Miracle-dz/UniFAR-FTUs huggingface dataset:
Single-molecule tracking in live Yersinia enterocolitica reveals distinct cytosolic complexes of injectisome subunits

In bacterial type 3 secretion, substrate proteins are actively transported from the bacterial cytoplasm into the cytoplasm of host cells by a large membrane-embedded machinery called the injectisome. Injectisomes transport secretion substrates in response to specific environmental signals, but the molecular details by which the cytosolic secretion substrates are selected and transported through the type 3 secretion pathway remain unclear. Secretion activity and substrate selectivity are thought to be controlled by a sorting platform consisting of the proteins SctK, SctQ, and SctL, which together localize to the cytoplasmic side of membrane-embedded injectisomes. However, recent work revealed that sorting platform proteins additionally exhibit substantial cytosolic populations and that SctQ reversibly binds to and dissociates from the cytoplasmic side of membrane-embedded injectisomes. Based on these observations, we hypothesized that dynamic molecular turnover at the injectisome and cytosolic assembly among sorting platform proteins is a critical regulatory component of type 3 secretion. To determine whether intact sorting platform complexes exist in the cytosol of living cells, we measured the diffusive properties of thousands of SctQ and SctL proteins using high-throughput 3D single-molecule tracking microscopy. The obtained single-molecule trajectories reveal that both SctQ and SctL exist in several distinct diffusive states in the cytosol of living Yersinia enterocolitica, indicating that these proteins are able to form stable oligomeric complexes in their native environment. Our findings provide new insights into the dynamic regulatory network that interfaces stationary membrane-embedded injectisomes with the soluble cytosolic components of the T3SS. Significance Statement Type 3 secretion system (T3SS) injectisomes are used for inter-kingdom transfer of proteins between bacterial pathogens and eukaryotic cells. In spite of recent progress in determining the in situ morphology of fully assembled injectisomes, the functional regulation of the T3SS remains unresolved. Using 3D single-molecule tracking microscopy, we found that injectisome subunits that are thought to control the substrate selectivity of the T3SS assemble into high molecular weight complexes in the cytosol of living cells. The formation of these complexes requires the presence of other T3SS proteins and correlates with the cell’s secretion activity. Cytosolic assembly of protein subunits may be a general mechanism to control the T3SS and similar membrane-embedded biomolecular assemblies.
Depression is associated with self-rated frailty in older adults from an outpatient clinic: a prospective study

ABSTRACT Objectives: The aim of the present study was to evaluate the association between depression and SSRI monotherapy and frailty both baseline and prospectively in older adults. Design: Prospective cohort study, 12-month follow-up. Setting: Geriatric outpatient clinic in São Paulo, Brazil. Participants: A total of 811 elderly adults aged 60 or older. Measurements: Depression was diagnosed as follows: (1) a diagnosis of major depression disorder (MDD) according to DSM-5; or (2) an incomplete diagnosis of MDD, referred to as minor or subsyndromic depression, plus Geriatric Depression Scale 15-itens ≥ 6 points, and social or functional impairment secondary to depressive symptoms and observed by relatives. Frailty evaluation was performed through the FRAIL questionnaire, which is a self-rated scale. Trained investigators blinded to the baseline assessment conducted telephone calls to evaluate frailty after 12-month follow-up. The association between depression and the use of SSRI with frailty was estimated through a generalized estimating equation adjusted for age, gender, total drugs, and number of comorbidities. Results: Depression with SSRI use was associated with frailty at baseline (OR 2.82, 95% CI = 1.69–4.69) and after 12 months (OR 2.75, 95% CI = 1.84–4.11). Additionally, depression with SSRI monotherapy was also associated with FRAIL subdomains Physical Performance (OR 1.99, 95% CI = 1.29–3.07) and Health Status (OR 4.64, 95% CI = 2.11–10.21). SSRI use, without significant depressive symptoms, was associated with subdomain Health Status (OR 1.52, 95% CI = 1.04–2.23). Conclusion: It appears that depression with SSRI is associated to frailty, and this association cannot be explained only by antidepressant use.
Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation

Background/Aims: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. Methods: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. Results: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. Conclusion: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.
Antibiotic therapy of diabetic foot infections: A systematic review of randomized controlled trials

Diabetic foot infection is a common diabetic complication that may end in lower limb amputation if not treated properly. We performed this systematic review to assess the clinical efficacy of different antibiotic regimens, whether systemic or topical, in the treatment of moderate to severe diabetic foot infections. We searched Medline, Web of Science, SCOPUS, Cochrane CENTRAL, and ScienceDirect for randomized controlled trials that evaluated the efficacy of antibiotic regimens in moderate to severe diabetic foot infections. The primary outcome of interest was the clinical efficacy (cure/improvement rates) of the regimens. We included 16 trials (4,158 patients) in this review, from which we extracted 10 comparisons: some trials compared systemic antibiotics to each other, others compared systemic to topical agents, while one study compared the combined topical and systemic agents to systemic antibiotics alone. Qualitative analysis of the findings of these studies showed that: (1) pipracillin/tazobactam was superior to ertapenem in severe infections (clinical resolution rate: 91.5% compared with PIP/TAZ 97.2%, p ≤ 0.04), but had similar efficacy in moderate infections, (2) ertapenem was more effective than tigecycline in moderate to severe infections (absolute difference −5.5, [95% CI −11.0, 0.1]), (3) the adjuvant use of topical agents with systemic antibiotics improved the outcomes, compared with systemic antibiotics alone (p = 0.024), (4) the rates of recurrence and re‐ulceration were significantly lower in patients using the amino‐penicillin regimen, compared with those using oral/intravenous ofloxacin, and (5) lower rates of complications accompanied the imipenem/cilastatin regimen, compared with the pipracillin/tazobactam regimen (p = 0.13). In conclusion, data from the included studies showed better results for ertapenem when compared with tigecycline; however, it was inferior to pipracillin/tazobactam in severe infections. The adjuvant use of topical agents improves the efficacy of systemic antibiotics in diabetic foot infection.
Prognostic role of Toll-like receptors in cancer: a meta-analysis

Background Recent studies have shown that Toll-like receptors (TLRs) may be associated with cancers. The aim of this meta-analysis is to summarize the predicting role of TLRs for survival in patients with a variety of carcinomas. Materials and methods Eligible studies were identified and assessed for quality through multiple search strategies. We collected data from studies investigating the relationship between the expression level of TLRs and survival in cancer patients. Studies were pooled and combined hazard ratios (HRs) of TLRs for survival were analyzed. Results A total of 24 studies, including 2,812 patients with various cancers, were identified for the meta-analysis. Importantly, this meta-analysis showed that higher expression levels of TLR4 or TLR7 in tumor tissues could predict poorer survival, with the pooled HR being 1.29 (95% CI: 1.17, 1.42) and 1.71 (95% CI: 1.38, 2.12), respectively. However, higher expression of TLR9 had no significant association with outcome as HR was 0.84 (95% CI: 0.62, 1.115). Heterogeneity existed in TLR4 and TLR9 studies (P-value <0.001) but not in TLR7 studies (P-value >0.05). Conclusion The expression level of TLR4 or TLR7 in cancerous tissue may have a prognosis value in patients with various cancers.
Interoceptive Impairments Do Not Lie at the Heart of Autism or Alexithymia

Quattrocki and Friston (2014) argued that abnormalities in interoception—the process of representing one’s internal physiological states—could lie at the heart of autism, because of the critical role interoception plays in the ontogeny of social-affective processes. This proposal drew criticism from proponents of the alexithymia hypothesis, who argue that social-affective and underlying interoceptive impairments are not a feature of autism per se, but of alexithymia (a condition characterized by difficulties describing and identifying one’s own emotions), which commonly co-occurs with autism. Despite the importance of this debate for our understanding of autism spectrum disorder (ASD), and of the role of interoceptive impairments in psychopathology, more generally, direct empirical evidence is scarce and inconsistent. Experiment 1 examined in a sample of 137 neurotypical (NT) individuals the association among autistic traits, alexithymia, and interoceptive accuracy (IA) on a standard heartbeat-tracking measure of IA. In Experiment 2, IA was assessed in 46 adults with ASD (27 of whom had clinically significant alexithymia) and 48 NT adults. Experiment 1 confirmed strong associations between autistic traits and alexithymia, but yielded no evidence to suggest that either was associated with interoceptive difficulties. Similarly, Experiment 2 provided no evidence for interoceptive impairments in autistic adults, irrespective of any co-occurring alexithymia. Bayesian analyses consistently supported the null hypothesis. The observations pose a significant challenge to notions that interoceptive impairments constitute a core feature of either ASD or alexithymia, at least as far as the direct perception of interoceptive signals is concerned.
An Acquired Epidermal Growth Factor Receptor T790M Mutation after the Addition of Bevacizumab to Preceding Erlotinib Monotherapy in a Lung Cancer Patient with Leptomeningeal Metastases

A 53-year-old man with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 19 deletion received erlotinib. After 12 months of disease control with erlotinib monotherapy, leptomeningeal metastases (LM) occurred. A cerebrospinal fluid examination demonstrated a pre-existing EGFR exon 19 deletion. Bevacizumab was combined with erlotinib, and the LM improved. After six months of combination therapy, however, the LM was exacerbated. A re-examination of the cerebrospinal fluid revealed a T790M mutation and exon 19 deletion. Osimertinib was administered, and the LM improved. The combination of bevacizumab and erlotinib was effective for erlotinib-resistant LM and resulted in the expression of a newly acquired T790M mutation, which enabled successful treatment with osimertinib.
From Default Mode Network to the Basal Configuration: Sex Differences in the Resting-State Brain Connectivity as a Function of Age and Their Clinical Correlates

Connectomics is a framework that models brain structure and function interconnectivity as a network, rather than narrowly focusing on select regions-of-interest. MRI-derived connectomes can be structural, usually based on diffusion-weighted MR imaging, or functional, usually formed by examining fMRI blood-oxygen-level-dependent (BOLD) signal correlations. Recently, we developed a novel method for assessing the hierarchical modularity of functional brain networks—the probability associated community estimation (PACE). PACE uniquely permits a dual formulation, thus yielding equivalent connectome modular structure regardless of whether positive or negative edges are considered. This method was rigorously validated using the 1,000 functional connectomes project data set (F1000, RRID:SCR_005361) (1) and the Human Connectome Project (HCP, RRID:SCR_006942) (2, 3) and we reported novel sex differences in resting-state connectivity not previously reported. (4) This study further examines sex differences in regard to hierarchical modularity as a function of age and clinical correlates, with findings supporting a basal configuration framework as a more nuanced and dynamic way of conceptualizing the resting-state connectome that is modulated by both age and sex. Our results showed that differences in connectivity between men and women in the 22–25 age range were not significantly different. However, these same non-significant differences attained significance in both the 26–30 age group (p = 0.003) and the 31–35 age group (p < 0.001). At the most global level, areas of diverging sex difference include parts of the prefrontal cortex and the temporal lobe, amygdala, hippocampus, inferior parietal lobule, posterior cingulate, and precuneus. Further, we identified statistically different self-reported summary scores of inattention, hyperactivity, and anxiety problems between men and women. These self-reports additionally divergently interact with age and the basal configuration between sexes.
Greater naturally occurring expressive suppression is associated with poorer executive functioning and motor-sequence learning among older adults

ABSTRACT Objectives: Unusually high engagement in expressive suppression (i.e., purposeful regulation of overt affect) has been associated with poorer performance on executive functioning (EF) and motor-sequence learning tasks. As such, expressive suppression represents one possible source of fluctuations in executive test performance. However, the relationship between expressive suppression and EF and motor performance has not yet been examined in older adults, who are more prone to EF and motor fluctuations than are younger adults. The purpose of this study was to test whether greater self-reported, naturally occurring expressive suppression is related to poorer EF performance and motor-sequence learning in older adults. Method: One hundred and ten community-dwelling older adults completed a self-report measure of expressive suppression, a battery of EF tests, and a computer-based measure of motor-sequence learning. Results: As expected, higher self-reported burden of expressive suppression in the 24 hours prior to testing was related to poorer performance on EF tests and on multiple aspects of motor-sequence learning (action planning latencies and sequencing errors) even after accounting for age, depressive symptoms, and component processes (e.g., processing speed). Conclusions: The current results suggest that naturally occurring expressive suppression depletes EF, which builds on previous findings from experimental studies that show that expressive suppression leads to reduced EF performance. Furthermore, this effect can be captured using self-report methods. These findings highlight expressive suppression as one source of intraindividual fluctuations in executive and motor functioning, which likely place older adults at risk for both functional and motor lapses (e.g., medication mistakes, falls).
Displacement of the transcription factor B reader domain during transcription initiation

Abstract Transcription initiation by archaeal RNA polymerase (RNAP) and eukaryotic RNAP II requires the general transcription factor (TF) B/ IIB. Structural analyses of eukaryotic transcription initiation complexes locate the B-reader domain of TFIIB in close proximity to the active site of RNAP II. Here, we present the first crosslinking mapping data that describe the dynamic transitions of an archaeal TFB to provide evidence for structural rearrangements within the transcription complex during transition from initiation to early elongation phase of transcription. Using a highly specific UV-inducible crosslinking system based on the unnatural amino acid para-benzoyl-phenylalanine allowed us to analyze contacts of the Pyrococcus furiosus TFB B-reader domain with site-specific radiolabeled DNA templates in preinitiation and initially transcribing complexes. Crosslink reactions at different initiation steps demonstrate interactions of TFB with DNA at registers +6 to +14, and reduced contacts at +15, with structural transitions of the B-reader domain detected at register +10. Our data suggest that the B-reader domain of TFB interacts with nascent RNA at register +6 and +8 and it is displaced from the transcribed-strand during the transition from +9 to +10, followed by the collapse of the transcription bubble and release of TFB from register +15 onwards.
The effect of the carbodiimide cross-linker on the structural and biocompatibility properties of collagen–chondroitin sulfate electrospun mat

Background Collagen and chondroitin sulfate (CS) are an essential component of the natural extracellular matrix (ECM) of most tissues. They provide the mechanical stability to cone the compressive forces in ECM. In tissue engineering, electrospun nanofibrous scaffolds prepared by electrospinning technique have emerged as a suitable candidate to imitate natural ECM functions. Cross-linking with 1-ethyl-3-(3-dimethyl-aminopropyl)-1-carbodiimide hydrochloride/N-hydroxy succinimide can overcome the weak mechanical integrity of the engineered scaffolds in addition to the increased degradation stability under physiological conditions. Materials and methods This study has synthesized nanofibrous collagen–CS scaffolds by using the electrospinning method. Results The results have shown that incorporation of CS in higher concentration, along with 1-ethyl-3-(3-dimethyl-aminopropyl)-1-carbodiimide hydrochloride/N-hydroxy succinimide, enhanced mechanical stability. Scaffolds showed more resistance to collagenase digestion. Fabricated scaffolds showed biocompatibility in corneal epithelial cell attachment. Conclusion These results demonstrate that cross-linked electrospun CO–CS mats exhibited a uniform nanofibrous and porous structure, especially for lower concentration of the cross-linker and may be utilized as an alternative effective substrate in tissue engineering.
Efficient Measurement on Programmable Switches Using Probabilistic Recirculation

Programmable network switches promise flexibility and high throughput, enabling applications such as load balancing and traffic engineering. Network measurement is a fundamental building block for such applications, including tasks such as the identification of heavy hitters (largest flows) or the detection of traffic changes. However, high-throughput packet processing architectures place certain limitations on the programming model, such as restricted branching, limited capability for memory access, and a limited number of processing stages. These limitations restrict the types of measurement algorithms that can run on programmable switches. In this paper, we focus on the RMT programmable high-throughput switch architecture, and carefully examine its constraints on designing measurement algorithms. We demonstrate our findings while solving the heavy hitter problem. We introduce PRECISION, an algorithm that uses Probabilistic Recirculation to find top flows on a programmable switch. By recirculating a small fraction of packets, PRECISION simplifies the access to stateful memory to conform with RMT limitations and achieves higher accuracy than previous heavy hitter detection algorithms that avoid recirculation. We also analyze the effect of each architectural constraint on the measurement accuracy and provide insights for measurement algorithm designers.
Effects of Omitting Non-confounding Predictors From General Relative-Risk Models for Binary Outcomes

Background The effects, in terms of bias and precision, of omitting non-confounding predictive covariates from generalized linear models have been well studied, and it is known that such omission results in attenuation bias but increased precision with logistic regression. However, many epidemiologic risk analyses utilize alternative models that are not based on a linear predictor, and the effect of omitting non-confounding predictive covariates from such models has not been characterized. Methods We employed simulation to study the effects on risk estimation of omitting non-confounding predictive covariates from an excess relative risk (ERR) model and a general additive-multiplicative relative-risk mixture model for binary outcome data in a case-control setting. We also compared the results to the effects with ordinary logistic regression. Results For these commonly employed alternative relative-risk models, the bias was similar to that with logistic regression when the risk was small. More generally, the bias and standard error of the risk-parameter estimates demonstrated patterns that are similar to those with logistic regression, but with greater magnitude depending on the true value of the risk. The magnitude of bias and standard error had little relation to study size or underlying disease prevalence. Conclusions Prior conclusions regarding omitted covariates in logistic regression models can be qualitatively applied to the ERR and the general additive-multiplicative relative-risk mixture model without substantial change. Quantitatively, however, these alternative models may have slightly greater omitted-covariate bias, depending on the magnitude of the true risk being estimated.
Tension pneumocephalus from skull base surgery: A case report and review of the literature

Background: Tension pneumocephalus from skull base surgery is a rare occurrence that mandates urgent neurosurgical attention. Case Description: We describe a case of tension pneumocephalus secondary to an endoscopic endonasal resection of an adamantinomatous craniopharyngioma and how it was successfully managed at our institution. Conclusion: Our experience reflects that definitive treatment of tension pneumocephalus is required with multilayered dural repair, but temporising measures should be used immediately to prevent neurological deterioration prior to the definitive repair.