Miracle-dz/UniFAR-FTUs huggingface dataset:
Biotechnological production optimization of argyrins – a potent immunomodulatory natural product class

Argyrins represent a family of cyclic octapeptides exhibiting promising immunomodulatory activity via inhibiting mitochondrial protein synthesis, which leads to reduced IL‐17 production by the T‐helper 17 cells. Argyrins are formed by a non‐ribosomal peptide synthetase (NRPS), originating from the myxobacterial producer strains Archangium gephyra Ar8082 and Cystobacter sp. SBCb004. In this work, a previously established heterologous production platform was employed to provide evidence of direct D‐configured amino acid incorporation by the argyrin assembly line. An adenylation domain of the argyrin NRPS was characterized and shown to have a high preference for D‐configured amino acids. Eight novel argyrin derivatives were generated via biosynthetic engineering of the heterologous production system. The system was also optimized to enable formation of methylated argyrin C and D derivatives with improved immunosuppressive activity compared with their unmethylated counterparts. Furthermore, the optimization of cultivation conditions allowed exclusive production of one major derivative at a time, drastically improving the purification process. Importantly, engineering of transcription and translation initiation resulted in a substantially improved production titre reaching 350–400 mg l−1. The optimized system presented herein thus provides a versatile platform for production of this promising class of immunosuppressants at a scale that should provide sufficient supply for upcoming pre‐clinical development.
Obesity as a predictor of treatment‐related toxicity in children with acute lymphoblastic leukaemia

Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment‐related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2·0–17·9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non‐high‐risk protocol. Prospective treatment‐related toxicities registered every three‐month interval were used. Patients were classified according to sex‐ and age‐adjusted international childhood cut‐off values, corresponding to adult body mass index: underweight, <17 kg/m2; healthy weight, 17 to <25 kg/m2; overweight, 25 to <30 kg/m2; and obese, ≥30 kg/m2. Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1·55 [95% confidence interval (CI) 1·07–2·50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy‐weight children. Obese children aged ≥10 years had increased IRRs for asparaginase‐related toxicities compared with healthy‐weight older children: thromboses [IRR 2·87 (95% CI 1·00–8·21)] and anaphylactic reactions [IRR 7·95 (95% CI 2·15–29·37)] as well as higher risk for truncation of asparaginase [IRR 3·54 (95% CI 1·67–7·50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged ≥10 years with ALL.
Pitfalls in EEG Analysis in Patients With Nonconvulsive Status Epilepticus: A Preliminary Study

Objective: Electroencephalography (EEG) interpretations through visual (by human raters) and automated (by computer technology) analysis were still not reliable for the diagnosis of nonconvulsive status epilepticus (NCSE). This study aimed to identify typical pitfalls in the EEG analysis and make suggestions as to how those pitfalls might be avoided. Methods: We analyzed the EEG recordings of individuals who had clinically confirmed or suspected NCSE. Epileptiform EEG activity during seizures (ictal discharges) was visually analyzed by 2 independent raters. We investigated whether unreliable EEG visual interpretations quantified by low interrater agreement can be predicted by the characteristics of ictal discharges and individuals’ clinical data. In addition, the EEG recordings were automatically analyzed by in-house algorithms. To further explore the causes of unreliable EEG interpretations, 2 epileptologists analyzed EEG patterns most likely misinterpreted as ictal discharges based on the differences between the EEG interpretations through the visual and automated analysis. Results: Short ictal discharges with a gradual onset (developing over 3 s in length) were liable to be misinterpreted. An extra 2 min of ictal discharges contributed to an increase in the kappa statistics of >0.1. Other problems were the misinterpretation of abnormal background activity (slow-wave activities, other abnormal brain activity, and the ictal-like movement artifacts), continuous interictal discharges, and continuous short ictal discharges. Conclusion: A longer duration criterion for NCSE-EEGs than 10 s that is commonly used in NCSE working criteria is recommended. Using knowledge of historical EEGs, individualized algorithms, and context-dependent alarm thresholds may also avoid the pitfalls.
Vaginal cancer treated with curative radiotherapy with or without concomitant chemotherapy: oncologic outcomes and prognostic factors

Background: Vaginal cancer is a rare disease for which prospective randomized trials do not exist. We aimed to assess survival outcomes, patterns of recurrence, prognostic factors, and toxicity in the curative treatment using image-guided radiotherapy (RT). Methods: In this retrospective review, we identified 53 patients who were treated at a single center with external beam radiotherapy and brachytherapy with or without concomitant chemotherapy from 2000 to 2021. Results: With a median follow-up of 64.5 months, the Kaplan-Meier 2-, 5-, and 7-year overall survival (OS) was found to be 74.8%, 62.8%, and 58.9%, respectively. Local and distant control were 67.8%, 65.0%, and 65.0% and 74.4%, 62.6%, and 62.6% at 2, 5, and 7 years, respectively. In univariate Cox proportional hazards ratio analysis, OS was significantly correlated to FIGO stage (hazard ratio [HR] 1.78, p = 0.042), postoperative RT (HR 0.41, p = 0.044), and concomitant chemotherapy (HR 0.31, p = 0.009). Local control rates were superior when an equivalent dose in 2-Gy fractions (EQD2) of ⩾65 Gy was delivered (HR 0.216, p = 0.028) and with the use of concurrent chemotherapy (HR 0.248, p = 0.011). Not surprisingly, local control was inferior for patients with a higher TNM stage (HR 3.303, p = 0.027). Minimal toxicity was observed with no patients having documentation of high-grade toxicity (CTCAE grade 3+). Conclusion: In treatment of vaginal cancer, high-dose RT in combination with brachytherapy is well tolerated and results in effective local control rates, which significantly improve with an EQD2(α/β=10) ⩾65 Gy. Multivariate analyses revealed concomitant chemotherapy was a positive prognostic factor for overall and progression-free survival.
Cyclohexyl-griselimycin Is Active against Mycobacterium abscessus in Mice

Cyclohexyl-griselimycin is a preclinical candidate for use against tuberculosis (TB). Here, we show that this oral cyclodepsipeptide is also active against the intrinsically drug-resistant nontuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. ABSTRACT Cyclohexyl-griselimycin is a preclinical candidate for use against tuberculosis (TB). Here, we show that this oral cyclodepsipeptide is also active against the intrinsically drug-resistant nontuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast-track the discovery of novel antibiotics against M. abscessus.
Activated Carbons Derived from High-Temperature Pyrolysis of Lignocellulosic Biomass

Biomass pyrolysis to produce biofuel and hydrogen yields large amounts of charred byproducts with low commercial value. A study was conducted to evaluate their potential for being converted into higher value activated carbons by a low-cost process. Six chars derived from various lignocellulosic precursors were activated in CO2 at 800 °C to 30–35% weight loss, and their surface area and porosity were characterized by nitrogen adsorption at 77 K. It was found that, in similar activation conditions, the surface area of the activated carbons correlates with the activation energy of the oxidation reaction by CO2, which in turn varies inversely with the carbon yield after thermolysis in nitrogen at 1000 °C. Since lignin is the most thermally-stable component of lignocellulosic biomass, these results demonstrate, indirectly, that robust, lignin-rich vegetal precursors are to be preferred to produce higher quality activated carbons. The chars derived from white pine (pinus strobus) and chestnut oak (quercus prinus) were converted to activated carbons with the highest surface area (900–1100 m2/g) and largest mesopores volume (0.85–1.06 cm3/g). These activated carbons have properties similar to those of commercially-available activated carbons used successfully for removal of pollutants from aqueous solutions.
The effects and the potential mechanism of environmental transformation of metal nanoparticles on their toxicity in organisms

The rapid development of nanotechnology has raised great concern over its effect on environmental health and safety (EHS). Due to their novel physicochemical properties, metal nanoparticles (MNPs) are the most widely adopted engineered nanomaterials that have been utilized in industrial production, environmental governance and commercial products. Although significant progress has been made towards the toxicity assessment of pristine MNPs, knowledge gaps regarding their EHS impacts have yet to be addressed. Transformation of MNPs in the environment can result in toxicity of transformed nanoparticles being different from that of pristine particles. Despite recent investigations into MNP-mediated toxicity, most of them only focused on the toxic effects of pristine nanoparticles, which does not fully elucidate the harmful effects of MNPs under environmental exposure conditions. Therefore, it is crucial to achieve a comprehensive understanding of the transformation-related toxic properties of MNPs. In this review, we briefly presented the main transformation processes in the natural environments followed by summarizing the toxicity of transformed MNPs in organisms and cells compared to that of the pristine forms. Finally, we also hypothesized possible mechanisms through which transformation could affect MNP-induced toxicity under environmental exposure.
Ancestral sequences of a large promiscuous enzyme family correspond to bridges in sequence space in a network representation

Evolutionary relationships of protein families can be characterized either by networks or by trees. Whereas trees allow for hierarchical grouping and reconstruction of the most likely ancestral sequences, networks lack a time axis but allow for thresholds of pairwise sequence identity to be chosen and, therefore, the clustering of family members with presumably more similar functions. Here, we use the large family of arylsulfatases and phosphonate monoester hydrolases to investigate similarities, strengths and weaknesses in tree and network representations. For varying thresholds of pairwise sequence identity, values of betweenness centrality and clustering coefficients were derived for nodes of the reconstructed ancestors to measure the propensity to act as a bridge in a network. Based on these properties, ancestral protein sequences emerge as bridges in protein sequence networks. Interestingly, many ancestral protein sequences appear close to extant sequences. Therefore, reconstructed ancestor sequences might also be interpreted as yet-to-be-identified homologues. The concept of ancestor reconstruction is compared to consensus sequences, too. It was found that hub sequences in a network, e.g. reconstructed ancestral sequences that are connected to many neighbouring sequences, share closer similarity with derived consensus sequences. Therefore, some reconstructed ancestor sequences can also be interpreted as consensus sequences.
Detection and genetic characterization of the novel torque teno virus group 6 in Taiwanese general population

Torque teno virus (TTV) is one of the most common human viruses and can infect an individual with multiple genotypes chronically and persistently. TTV group 6 is a recently discovered phylogenetic group first isolated from eastern Taiwan indigenes, but whether the TTV group 6 was also prevalent in the general population still unknown. One hundred and three randomly collected blood samples from general population and 66 TTV positive DNA samples extracted from Taiwan indigenes were included. A group-6-specific PCR was developed for re-screen over TTV positive samples. Two TTV group 6 positive samples from general population were cloned and sequenced for identifying mix-infected TTVs and confirming their classification by maximum-likelihood and Bayesian inference phylogeny. TTV group 6 can be detected in 4.5% (4/89) and 7.6% (5/66) of TTV positive samples from Taiwanese general population and eastern Taiwan indigenes, respectively. Sample VC09 was mix-infected with TTV groups 3 and 6. Sample VC99 was mix-infected with TTV groups 3, 4 and 6. A highly diverse triple overlapping region was observed, which may represent a unique phenomenon of TTV. The group-6-specific PCR can successfully detect TTV group 6. TTV group 6 may be prevalent worldwide regardless of the geographic region and/or ethnic groups.
Effects of physical impairments on fitness correlates of the white-footed mouse, Peromyscus leucopus

Physical impairments are widely assumed to reduce the viability of individual animals, but their impacts on individuals within natural populations of vertebrates are rarely quantified. By monitoring wild populations of white-footed mice over 26 years, we assessed whether missing or deformed limbs, tail or eyes influenced the survival, body mass, movement and ectoparasite burden of their bearers. Of the 27 244 individuals monitored, 543 (2%) had visible physical impairments. Persistence times (survival) were similar between mice with and without impairments. Mice with eye and tail impairments had 5% and 6% greater mass, respectively, than unimpaired mice. Mice with tail impairments had larger home ranges than did unimpaired mice. Burdens of black-legged ticks (Ixodes scapularis) were higher among mice with tail and limb impairments while burdens of bot fly larvae (Cuterebra) were higher among mice with cataracts compared to mice without impairments. Our findings do not support the presupposition that physical impairments reduce viability in their bearers and are inconsistent with the devaluation of impaired individuals that pervaded early thinking in evolutionary biology.
Depressive symptoms among primary healthcare workers during the novel SARS-CoV-2 coronavirus pandemic in the Muscat governorate

Abstract Background: With the unprecedented spread of the novel SARS-CoV-2 coronavirus, primary healthcare workers (PHCWs) are having to shoulder the increasing weight of this ongoing pandemic. Aims: This study explored the rate and covariates of depressive symptoms among PHCWs in the Muscat governorate. Methods: A cross-sectional online survey was conducted from 10 May to 10 June 2020 among PHCWs working in all primary healthcares across the Muscat governorate. Data on sociodemographic and risk factors of having at least one underlying physical health condition, a psychiatric history, family history of psychiatric disorders, and direct involvement with COVID-19 positive patients were sought. The Patient Health Questionnaire (PHQ-9) was then used to solicit the presence of depressive symptoms. Those with a cutoff point ≥10 were considered as showing depressive symptoms. Logistic regression was used to determine risk factors associated with depressive symptoms in PHCWs after adjusting for all sociodemographic factors. Findings: A total of 432 (72%) out of 600 PHCWs with an average age of 39.2 years (SD = 7.8 years) ranging between 25.0 and 75.0 years responded to the survey. There were more females (n = 281, 65.3%) than males, and more than 45% (n = 195) of them were physicians. Additionally, more than 78% (n = 338) had been in contact with COVID-19 patients. There was a significant association between different age groups and profession (P < .001), having at least one underlying physical health condition (P = 0.001) and depressive symptom status (P = 0.038). A total of 78 out of the 423 subjects (18.1%) were considered to have depressive symptoms. After adjusting for all factors, the logistic regression model showed that an age of 34 years or below (OR = 2.079, P = 0.021) and having at least one underlying physical health condition (OR = 2.216, P = 0.007) were factors contributing significantly to depressive symptoms among the PHCWs.
On the merging and splitting processes in the lobe-and-cleft structure at a gravity current head

Abstract High-resolution simulations are performed for gravity currents propagating on a no-slip boundary to study the merging and splitting processes in the lobe-and-cleft structure at a gravity current head. The simulations reproduce the morphological features observed in the laboratory and provide more detailed flow information to elucidate the merging and splitting processes. Our mean lobe width $\tilde {b}$ and mean maximum lobe width $\tilde {b}_{max}$ satisfy the empirical relationships $\tilde {b}/\tilde {d}=7.4 Re^{-0.39}_f$ and $\tilde {b}_{max}/\tilde {d}=12.6 Re^{-0.38}_f$, respectively, over the front Reynolds number in the range $383 \le Re_f \le 3267$, where the front Reynolds number is defined as $Re_f= \tilde {u}_f \tilde {d} / \tilde {\nu }, \tilde {u}_f$ is the front velocity, $\tilde {d}$ is the height of the gravity current head and $\tilde {\nu }$ is the fluid kinematic viscosity. When measured in terms of the viscous length scale $\tilde {\delta }_\nu = \tilde {\nu }/\tilde {u}^*$, where $\tilde {u}^*$ is the shear velocity at the gravity current head, the mean lobe width and the mean maximum lobe width increase with increasing front Reynolds number and asymptotically approach $126 \tilde {\delta }_\nu$ and $230 \tilde {\delta }_\nu$ at $Re_f=3267$, respectively. The vortical structure inside a lobe has an elongated tooth-like shape and a pair of counter-rotating streamwise vortices are positioned on the left- and right-hand sides of each cleft. For the merging process, it requires the interaction of three tooth-like vortices and the middle tooth-like vortex breaks up and reconnects with the two neighbouring tooth-like vortices. Therefore, a cleft may continually merge with another neighbouring cleft but may never disappear. For the splitting process, even before the new cleft appears, a new born streamwise vortex is created by the parent vortex of opposite orientation and the parent vortex can be either the left part or the right part of the existing tooth-like vortex inside the splitting lobe. The new born streamwise vortex then induces the other counter-rotating streamwise vortex as the new cleft develops. The initiation of the splitting process can be attributed to the Brooke–Hanratty mechanism reinforced by the baroclinic production of vorticity. Depending on the orientation of the parent vortex, the resulting new cleft after the splitting process can shift laterally in the positive or negative spanwise direction along the leading edge of the gravity currents as the lobe-and-cleft structure moves forward in the streamwise direction. For gravity currents propagating on a no-slip boundary, the lobe-and-cleft structure is self-sustaining and the manifestations of the merging and splitting processes are in accord with reported laboratory observations.
Immune cell arrival kinetics to peritoneum and role during murine-experimental trichomoniasis

Abstract Trichomonas vaginalis causes trichomoniasis, an inflammatory process related to an increased rate of HIV transmission. In order to study T. vaginalis infection response in a microorganism-free environment, an infection model was established providing a host–parasite interaction system useful to study the interplay between immune cells and the parasite. Infected mice peritoneal cells were immunophenotyped at different times after infection using flow cytometry. Neutrophils and macrophages showed the most relevant increase from third to 12th day post-infection. A high number of B lymphocytes were present on 15th day post-infection, and an increase in memory T cells was observed on sixth day post-infection. The levels of NO increased at day 10 post-infection; no significant influence was observed on T. vaginalis clearance. Increased viability of T. vaginalis was observed when the NETs inhibitors, metformin and Cl− amidine, were administrated, highlighting the importance of this mechanism to control parasite infection (43 and 86%, respectively). This report presents a comprehensive cell count of the immune cells participating against trichomoniasis in an in vivo interaction system. These data highlight the relevance of innate mechanisms such as specific population changes of innate immune cells and their impact on the T. vaginalis viability.
The Lancet Regional Health-Europe

a Centre for Primary Care and Health Services Research, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, UK b National Institute for Health Research Academic Clinical Fellow in General Practice (award ref: ACF-2016-06-013) c Newson Health Menopause and Wellbeing Centre, Church Street, Stratford-upon-Avon, UK d NW Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK Warwick Medical School, University of Warwick, Coventry, UK g Institute of Precision Diagnostics and Translational Medicine, University Hospital Coventry and Warwickshire (UHCW), NHS Trust, Coventry, UK
Effects of organic loading rates on microbial communities and biogas production from water hyacinth: a case of mono‐ and co‐digestion

BACKGROUND: Anaerobic digestion is a microbial driven process, which results in biogas production. Although important, the relative abundance of microbial communities can be affected by disturbances such as feeding rates. In this study, the effects of irregular organic loading rates on anaerobic digestion of water hyacinth (mono‐ and co‐digestion) as well as on bacterial and archaeal communities were investigated. The process was conducted at different feeding stages during which the process stability, biogas production, composition and microbial community structure were monitored. RESULTS: Bacterial communities were more influenced by irregular organic loading rates in comparison with archaeal communities. Although microbial community shifts were observed in both mono‐ and co‐digestion, the shift was more prevalent in co‐digestion. Moreover, process stability was evidenced in some stages of mono‐digestion, where the FOS/TAC ratio was within the optimal range. However, for co‐digestion, the low FOS/TAC ratio showed process instability. CONCLUSION: Overall, irregularity in organic loading rates affected the microbial community composition as well as their CH₄ production. © 2018 Society of Chemical Industry