Miracle-dz/UniFAR-FTUs huggingface dataset:
Transmembrane domains of type III-secreted proteins affect bacterial-host interactions in enteropathogenic E. coli

ABSTRACT Many bacterial pathogens utilize a specialized secretion system, termed type III secretion system (T3SS), to translocate effector proteins into host cells and establish bacterial infection. The T3SS is anchored within the bacterial membranes and contains a long needle/filament that extends toward the host-cell and forms, at its distal end, a pore complex within the host membrane. The T3SS pore complex consists of two bacterial proteins, termed SctB and SctE, which have conflicting targeting indications; a signal sequence that targets to secretion to the extracellular environment via the T3SS, and transmembrane domains (TMDs) that target to membrane localization. In this study, we investigate whether the TMD sequences of SctB and SctE have special features that differentiate them from classical TMDs and allow them to escape bacterial membrane integration. For this purpose, we exchanged the SctB and SctE native TMDs for alternative hydrophobic sequences and found that the TMD sequences of SctB and SctE dictate membrane destination (bacterial versus host membrane). Moreover, we examined the role of the SctB TMD sequence in the activity of the full-length protein, post secretion, and found that the TMD does not serve only as a hydrophobic segment, but is also involved in the ability of the protein to translocate itself and other proteins into and across the host cell membrane.
Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging

Significance There is an unmet clinical need for sensitive methods for detecting cell death in vivo, for example, in disease and following tumor treatment. We show here that deuterium magnetic resonance measurements at 7 T of labeled malate production from injected 2H-labeled fumarate provide a sensitive method for detecting tumor cell death in vivo following treatment. Malate production was relatively slow in viable cells but was markedly increased in necrotic tissue. 2H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-2H2]malate, following injection of [2,3-2H2]fumarate (1 g/kg) into tumor-bearing mice, was measured in a murine lymphoma (EL4) treated with etoposide, and in human breast (MDA-MB-231) and colorectal (Colo205) xenografts treated with a TRAILR2 agonist, using surface-coil localized 2H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast 2H chemical shift imaging sequence. The malate/fumarate ratio increased from 0.016 ± 0.02 to 0.16 ± 0.14 in EL4 tumors 48 h after drug treatment (P = 0.0024, n = 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (P = 0.0001, n = 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (P = 0.0002, n = 5) 24 h after drug treatment. These increases were correlated with increased levels of cell death measured in excised tumor sections obtained immediately after imaging. 2H MR measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than 13C MR measurements of hyperpolarized [1,4-13C2]fumarate metabolism, which have been used previously for this purpose.
Cost-utility analysis of stereotactic body radiotherapy plus cetuximab in previously irradiated recurrent squamous cell carcinoma of the head and neck

ABSTRACT Background This study aimed to estimate the cost-utility of stereotactic body radiotherapy (SBRT) plus cetuximab for patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. Methods We constructed a Markov health-state transition model to simulate costs and clinical outcomes of recurrent squamous cell carcinoma of the head and neck. Model parameters were derived from the published literature and the National Health Insurance Administration reimbursement price list. Incremental cost-effectiveness ratio and the net monetary benefit were calculated from a health payer perspective. The impact of uncertainty was modeled with one-way and probabilistic sensitivity analyses. Results In the base-case, SBRT plus cetuximab compared to SBRT alone resulted in an ICER of NT$ 840,455 per QALY gained. In the one-way sensitivity analysis, the utility of progression-free state for patients treated with SBRT plus cetuximab or SBRT alone and the cost of progression-free survival for SBRT+Cet were the most sensitive parameters in the model. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness-to-pay threshold of NT$ 2,252,340 per QALY was 100% for SBRT plus cetuximab but 0% for SBRT alone. Conclusions This study showed that SBRT+Cet was cost-effective and benefited patients with previously irradiated rSCCHN.
Clinical and Epidemiologic Findings from Enhanced Monkeypox Surveillance in Tshuapa Province, Democratic Republic of the Congo During 2011–2015

Summary: We analyzed epidemiological data from 1,057 PCR-confirmed monkeypox cases. Increased incidence coincided with declining smallpox vaccine-derived immunity. Exposures varied by demographic characteristics, supporting the value of targeted health communication. High proportion of cases attributed to human exposures suggests changing exposures. Abstract Background Monkeypox is a poorly described emerging zoonosis endemic to Central and Western Africa. Methods Using surveillance data from Tshuapa Province, Democratic Republic of the Congo during 2011– 2015, we evaluated differences in incidence, exposures, and clinical presentation of PCR-confirmed cases by sex and age. Results We report 1,057 confirmed cases. Average annual incidence was 14·1 per 100,000 (95% CI: 13·3– 15·0). Incidence was higher in males (incidence rate ratio [IRR] males: females: 1·21, 95% CI 1·07– 1·37), except among 20–29-year-old (IRR: 0·70, 95% CI: 0·51–0·95). Females aged 20–29 years also reported a high frequency of exposures (26·2%) to people with monkeypox-like symptoms. Highest incidence was among 10–19-year-old males, the cohort reporting the highest proportion of animal exposures (37·5%). Incidence was lower among those presumed to have received smallpox vaccination versus those presumed unvaccinated. No differences were observed by age group in lesion count or lesion severity score. was possibly high changing were distributed across and suggesting that socio-cultural norms. Based on 5 years of enhanced surveillance in Province, this dataset represents one of the largest cohorts of laboratory confirmed monkeypox cases. This provides uniquely detailed insight into the clinical and epidemiological features of monkeypox in an endemic setting, and identification of specific risk groups such as females of childbearing age or young males who might benefit from targeted interventions. An evaluation of film-based educational activities demonstrated that it could increase awareness on MPX [35] and be an effective medium for targeted health education on MPX. Our findings reveal potential changes in monkeypox epidemiology, including the effects of waning immunity to orthopoxviruses, and increasing proportion of cases attributed to human exposures. Continued surveillance could help understand the relative importance of behavioral risk factors and waning smallpox immunity on incidence. Difference in incidence and exposure histories by sex and age are complicated by the diversity and intensity of animal-human interactions, and are best elucidated through collaborative epidemiological, anthropological, and ecological approaches.
Decarboxylative acylation of arenes with mandelic acid derivatives via palladium-catalyzed oxidative sp2 C–H activation

An efficient palladium catalyzed decarboxylative acylation of arenes with mandelic acid derivatives via oxidative sp2 C–H activation in the presence of tert-butyl hydroperoxide has been developed. The acylation reaction is assisted by a pyridine directing group. The starting materials are inexpensive and readily available. This method provides an economical and convenient way to synthesize aryl ketones.
Charges and Potentials at the Nerve Surface

The voltage dependence of the voltage clamp responses of myelinated nerve fibers depends on the concentration of divalent cations and of hydrogen ions in the bathing medium. In general, increases of the [Ca], [Ni], or [H] increase the depolarization needed to elicit a given response of the nerve. An e-fold increase of the [Ca] produces the following shifts of the voltage dependence of the parameters in the Hodgkin-Huxley model: m ∞, 8.7 mv; h ∞, 6.5 mv; τn, 0.0 mv. The same increase of the [H], if done below pH 5.5, produces the following shifts: m ∞, 13.5 mv; h ∞, 13.5 mv; τn, 13.5 mv; and if done above pH 5.5: m ∞, 1.3 mv; h ∞, 1.3 mv; τn, 4.0 mv. The voltage shifts are proportional to the logarithm of the concentration of the divalent ions and of the hydrogen ion. The observed voltage shifts are interpreted as evidence for negative fixed charges near the sodium and potassium channels. The charged groups are assumed to comprise several types, of varying affinity for divalent and hydrogen ions. The charges near the sodium channels differ from those near the potassium channels. As the pH is lowered below pH 6, the maximum sodium conductance decreases quickly and reversibly in a manner that suggests that the protonation of an acidic group with a pKa of 5.2 blocks individual sodium channels.
Being born and growing up in the Ribeirão Preto and São Luís cohorts

This thematic issue consists of 14 articles derived from studies of the BRISA birth cohort (Ribeirão Preto, State of São Paulo and São Luís, State of Maranhão, northeastern Brazil, a socially and economically less developed region). In these more than 40 years of existence, these cohorts have been able to document the increase in women's education, the improvement of health conditions, the creation of a public Unified Health System (SUS) that provides universal and free access to health care, eradication of hunger, and transition of the nutritional status characterized by a decrease in malnutrition rates and an increase in obesity in Brazil. Particularly in reproductive health, the country experienced a significant drop in fertility, a decrease in maternal and child mortality, and an increase in breastfeeding rates. Universal access to prenatal care and hospital delivery was accompanied by an excessive number of cesareans without clinical indication and early-term births and premature births, largely due to scheduled cesareans. Articles with a longitudinal and transversal methodological approach are presented, using structural equation analysis and propensity score, together with multivariate regressions, which gave a robust analytical treatment to articles in this thematic issue.
Antivirals against human polyomaviruses: Leaving no stone unturned

Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%–90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus‐associated nephropathy (PyVAN), polyomavirus‐associated haemorrhagic cystitis (PyVHC), polyomavirus‐associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus‐specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus‐specific immunity. However, the small dsDNA genome of only 5 kb of the non‐enveloped HPyVs only encodes 5–7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus‐encoded antiviral targets. Lack of cost‐effective high‐throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.
Successful defibrillation using double sequence defibrillation

Abstract Introduction: Defibrillation is effective and the most common treatment for ventricular fibrillation (VF) and pulseless ventricular tachycardia in patients with cardiac arrest. Patient concerns: Recently we experienced 3 cases refractory ventricular fibrillation (RVF) which was successfully terminated with double sequence defibrillation (DSD) in our emergency department, so we’d like to report and discuss it. Diagnosis: Cardiac arrest Interventions: A single defibrillation 200J was performed twice for patients with ventricular fibrillation in the initial rhythm of the emergency room. At the same time, intubation and intravenous access were achieved and epinephrine and amiodarone were administered. The 400J DSD was performed on RVF patients with sustained VFs, despite several trials of 150-200J defibrillation and adherence to advanced cardiac life support. Outcomes: All three RVF patients recovered spontaneous circulation after DSD. Conclusion: The three cases we have shown are small, but DSD improves the chance of spontaneous circulation. Therefore it is suggested that attempts of DSD to patients with RVF, especially in the prehospital stages as a way to improve the return of spontaneous circulation.
Effects of full-time v. part-time grazing on seasonal changes in milk coagulation properties and fatty acid composition

Abstract For this research communication our objective was to investigate to what extent milk coagulation properties and milk fatty acid (FA) composition were affected by different feeding systems, season and their interaction. Eighteen cows in total were subjected to one of three different feeding system treatments: full-time grazing or part-time grazing combined with indoor feeding of fresh grass with low or high concentrate supplementation. Milk was sampled in spring, summer and autumn. Milk coagulation time was 15.0, 19.0 and 17.7 min, coagulation dynamics 1.67, 3.41 and 1.79 min, and curd firmness 52.7, 32.4 and 47.0 mm in spring, summer and autumn, respectively. Thus, milk coagulation properties of the milk were lower during summer. There were strong seasonal effects on milk FA proportions, but there were not always changes with progressing season, or changes were different with respect to the impact of the feeding systems (system × season interaction). The milk fat was favourably rich in oleic acid, conjugated linoleic acid and α-linolenic acid and had a low n-6/n-3 fatty acid ratio in all systems. Factors like seasonal variations in grass composition and the energy balance of the cows were considered relevant for the milk FA composition. Overall, seasonal variations in milk quality were less pronounced with part-time grazing with fresh grass indoors as compared to full-time grazing without concentrate.
Mitochondrion-Dependent Apoptosis Is Essential for Rickettsia parkeri Infection and Replication in Vector Cells

Rickettsioses, infections caused by the genus Rickettsia, are among the oldest known infectious diseases. Ticks are essential arthropod vectors for rickettsiae, and knowledge about the interactions between ticks, their hosts, and pathogens is fundamental for identifying drivers of tick-borne rickettsioses. ABSTRACT Apoptosis is an innate immune response induced by infection in eukaryotes that contributes significantly to protection from pathogens. However, little is known about the role of apoptosis in the interactions of arthropod vectors with the rickettsiae that they transmit. Rickettsia spp. are vector-borne obligately intracellular bacteria and display different degrees of virulence in their eukaryotic hosts. In this study, we found that infection with Rickettsia parkeri (Rp) activated the apoptosis pathway in an Amblyomma americanum tick cell line (AAE2), as evidenced by the loss of phospholipid membrane asymmetry and DNA fragmentations. Additionally, infection with Rp also led to apoptosis activation in cell lines of different tick species. Interestingly, suppressing apoptosis decreased Rp infection and replication, while the activation of apoptosis increased Rp accumulation at the early stage of infection. Moreover, mitochondrion-dependent apoptosis was essential for Rp infection and replication in vector cells, and apoptosis induction required intracellular rickettsia replication. We further showed that Rp utilizes two different survival strategies to modulate apoptosis in the arthropod vectors and mammalian host cells. There was no direct correlation between apoptosis activation in vector cells and rickettsial pathogenicity. These novel findings indicate a possible mechanism whereby apoptosis facilitates infection and replication of a Rickettsia sp. in an arthropod vector. These results contribute to our understanding of how the vector's responses to pathogen infection affect pathogen replication and therefore transmission. IMPORTANCE Rickettsioses, infections caused by the genus Rickettsia, are among the oldest known infectious diseases. Ticks are essential arthropod vectors for rickettsiae, and knowledge about the interactions between ticks, their hosts, and pathogens is fundamental for identifying drivers of tick-borne rickettsioses. Despite the rapid development in apoptosis research with rickettsiae, little is known regarding the role of apoptosis in the interactions between Rickettsia spp. , vertebrate hosts, and arthropod vectors. Here, we demonstrated that mitochondrion-dependent apoptosis is essential for rickettsial infection and replication in vector cells and that apoptosis induction requires intracellular rickettsial replication. However, rickettsial pathogenicity is not linked with apoptosis activation in tick cells. Our findings improve understanding of the apoptosis mechanism in arthropods exploited by rickettsiae and also the potential to discover specific targets for new vaccines and drugs to prevent or treat rickettsial infections.
Nuclear tRNA export in trypanosomes: a journey full of twists and turns guided by tRNA modifications

Abstract Abstract Transfer RNAs play a key role in protein synthesis. Following transcription, tRNAs are extensively processed prior to their departure from the nucleus to become fully functional during translation. This includes removal of 5′ leaders and 3′ trailers by a specific endo- and/or exonuclease, 3′ CCA tail addition, posttranscriptional modifications and in some cases intron removal. In this minireview, the critical factors of nuclear tRNA trafficking are described based on studies in classical models such as yeast and human cell lines. In addition, recent findings and identification of novel regulatory loops of nuclear tRNA trafficking in trypanosomes are discussed with emphasis on tRNA modifications. The comparison between the representatives of opisthokonts and excavates serves here to understand the evolutionary conservation and diversity of nuclear tRNA export mechanisms.
Correlation between the sulfamethoxazole-trimethoprim resistance of Shigella flexneri and the sul genes

Abstract The aim of this study was to discuss the correlation between the sulfamethoxazole-trimethoprim resistance of Shigella flexneri (S. flexneri) and the antibiotic resistance genes sul1, sul2, and sul3 and SXT element. From May 2013 to October 2018, 102 isolates of S. flexneri were collected from the clinical samples in Jinan. The Kirby–Bauer (K-B) test was employed to determine the antibiotic susceptibility of the S. flexneri isolates. The antibiotic resistance rate was analyzed with the WHONET5.4 software. The isolates were subject to the PCR amplification of the sul genes (sul1, sul2, and sul3) and the SXT element. On the basis of the sequencing results, the correlation between the sulfamethoxazole-trimethoprim resistance of the S. flexneri isolates and the sul genes was analyzed. The antibiotic resistance rates of the 102 S. flexneri isolates to ampicillin, streptomycin, chloramphenicol, tetracycline, and sulfamethoxazole-trimethoprim were 90.2%, 90.2%, 88.2%, 88.2%, and 62.7%, respectively. The antibiotic resistance rates of these isolates to cefotaxime, ceftazidime, and ciprofloxacin varied between 20% and 35%. However, these isolates were 100% susceptible to cefoxitin. Positive fragments were amplified from 59.8% (61/102) of the 102 S. flexneri isolates, the sizes of the sul1 and sul2 genes being 338 bp and 286 bp, respectively. The sequence alignment revealed the presence of the sul1 and sul2 genes encoding for dihydrofolate synthase. The carrying rate of the sul1 gene was 13.7% (14/102), and that of the sul2 gene was 48.0% (49/102). No target gene fragments were amplified from the 3 isolates resistant to sulfamethoxazole-trimethoprim. The sul3 gene and SXT element were not amplified from any of the isolates. The testing and statistical analysis showed that the resistance of the S. flexneri isolates to sulfamethoxazole-trimethoprim correlated to the sul1 and sul2 genes. The acquired antibiotic resistance genes sul1 and sul2 were closely associated with the resistance of the 102 S. flexneri isolates to sulfamethoxazole-trimethoprim.
Surface proteomics reveals CD72 as a target for in vitro-evolved nanobody-based CAR-T cells in KMT2A/MLL1-rearranged B-ALL.

Alternate strategies are needed for B-cell malignancy patients relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-ALL, which we further found to be expressed in other B-cell malignancies. Using a recently-described, fully-in vitro system we selected synthetic CD72-specific nanobodies, incorporated them into CARs, and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of CD72's role in inhibiting B-cell receptor signaling, we found that pharmacologic SHIP1 inhibition increased CD72 surface density. We establish CD72-nanobody CAR T's as a promising therapy for MLLr B-ALL.
Novel regio- and stereoselective modifications of heparin in alkaline solution. Nuclear magnetic resonance spectroscopic evidence

Nuclear magnetic resonance spectroscopic evidence is presented in characterizing three new structurally modified forms of heparin. One of these, polymer M-I, represents a conversion of about two-thirds of the α-L-iduronic acid 2-sulfate residues (1) into residues of a 2,3-anhydro derivative (3), through the action of sodium hydroxide. The formation of 3 is attributed to a base-catalysed displacement of the sulfate group of 1 by an intramolecular attack of O-3 on C-2. In more concentrated sodium hydroxide solution, heparin is transformed almost quantitatively into polymer M-II, which differs from it in having residues of (non-sulfated) α-L-iduronic acid (4) in place of 1. It is likely that 3 is an intermediate, and that a selective nucleophilic attack of hydroxide ion at C-2 accounts for the ido configuration in 4. The third modification, giving polymer M-III, is induced when a neutral or weakly alkaline solution of M-I is heated at 70 °C or above, which promotes a different stereochemistry in the hydrolys.