Miracle-dz/UniFAR-FTUs huggingface dataset:
Metabolomics Reveal Potential Natural Substrates of AcrB in Escherichia coli and Salmonella enterica Serovar Typhimurium

Multidrug-resistant Gram-negative bacteria pose a global threat to human health. The AcrB efflux pump confers inherent and evolved drug resistance to Enterobacterales, including Escherichia coli and Salmonella enterica serovar Typhimurium. ABSTRACT In the fight against antibiotic resistance, drugs that target resistance mechanisms in bacteria can be used to restore the therapeutic effectiveness of antibiotics. The multidrug resistance efflux complex AcrAB-TolC is the most clinically relevant efflux pump in Enterobacterales and is a target for drug discovery. Inhibition of the pump protein AcrB allows the intracellular accumulation of a wide variety of antibiotics, effectively restoring their therapeutic potency. To facilitate the development of AcrB efflux inhibitors, it is desirable to discover the native substrates of the pump, as these could be chemically modified to become inhibitors. We analyzed the native substrate profile of AcrB in Escherichia coli MG1655 and Salmonella enterica serovar Typhimurium SL1344 using an untargeted metabolomics approach. We analyzed the endo- and exometabolome of the wild-type strain and their respective AcrB loss-of-function mutants (AcrB D408A) to determine the metabolites that are native substrates of AcrB. Although there is 95% homology between the AcrB proteins of S. Typhimurium and E. coli, we observed mostly different metabolic responses in the exometabolomes of the S. Typhimurium and E. coli AcrB D408A mutants relative to those in the wild type, potentially indicating a differential metabolic adaptation to the same mutation in these two species. Additionally, we uncovered metabolite classes that could be involved in virulence of S. Typhimurium and a potential natural substrate of AcrB common to both species. IMPORTANCE Multidrug-resistant Gram-negative bacteria pose a global threat to human health. The AcrB efflux pump confers inherent and evolved drug resistance to Enterobacterales, including Escherichia coli and Salmonella enterica serovar Typhimurium. We provide insights into the physiological role of AcrB: (i) we observe that loss of AcrB function in two highly related species, E. coli and S. Typhimurium, has different biological effects despite AcrB conferring drug resistance to the same groups of antibiotics in both species, and (ii) we identify potential natural substrates of AcrB, some of which are in metabolite classes implicated in the virulence of S. Typhimurium. Molecules that inhibit multidrug efflux potentiate the activity of old, licensed, and new antibiotics. The additional significance of our research is in providing data about the identity of potential natural substrates of AcrB in both species. Data on these will facilitate the discovery of, and/or could be chemically modified to become, new efflux inhibitors.
Cellular and synaptic mechanisms for Parkinson’s disease-related chronic pain

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. Chronic pain is experienced by the vast majority of patients living with Parkinson’s disease. The degeneration of dopaminergic neuron acts as the essential mechanism of Parkinson’s disease in the midbrain dopaminergic pathway. The impairment of dopaminergic neurons leads to dysfunctions of the nociceptive system. Key cortical areas, such as the anterior cingulate cortex (ACC) and insular cortex (IC) that receive the dopaminergic projections are involved in pain transmission. Dopamine changes synaptic transmission via several pathway, for example the D2-adenly cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway and D1-G protein-coupled receptor kinase 2 (GRK2)-fragile X mental retardation protein (FMRP) pathway. The management of Parkinson’s disease-related pain implicates maintenance of stable level of dopaminergic drugs and analgesics, however a more selective drug targeting at key molecules in Parkinson’s disease-related pain remains to be investigated.
Role of circRNAs in viral infection and their significance for diagnosis and treatment (Review)

Circular RNAs (circRNAs) are a class of non-coding RNAs with a circular, covalent structure that lack both 5' ends and 3' poly(A) tails, which are stable and specific molecules that exist in eukaryotic cells and are highly conserved. The role of circRNAs in viral infections is being increasingly acknowledged, since circRNAs have been discovered to be involved in several viral infections (such as hepatitis B virus infection and human papilloma virus infection) through a range of circRNA/microRNA/mRNA regulatory axes. These findings have prompted investigations into the potential of circRNAs as targets for the diagnosis and treatment of viral infection-related diseases. The aim of the present review was to systematically examine and discuss the role of circRNAs in several common viral infections, as well as their potential as diagnostic markers and therapeutic targets.
Warming induces divergent stomatal dynamics in co‐occurring boreal trees

Climate warming will alter photosynthesis and respiration not only via direct temperature effects on leaf biochemistry but also by increasing atmospheric dryness, thereby reducing stomatal conductance and suppressing photosynthesis. Our knowledge on how climate warming affects these processes is mainly derived from seedlings grown under highly controlled conditions. However, little is known regarding temperature responses of trees growing under field settings. We exposed mature tamarack and black spruce trees growing in a peatland ecosystem to whole‐ecosystem warming of up to +9°C above ambient air temperatures in an ongoing long‐term experiment (SPRUCE: Spruce and Peatland Responses Under Changing Environments). Here, we report the responses of leaf gas exchange after the first two years of warming. We show that the two species exhibit divergent stomatal responses to warming and vapor pressure deficit. Warming of up to 9°C increased leaf N in both spruce and tamarack. However, higher leaf N in the warmer plots translate into higher photosynthesis in tamarack but not in spruce, with photosynthesis being more constrained by stomatal limitations in spruce than in tamarack under warm conditions. Surprisingly, dark respiration did not acclimate to warming in spruce, and thermal acclimation of respiration was only seen in tamarack once changes in leaf N were considered. Our results highlight how warming can lead to differing stomatal responses to warming in co‐occurring species, with consequent effects on both vegetation carbon and water dynamics.
Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report

This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.
The correlation between chili pepper consumption and gastric cancer risk: A meta-analysis.

BACKGROUND AND OBJECTIVES The correlation between chili pepper intake and gastric cancer (GC) risk has been controversial. We conducted a meta-analysis of 16 studies to provide updated evidence for this uncertainty. METHODS AND STUDY DESIGN Medline, and China National Knowledge Infrastructure (CNKI) databases were searched to obtain all qualified literature related to pepper consumption and GC incidence before June 2020. Random effects models were adopted to integrate the relative risk of individual studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literature of each included study. Dose response meta-analysis was implemented through the one-stage robust error meta-regression (REMR) approach. RESULTS 16 studies (8337 cases) were included in quantitative meta-analysis. The pooled odds ratio (OR) of GC for the highest versus the lowest category of chili consumption were 1.51 (95% confidence interval [CI]=1.02-2.00) for all countries, 2.05 (95% CI=1.15-2.95) for Mexican, 2.03 (95% CI =0.71-3.34) for Colombian, 1.92 (95% CI=1.21-2.64) for Asian and 0.48 (95% CI=0.24-0.72) for other countries. Dose-response meta-analysis showed that there was a positive linear correlation between the risk of GC and the daily frequency of chili consumption. CONCLUSIONS Significantly increased consumption of chili pepper or capsaicin has the potential to increase the risk of gastric cancer, however, inconsistencies still exist in subgroup analysis between different regions.
Quantitative Analysis of the Activity in Choroidal Neovascularizations after a Single Anti-VEGF Injection: OCT Versus OCT Angiography

ABSTRACT Purpose To analyze early quantitative changes in the choroidal neovascularization (CNV) area observed with optical coherence tomography angiography (OCTA) after single anti-vascular endothelial growth factor (anti-VEGF) injection. Materials and Methods Treatment-naive patients with CNV secondary to neovascular age-related macular degeneration were analyzed immediately before and ~4 weeks after anti-VEGF injection. The primary endpoints of the study included changes in CNV total and vascular area. Secondary endpoints were best-corrected visual acuity (BCVA), central macular thickness (cMT), central total macular thickness (cTMT), and subfoveal choroidal thickness (SFCT). Results A total of 27 patients (69.19 ± 5.91 years, 21 men/6 women, 14 type 1 NV, 11 type 2 NV, and 2 type 3 NV) were included in the study. There was a significant increase in BCVA and decreases in cMT, cTMT, and SFCT after treatment (p<0.05 for all). CNV total and vascular area changed by −11.55 ± 44.26% (95% confidence interval [CI]: −29.06 and 5.95; p=0.269) and −21.06 ± 41.2% (95% CI: −36.45/−5.67; p=0.786), respectively. The cases with decreased cTMT were accompanied by a decrease in CNV area only in 37% of the cases. No significant correlation was detected between cTMT and CNV total and vascular area percentage changes (r = −0.06, p=0.74; r = 0.02, p=0.9, respectively). Conclusions Changes in CNV total and vascular area seem to have limited sensitivity as a biomarker in terms of activation, as wide variability was observed in CNV area after anti-VEGF injection.
Endocrinological features of a patient with 14q microdeletion and Dubowitz phenotype

Dubowitz syndrome (DS) is a complex and rare condition characterized by postnatal growth retardation, microcephaly, short stature, mild developmental delay, facial dysmorphism, skin eruption and bone marrow failure. Though approximately 200 cases have been described so far, no specific genetic analysis, laboratory tests or radiological exams are available to confirm the diagnosis which is still based on clinical and facial features. Although short stature is a major feature of the syndrome, no endocrine alterations have been reported so far and scant data are available about the efficacy and safety of GH treatment in these patients.
Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Despite the recent launch of tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) is contained in a number of commercially available antifungal agents. CPX is also reported to possess anticancer activity. Several mechanisms of action have been proposed, including chelation of iron and inhibition of iron-dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human PKD cyst-lining epithelial cells cultured in a 3D collagen matrix. To assess the in vivo role of CPX-O, we treated PKD mice with CPX-O. CPX-O reduced the kidney-to-body weight ratios of PKD mice. The CPX-O treatment was also associated with decreased cell proliferation, decreased cystic area, and improved renal function. Ferritin levels were markedly elevated in cystic kidneys of PKD mice, and CPX-O treatment reduced renal ferritin levels. The reduction in ferritin was associated with increased ferritinophagy marker nuclear receptor coactivator 4, which reversed upon CPX-O treatment in PKD mice. Interestingly, these effects on ferritin appeared independent of iron. These data suggest that CPX-O can induce ferritin degradation via ferritinophagy, which is associated with decreased cyst growth progression in PKD mice. Most importantly these data indicate that CPX-O has the potential to treat autosomal dominant PKD.
ER-positive endocervical adenocarcinoma mimicking endometrioid adenocarcinoma in morphology and immunohistochemical profile

Abstract Rationale: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC). Patient concerns: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its “endometrioid” morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive). Diagnoses: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA. Interventions: The patient underwent total hysterectomy with lymph node dissection. Outcomes: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination. Lessons subsections: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases.
Effect of Achilles Tendon Mechanics on the Running Economy of Elite Endurance Athletes

Abstract The Achilles tendon stores and releases strain energy, influencing running economy. The present study aims to verify the influence of the Achilles tendon tangent modulus, as a material property, on running economy by comparing two groups of elite endurance-performance athletes undergoing different running training volumes. Twelve athletes, six long-distance runners and six pentathletes, were studied. Long-distance runners had a higher weekly running training volume (116.7±13.7 vs. 58.3±20.4 km, p<0.05) and a better running economy (204.3±12.0 vs. 222.0±8.7 O2 mL ∙ kg−1 ∙ km−1, p<0.05) evaluated in a treadmill at 16 km·h–1, 1% inclination. Both groups presented similar VO2max (68.5±3.8 vs. 65.7±5.0 mL ∙ min−1 ∙ kg−1, p>0.05). Achilles tendon tangent modulus was estimated from ultrasound-measured deformations, with the ankle passively mobilized by a dynamometer. True stress was calculated from the measured torque. The long-distance runners had a higher maximum tangent modulus (380.6±92.2 vs. 236.2±82.6 MPa, p<0.05) and maximum true stress than pentathletes (24.2±5.1 vs. 16.0±3.5 MPa, p<0.05). The correlation coefficient between tangent modulus at larger deformations was R=–0.7447 (p<0.05). Quantifying tendon tissue adaptations associated with different running training volumes will support subject and modality-specific workouts prescription of elite endurance athletes.
ACUTE AND SUBACUTE TOXICITY STUDIES OF SANSEVIERIA LIBERICA AQUEOUS LEAF EXTRACTS

The toxicological effects of various concentrations of an aqueous extract of Sansevieria liberica on some hepatospecific markers were investigated in Wister strain rats. The extract was prepared by macerations in sterile distilled water and soaking for 48h. A yield of 11.3% w/w dry extract was obtained for the aqueous extractions. Oral administration of aqueous extract of S.liberica at the doses ranging from 50-1000 mg/kg body weight did not produce mortality or any significant change in treated animals over a 14-day period when compared to the control. Acute toxicity test in rats gave an LD 50 of 4570 mg/kg. There were no significant difference (P<0.05) in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activities. Total, conjugated and unconjugated bilirubin levels, albumin, globulin and total protein levels were not altered by the extract in the experimental groups when compared with the control group. The concentrations of plasma creatinine and urea were also significantly not affected. The aqueous extracts of S. liberica showed no effect in rats and therefore no evidence of hepatotoxicity of the extract was established.
Profiling immuno-metabolic mediators of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in Ghana

Background The association between prolong metformin usage and B12 deficiency has been documented. However, the prevalence estimates of metformin-induced vitamin B12 deficiency showed substantial disparity among studies due to varied study definitions of vitamin B12 deficiency. Metformin blocks the calcium dependent absorption of the vitamin B12-Intrinsic Factor complex at the terminal ileum. Lack of intrinsic factor due to the presence of auto-antibodies to parietal cells (IFA) could lead to vitamin B12 deficiency and subsequently cause peripheral neuropathy. We investigated the prevalence of vitamin B12 deficiency using more sensitive, combined markers of vitamin B12 status (4cB12) and the immuno-biochemical mediators of vitamin B12 deficiency. Methods In this observational study, 200 consecutive consenting metformin-treated T2DM patients, aged 35 and above, attending the diabetic clinic at KATH were recruited. Vitamin B12 deficiency was classified based on the Fedosov age-normalized wellness quotient. Anthropometric measurement was taken as well as blood samples for immunological and biochemical mediators. Peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Statistical analysis was performed using the R Language for Statistical Computing. Results Using the combined indicator (4cB12), the prevalence of metformin induced vitamin B12 deficiency was 40.5% whilst the prevalence of MNSI-Q and MNSI-PE diabetic neuropathy was 32.5% and 6.5% respectively. Participants with vitamin B12 deficiency had significantly higher levels of IFA, GPA, TNF-α, TC, LDL and albumin compared to those with normal vitamin B12 levels (p < 0.05). Correlation analysis revealed a statistically significant negative association between 4cB12 and the immunological markers [IFA (rs = -0.301, p<0.0001), GPA (rs = -0.244, p = 0.001), TNF-α (rs = -0.242, p = 0.001) and IL-6 (rs = -0.145, p = 0.041)]. Likewise, 4cB12 was negatively associated with TC (rs = -0.203, p = 0.004) and LDL (rs = -0.222, p = 0.002) but positively correlated with HDL (rs = 0.196, p = 0.005). Conclusion Vitamin B12 deficiency and diabetic neuropathy are very high among metformin-treated T2DM patients and it is associated with increased GPA, IFA, TNF-α and cardiometabolic risk factors (higher LDL and TC and lower HDL). Upon verification of these findings in a prospective case-control study, it may be beneficial to include periodic measurement of Vitamin B12 using the more sensitive combined indicators (4cB 12) in the management of patients with T2DM treated with metformin in Ghana.
Functional Polymorphism of MMP9 and BDNF as Potential Biomarker of Auditory Neuroplasticity in Prelingual Deafness Treatment With Cochlear Implantation—A Retrospective Cohort Analysis

Genetic biomarkers of neuroplasticity in deaf children treated with cochlear implantation (CI) might facilitate their clinical management, especially giving them better chances of developing proficient spoken language. We investigated whether carrying certain variants of the genes encoding matrix metalloproteinase MMP9 and neurotrophin brain-derived neurotrophic factor (BDNF), involved in synaptic plasticity, can be taken as prognostic markers of how well auditory skills might be acquired. Association analysis of functional MMP9 rs3918242 and BDNF rs6265 variants and the child’s auditory development measured at CI activation and 1, 5, 9, 14, and 24 months post CI activation with LittlEARS Questionnaire (LEAQ) was conducted in a group of 100 children diagnosed with DFNB1-related deafness, unilaterally implanted before the age of 2 years. Statistical analysis in the subgroup implanted after 1 year of life (n = 53) showed significant association between MMP9 rs3918242 and LEAQ scores at 1 month (p = .01), at 5 months (p = .01), at 9 months (p = .01), and at 24 months (p = .01) after CI activation. No significant associations in the subgroup implanted before 1 year of life were observed. No significant associations between the BDNF rs6265 and LEAQ score were found. Multiple regression analysis (R2 = .73) in the subgroup implanted after 1 year of life revealed that MMP9 rs3918242 was a significant predictor of treatment outcome. In conclusion, C/C rs3918242 MMP9 predisposes their deaf carriers to better CI outcomes, especially when implanted after the first birthday, than carriers of C/T rs3918242MMP9.