC represents a family of bacterial effector proteins that ADP-ribosylate ubiquitin
CteC from Chromobacterium violaceum represents a family of bacterial effector proteins that harbors adenosine diphosphate (ADP)-ribosyltransferase activities and specifically modifies ubiquitin on residue T66, which causes the shutdown of polyubiquitin synthesis and disrupts the recognition and reversal of polyubiquitin in host cells.
The pathogenesis of Henoch-Schönlein purpura nephritis (HSPN) is closely associated with mucosal infection. But whether intestinal microbiota dysbiosis plays a role in it is not clear.
A total of 52 ...participants including 26 HSPN patients and 26 healthy controls were included. By using 16S ribosomal RNA gene sequencing, the intestinal microbiota composition between HSPN and healthy controls was compared. The diagnostic potency was evaluated by Receiver operating characteristic (ROC) with area under curves (AUC). Meanwhile, correlation analysis was also performed.
The lower community richness and diversity of fecal microbiota was displayed in HSPN patients and the structure of gut microbiota was remarkedly different. A genus-level comparison indicated a significant increase in the proportions of g-Bacteroides, g-Escherichia-Shigella and g-Streptococcus, and a marked reduction of g-Prevotella_9 in HSPN patients, suggesting that the overrepresentation of potential pathogens and reduction of profitable strains were the main feature of the dysbiosis. The differential taxonomic abundance might make sense for distinguishing HSPN from healthy controls, with AUC of 0.86. The relative abundance of the differential bacteria was also concerned with clinical indices. Among them, Streptococcus spp. was positively associated with the severity of HSPN (P < 0.050). It was found that HSPN patients with higher level of Streptococcus spp. were more likely to suffering from hematuria and hypoalbuminemia (P < 0.050).
The dysbiosis of gut microbiota was obvious in HSPN patients, and the intestinal mucosal streptococcal infection was distinctive, which was closely related to its severity.
Aim
The aim of this study was to explore the effect of sex on the clinicopathological features and long-term outcomes of IgAN patients.
Methods
A total of 1096 adult IgAN patients were divided into ...male and female groups. Clinicopathological features and risk factors of IgAN patients of different genders were contrasted. The primary endpoint was the combined endpoint of a 50% reduction in estimated glomerular filtration rate (eGFR) and/or end stage renal disease (ESRD: eGFR < 15 mL/min/1.73 m
2
or dialysis). The effect of gender on prognosis of IgAN was assessed using Kaplan–Meier and Cox proportional hazards models.
Results
In total, 475 male patients and 621 female patients were included in this study. At baseline, male patients had higher values for blood pressure, serum creatinine, urine protein and serum uric acid, as well as lower levels of eGFR. Further analysis indicated that tubular atrophy/interstitial fibrosis (T) lesions and vascular lesions were more frequent in male patients. During the follow-up period of 40.9 ± 24.2 months
,
kidney survival rates of male IgAN patients were remarkably lower than those of female patients. Using multivariate Cox regression analysis, male gender was identified as an independent risk factor for poor outcomes (
β
= 0.384, Wald = 4.290, Exp (
β
) = 1.47,
p
= 0.038), including hypertension, low eGFR, IgM deposition, arteriosclerosis lesions and T1–T2 lesions. However, male and female patients were characterized by different risk factors.
Conclusion
Male patients presented with more severe clinical and pathological changes than female patients. Renal survival rates of male patients were remarkably lower than those of female patients, and male gender was identified as an independent risk factor for poor outcomes.
Immunoglobulin A nephropathy (IgAN) is a common autoimmune glomerulonephritis that can result in end-stage renal disease (ESRD). Whether immunosuppressants are superior or equivalent to supportive ...care is still controversial. A network meta-analysis was conducted to compare the efficacy and safety of immunosuppressive treatment for IgAN. Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and EMBASE were searched on December 30, 2018. We used a random-effects model with a Bayesian approach to appraise both renal outcomes and serious adverse effects. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated to present the relative effects. The ranking probabilities were calculated by the surface under the cumulative ranking curve (SUCRA). In total, 24 RCTs comprising 6 interventions were analyzed. Steroids significantly delayed the progression of renal deterioration with acceptable serious adverse effects, compared with supportive care (RR = 0.28, 95% CI = 0.13-0.51, SUCRA = 48.7%). AZA combined with steroids might be an alternative immunosuppressive therapy. Tacrolimus might decrease the proteinuria level (RR = 3.1, 95% CI = 1.2-9.4, SUCRA = 66.5%) but cannot improve renal function, and the side effects of tacrolimus should not be neglected. MMF and CYC showed no superiority in the treatment of IgAN. In summary, steroids might be recommended as the first-line immunosuppressive therapy for IgAN.
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