Miracle-dz/UniFAR-FTUs huggingface dataset:
Extending the shikimate pathway for microbial production of maleate from glycerol in engineered Escherichia coli

Maleate is one of the most important unsaturated four‐carbon dicarboxylic acids. It serves as an attractive building block in cosmetic, polymer, and pharmaceutical industries. Currently, industrial production of maleate relies mainly on chemical synthesis using benzene or butane as the starting materials under high temperature, which suffers from strict reaction conditions and low product yield. Here, we propose a novel biosynthetic pathway for maleate production in engineered Escherichia coli. We screened a superior salicylate 5‐hydroxylase that can catalyze hydroxylation of salicylate into gentisate with high conversion rate. Then, introduction of salicylate biosynthetic pathway and gentisate ring cleavage pathway allowed the synthesis of maleate from glycerol. Further optimizations including enhancement of precursors supply, disruption of competing pathways, and construction of a pyruvate recycling system, boosted maleate titer to 2.4 ± 0.1 g/L in shake flask experiments. Subsequent scale‐up biosynthesis of maleate in a 3‐L bioreactor under fed‐batch culture conditions enabled the production of 14.5 g/L of maleate, indicating a 268‐fold improvement compared with the titer generated by the wildtype E. coli strain carrying the entire maleate biosynthetic pathway. This study provided a promising microbial platform for industrial level synthesis of maleate, and demonstrated the highest titer of maleate production in microorganisms so far.
Wearable Sensors for Assessing the Role of Olfactory Training on the Autonomic Response to Olfactory Stimulation

Wearable sensors are nowadays largely employed to assess physiological signals derived from the human body without representing a burden in terms of obtrusiveness. One of the most intriguing fields of application for such systems include the assessment of physiological responses to sensory stimuli. In this specific regard, it is not yet known which are the main psychophysiological drivers of olfactory-related pleasantness, as the current literature has demonstrated the relationship between odor familiarity and odor valence, but has not clarified the consequentiality between the two domains. Here, we enrolled a group of university students to whom olfactory training lasting 3 months was administered. Thanks to the analysis of electrocardiogram (ECG) and galvanic skin response (GSR) signals at the beginning and at the end of the training period, we observed different autonomic responses, with higher parasympathetically-mediated response at the end of the period with respect to the first evaluation. This possibly suggests that an increased familiarity to the proposed stimuli would lead to a higher tendency towards relaxation. Such results could suggest potential applications to other domains, including personalized treatments based on odors and foods in neuropsychiatric and eating disorders.
MCM7 as a marker of postsurgical progression in non-functioning pituitary adenomas.

OBJECTIVE Current markers predicting tumour progression of pituitary adenomas after surgery are insufficient. Our objective was to investigate if minichromosome maintenance protein 7 (MCM7) expression predicts tumour progression in non-functioning pituitary adenomas (NFPAs). METHODS In a cohort study of surgically treated NFPAs, two groups with distinctly different behaviour of a residual tumour were selected: one group requiring reintervention due to tumour progression (reintervention group, n=57) and one with residual tumours without progression (radiologically stable group, n=40). MCM7, Ki-67, estrogen receptor-⍺ expression, mitotic index and tumour subtype was assessed by immunohistochemistry and their association with tumour progression requiring reintervention was analysed. RESULTS Median (IQR) MCM7 expression was 7.4% (2.4-15.2) in the reintervention group compared with 2.0% (0.6-5.3) in the radiologically stable group (P<0.0001). Cox regression analysis showed an association between high (>13%) MCM7 expression and reintervention (HR 3.1; 95%CI:1.7-5.4; P=0.00012). The probability for reintervention within 6 years for patients with high MCM7 was 93%. Ki-67 expression >3% (P=0.00062), age ≤55 years (P=0.00034) and mitotic index ≥1 (P=0.024) were also associated with reintervention. Using a receiver operating characteristics curve, a predictive model for reintervention with all the above predictors yielded an area under the curve of 82%. All eight patients with both high MCM7 and high Ki-67 needed reintervention. CONCLUSION This cohort study shows that expression of MCM7 is a predictor for clinically significant postoperative tumour progression. Together with age, Ki-67 and mitotic index, MCM7 might be of added value as a predictive marker when managing patients with NFPA after surgery.
Smartphone-Detected Ambient Speech and Self-Reported Measures of Anxiety and Depression: Exploratory Observational Study

Background The ability to objectively measure the severity of depression and anxiety disorders in a passive manner could have a profound impact on the way in which these disorders are diagnosed, assessed, and treated. Existing studies have demonstrated links between both depression and anxiety and the linguistic properties of words that people use to communicate. Smartphones offer the ability to passively and continuously detect spoken words to monitor and analyze the linguistic properties of speech produced by the speaker and other sources of ambient speech in their environment. The linguistic properties of automatically detected and recognized speech may be used to build objective severity measures of depression and anxiety. Objective The aim of this study was to determine if the linguistic properties of words passively detected from environmental audio recorded using a participant’s smartphone can be used to find correlates of symptom severity of social anxiety disorder, generalized anxiety disorder, depression, and general impairment. Methods An Android app was designed to collect periodic audiorecordings of participants’ environments and to detect English words using automatic speech recognition. Participants were recruited into a 2-week observational study. The app was installed on the participants’ personal smartphones to record and analyze audio. The participants also completed self-report severity measures of social anxiety disorder, generalized anxiety disorder, depression, and functional impairment. Words detected from audiorecordings were categorized, and correlations were measured between words counts in each category and the 4 self-report measures to determine if any categories could serve as correlates of social anxiety disorder, generalized anxiety disorder, depression, or general impairment. Results The participants were 112 adults who resided in Canada from a nonclinical population; 86 participants yielded sufficient data for analysis. Correlations between word counts in 67 word categories and each of the 4 self-report measures revealed a strong relationship between the usage rates of death-related words and depressive symptoms (r=0.41, P<.001). There were also interesting correlations between rates of word usage in the categories of reward-related words with depression (r=–0.22, P=.04) and generalized anxiety (r=–0.29, P=.007), and vision-related words with social anxiety (r=0.31, P=.003). Conclusions In this study, words automatically recognized from environmental audio were shown to contain a number of potential associations with severity of depression and anxiety. This work suggests that sparsely sampled audio could provide relevant insight into individuals’ mental health.
Cognitive mechanisms of methylphenidate in ADHD: Do improvements in sustained attention mediate behavioral improvements in the natural environment?

ABSTRACT The relation between sustained attention in the laboratory and behaviors exhibited in naturalistic settings among children with Attention Deficit/Hyperactivity Disorder (ADHD) remains unclear. Additionally, research on stimulant medication effects in these areas and their association with one another remains scarce. Twenty-one children with ADHD and 21 children without ADHD completed a novel continuous performance test (CPT) involving high cognitive demands (e.g., visual search). Participants with ADHD also attended a Summer Treatment Program and received three doses of stimulant medication (placebo, low, and high). Their behavior in classroom and peer settings was observed and recorded, and they completed the CPT in each medication condition. The CPT measures of bias and sensitivity were used in analyses. Results indicated that children with ADHD had impaired overall performance and worse bias during the second half of the task compared to controls. Methylphenidate improved both naturalistic behavior and overall CPT performance but did not specifically improve the sustained attention deficit. Despite improvements in overall CPT performance, medication-related improvement in CPT performance did not mediate medication-related improvement in observed behavior in classroom or recreational settings. As such, our findings suggest that although children with ADHD do demonstrate a sustained attention deficit, salutary psychostimulant effects on CPT performance are not indicative of, or causally linked to, psychostimulant effects on presenting problems in naturalistic settings.
Effects of CREG1 on Age-Associated Metabolic Phenotypes and Renal Senescence in Mice

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.
Interaction of Ulva and Navicula Marine Algae with Surfaces of Pyridinium Polymers with Fluorinated Side-Chains

Adhesion is achieved by the secretion of a hydrophilic glycoprotein that crosslinks rapidly after release from the spore. 4 The goal of the work reported here was to investigate whether 4-vinylpyridinium polymers that formed bactericidal surfaces could also function as marine antifouling surfaces. Polystyrene-block-poly(4- vinylpyridine) (PS/P4VP) was quaternized with alkyl and fluoroalkyl bromides, and surface-activity against Ulva and Navicula was studied. The number of Ulva zoospores and Navicula cells settling and attaching to the these surfaces was determined and compared to hydrophobic poly(dimethyl siloxane) and hydrophilic glass controls. A block copolymer with fluoroalkyl side chains, but without the positive charge of the 4-vinylpyridinium polymers was also studied. The adhesion strengths of algal cells were characterized by the degree of removal under water shear stress in a turbulent flow channel.
The Future of Regenerative Medicine: Cell Therapy Using Pluripotent Stem Cells and Acellular Therapies Based on Extracellular Vesicles

The rapid progress in the field of stem cell research has laid strong foundations for their use in regenerative medicine applications of injured or diseased tissues. Growing evidences indicate that some observed therapeutic outcomes of stem cell-based therapy are due to paracrine effects rather than long-term engraftment and survival of transplanted cells. Given their ability to cross biological barriers and mediate intercellular information transfer of bioactive molecules, extracellular vesicles are being explored as potential cell-free therapeutic agents. In this review, we first discuss the state of the art of regenerative medicine and its current limitations and challenges, with particular attention on pluripotent stem cell-derived products to repair organs like the eye, heart, skeletal muscle and skin. We then focus on emerging beneficial roles of extracellular vesicles to alleviate these pathological conditions and address hurdles and operational issues of this acellular strategy. Finally, we discuss future directions and examine how careful integration of different approaches presented in this review could help to potentiate therapeutic results in preclinical models and their good manufacturing practice (GMP) implementation for future clinical trials.
Genomic Characterisation of a Novel Avipoxvirus Isolated from an Endangered Yellow-Eyed Penguin (Megadyptes antipodes)

Emerging viral diseases have become a significant concern due to their potential consequences for animal and environmental health. Over the past few decades, it has become clear that viruses emerging in wildlife may pose a major threat to vulnerable or endangered species. Diphtheritic stomatitis, likely to be caused by an avipoxvirus, has been recognised as a significant cause of mortality for the endangered yellow-eyed penguin (Megadyptes antipodes) in New Zealand. However, the avipoxvirus that infects yellow-eyed penguins has remained uncharacterised. Here, we report the complete genome of a novel avipoxvirus, penguinpox virus 2 (PEPV2), which was derived from a virus isolate obtained from a skin lesion of a yellow-eyed penguin. The PEPV2 genome is 349.8 kbp in length and contains 327 predicted genes; five of these genes were found to be unique, while a further two genes were absent compared to shearwaterpox virus 2 (SWPV2). In comparison with penguinpox virus (PEPV) isolated from an African penguin, there was a lack of conservation within the central region of the genome. Subsequent phylogenetic analyses of the PEPV2 genome positioned it within a distinct subclade comprising the recently isolated avipoxvirus genome sequences from shearwater, canary, and magpie bird species, and demonstrated a high degree of sequence similarity with SWPV2 (96.27%). This is the first reported genome sequence of PEPV2 from a yellow-eyed penguin and will help to track the evolution of avipoxvirus infections in this rare and endangered species.
Ex vivo potential of a quinoline-derivative nail lacquer as a new alternative for dermatophytic onychomycosis treatment.

Introduction. Onychomycosis infections currently show a significant increase, affecting about 10 % of the world population. Trichophyton rubrum is the main agent responsible for about 80 % of the reported infections. The clinical cure for onychomycosis is extremely difficult and effective new antifungal therapy is needed.Hypothesis/Gap Statement. Ex vivo onychomycosis models using porcine hooves can be an excellent alternative for evaluating the efficacy of new anti-dermatophytic agents in a nail lacquer.Aim. Evaluation of the effectiveness of a nail lacquer containing a quinoline derivative on an ex vivo onychomycosis model using porcine hooves, as well as the proposal of a plausible antifungal mechanism of this derivative against dermatophytic strains.Methodology. The action mechanism of a quinoline derivative was evaluated through the sorbitol protection assay, exogenous ergosterol binding, and the determination of the dose-response curves by time-kill assay. Scanning electron microscopy evaluated the effect of the derivative in the fungal cells. The efficacy of a quinoline-derivative nail lacquer on an ex vivo onychomycosis model using porcine hooves was evaluated as well.Results. The quinoline derivative showed a time-dependent fungicidal effect, demonstrating reduction and damage in the morphology of dermatophytic hyphae. In addition, the ex vivo onychomycosis model was effective in the establishment of infection by T. rubrum.Conclusion. Treatment with the quinoline-derivative lacquer showed a significant inhibitory effect on T. rubrum strain in this infection model. Finally, the compound presents high potential for application in a formulation such as nail lacquer as a possible treatment for dermatophytic onychomycosis.
Epidemiology and Characterization of CTX-M-55-Type Extended-Spectrum β-Lactamase-Producing Salmonella enterica Serovar Enteritidis Isolated from Patients in Shanghai, China

The emergence of extended-spectrum β-lactamase-producing Salmonella enterica serovar Enteritidis (ESBL-SE) in humans and foods has gained global attention. In particular, CTX-M-type ESBL-SE are increasingly being detected from various sample types. The aim of this study was to comprehensively analyze the epidemiology and characteristics of blaCTX-M-55-carrying ESBL-SE isolates of clinical origin in Shanghai, China. A total of 292 S. Enteritidis isolates were recovered from the feces and blood of outpatients and inpatients between 2006 and 2014. Overall, there was a high frequency of cefotaxime-resistant isolates (97.3%), which was significantly higher (p < 0.01) than that of isolates resistant to the other tested antibiotics. All S. Enteritidis isolates exhibited resistance to ≥1 antibiotic, and 98.0% were multidrug resistant. A total of 233 isolates were identified as ESBL-SE, 166 of which were CTX-M type. Six subtypes of CTX-M-encoding genes were detected, among which blaCTX-M-55 (91.6%, 152/166) was the most prevalent genotype. There was high genetic similarity among blaCTX-M-55-positive ESBL-SE. The blaCTX-M-55 gene in the ESBL-SE donor strains could be easily transferred into Enterobacteriaceae recipient strains. This study highlights that CTX-M-55 should be considered an important surveillance target in Shanghai, China. Cephalosporins, especially cefotaxime, must be used with caution in empirical treatment for Salmonella infections.
Relationship between lamellar sensory corpuscles distributed along the upper arm’s deep arteries and pulsating sensation of blood vessels

Vibration is detected by mechanoreceptors, including Pacinian corpuscles (PCs), which are widely distributed in the human body including the adventitia of large blood vessels. Although the distribution of PCs around large limb vessels has been previously reported, there remains no consensus on their distribution in the adventitia of the human deep blood vessels in the upper arm. In addition, the physiological functions of PCs located around the deep limb blood vessels remain largely unknown. This study aimed to elucidate detailed anatomical features and physiological function of lamellar sensory corpuscles structurally identified as PCs using the immunohistochemical methods around the deep vessels in the upper arm. We identified PCs in the connective tissue adjacent to the deep vessels in the upper arm using histological analysis and confirmed that PCs are located in the vascular sheath of the artery and its accompanying vein as well as in the connective tissue surrounding the vascular sheath and nerves. PCs were densely distributed on the distal side of deep vessels near the elbow. We also examined the relationship between vascular sound and pulsating sensation to evaluate the PCs functions around deep arteries and veins and found that the vascular sound made by pressing the brachial arteries in the upper arm was associated with the pulsating sensation of the examinee. Our results suggest that PCs, around deep vessels, function as bathyesthesia sensors by detecting vibration from blood vessels.
Relationship Between Remnant Pancreatic Volume and Endocrine Function After Pancreaticoduodenectomy

Background Decreased pancreatic volume (PV) is a predictive factor for diabetes mellitus (DM) after surgery. There are few reports on PV and endocrine function pre- and post-surgery. We investigated the correlation between PV and insulin secretion. Methods Seventeen patients underwent pancreaticoduodenectomy (PD) Pre- and post-surgery PV and C-peptide index (CPI) measurements were performed. Additionally, the correlation between PV and CPI was analyzed. Results The mean preoperative PV (PPV) was 55.1 ± 31.6 mL, postoperative remnant PV (RPV) was 25.3±17.3 mL, and PV reduction was 53%. The mean preoperative C-peptide immunoreactivity (CPR) was 1.39 ± . 51 and postoperative CPR was . 85±. 51. The mean preoperative CPI was 1.29±. 72 and postoperative CPI was . 73 ± . 48. Significant correlations were observed between RPV and post CPR (ρ = .507, P = .03) and post CPI (ρ = .619, P = .008). Discussion There was a significant correlation between RPV and CPI after PD. A smaller RPV resulted in lower insulin secretion ability, increasing the potential risk of new-onset DM after PD.
Urinary leucine aminopeptidase 3 in population environmentally exposed to airborne arsenic

Introduction: Environmental arsenic contamination is a major toxicological problem worldwide due to its carcinogenic and nephrotoxic potential. Aim: The purpose of this observational study was to determine the suspected association between urinary arsenic (uAs) and urinary leucine (or leucyl) aminopeptidase 3 (uLAP3) to evaluate uLAP3 as a candidate biomarker of exposure to airborne arsenic. Materials and Methods: A total of 918 adults occupationally and/or environmentally exposed to airborne arsenic were enrolled in the study. Baseline information (age; sex; history of smoking; alcohol, fish and seafood consumption) was gathered. Total uAs concentrations [μg/L] of 918 subjects, as well as the sum of arsenic species (ΣiAs) in 259 subjects, were obtained. Urinary LAP3 was measured by an immune-enzymatic assay using an ELISA kit. Urinary creatinine concentration was assessed with the IB/lAB/1289 research protocol (version II, 2015-09-17). The values of uAs and uLAP3 were recalculated per unit of creatinine. The association between uAs and uLAP3 was assessed using a logistic regression model adjusted for confounders. Results: The study identified a positive correlation between the logarithm of uAs and the logarithm of uLAP3 in the study population (r = 0.1737, p < 0.0000) and between urinary creatinine and uLAP3 concentration not adjusted for creatinine level (r = 0.1871, p < 0.001). In the logistic regression model, there was also an association between increased (≥15 µg/L) uAs and decreased (below the 25th quartile) uLAP3 [OR uLAP3 = 1.22 (95% CI 1.03 to 1.44, p < 0.02)]. Conclusions: These data suggest that urinary LAP3 may be a potential biomarker of arsenic exposure, which warrants further study.