The azithromycin resistance conferred by phosphotransferase is encoded in the gene mph(A). This gene has been discovered in and reported for many bacterial species. We examined the prevalence of azithromycin resistance in Vibrio fluvialis (AR-VF) isolated during 2014 to 2015 from the hospitalized acute diarrheal patients in Kolkata, India. Most of the V. fluvialis isolates are identified as the sole pathogen (54%). The prevalence of AR-VF was higher in 2015 (19 [68%]) than in 2014 (9 [32%]). Among AR-VF isolates, the azithromycin MICs ranged from 4 to >256 mg/liter. Twenty-eight of the 48 (58%) V. fluvialis isolates harbored the gene mph(A) and phenotypically resistant to azithromycin. All the AR-VF isolates remained susceptible to doxycycline. In addition to azithromycin, other antimicrobial resistance-encoding genes of AR-VF were also characterized. All the AR-VF isolates were positive for class 1 integron, and most of them (17/28) carried the dfrA1 gene cassettes. Only one isolate was positive for the ereA gene, which encodes resistance to erythomycin. The majority of the isolates were resistant to β-lactam antibiotics (blaOXA-1 [96%], blaOXA-7 [93%], and blaTEM-9 [68%]) and aminoglycoside actetyltransferase, conferring resistance to ciprofloxacin-modifying enzyme [aac(6')Ib-cr] (96%). Analyses by pulsed-field gel electrophoresis (PFGE) showed that the AR-VF isolates belonged to different genetic lineages. This is the first study to report azithromycin resistance and the presence of the mph(A) gene in V. fluvialis isolates. Circulation of AR-VF isolates with high azithromycin MICs is worrisome, since it may limit the treatment options for diarrheal infections.IMPORTANCE The progressive rise in antibiotic resistance among enteric pathogens in developing countries is becoming a big concern. India is one of the largest consumers of antibiotics, and their use is not well regulated. V. fluvialis is increasingly recognized as an emerging diarrheal pathogen of public health importance. Here we report the emergence of azithromycin resistance in V. fluvialis isolates from diarrheal patients in Kolkata, India. Azithromycin has been widely used in the treatment of various infections, both in children and in adults. Resistance to azithromycin is encoded in the gene mph(A). Emerging azithromycin resistance in V. fluvialis is a major public health challenge, and future studies should be focused on identifying ways to prevent the dissemination of this antibiotic resistance gene.

High myopia (HM) is one of the leading causes of vision impairment worldwide, accompanied by a series of pathological ocular complications. Studies have shown that genetic factors play an important role in the pathogenesis of HM. The aim of our study is to identify a candidate gene for a large family with non-syndromic HM.

A key challenge in neuroscience is understanding how sensory stimuli give rise to perception, especially when the process is supported by neural activity from an extended network of brain areas. Perception is inherently subjective, so interrogating its neural signatures requires, ideally, a combination of three factors: (1) behavioral tasks that separate stimulus-driven activity from perception per se; (2) human subjects who self-report their percepts while performing those tasks; and (3) concurrent neural recordings acquired at high spatial and temporal resolution. In this study, we analyzed human electrocorticographic recordings obtained during an auditory task which supported mutually exclusive perceptual interpretations. Eight neurosurgical patients (5 male; 3 female) listened to sequences of repeated triplets where tones were separated in frequency by several semitones. Subjects reported spontaneous alternations between two auditory perceptual states, 1-stream and 2-stream, by pressing a button. We compared averaged auditory evoked potentials (AEPs) associated with 1-stream and 2-stream percepts and identified significant differences between them in primary and nonprimary auditory cortex, surrounding auditory-related temporoparietal cortex, and frontal areas. We developed classifiers to identify spatial maps of percept-related differences in the AEP, corroborating findings from statistical analysis. We used one-dimensional embedding spaces to perform the group-level analysis. Our data illustrate exemplar high temporal resolution AEP waveforms in auditory core region; explain inconsistencies in perceptual effects within auditory cortex, reported across noninvasive studies of streaming of triplets; show percept-related changes in frontoparietal areas previously highlighted by studies that focused on perceptual transitions; and demonstrate that auditory cortex encodes maintenance of percepts and switches between them.SIGNIFICANCE STATEMENT The human brain has the remarkable ability to discern complex and ambiguous stimuli from the external world by parsing mixed inputs into interpretable segments. However, one's perception can deviate from objective reality. But how do perceptual discrepancies occur? What are their anatomical substrates? To address these questions, we performed intracranial recordings in neurosurgical patients as they reported their perception of sounds associated with two mutually exclusive interpretations. We identified signatures of subjective percepts as distinct from sound-driven brain activity in core and non-core auditory cortex and frontoparietal cortex. These findings were compared with previous studies of auditory bistable perception and suggested that perceptual transitions and maintenance of perceptual states were supported by common neural substrates.

To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health.

Social workers are among the largest group of professionals in the mental health workforce and play a key role in the assessment of mental health, addictions and suicide. Most social workers provide services to individuals with mental health concerns, yet there are gaps in research on social work education and training programmes. The objective of this scoping review is to examine literature on social work education and training in mental health, addictions and suicide.

To assess the effects of an integrated care pathway on the use of primary and secondary healthcare by patients at high risk of emergency inpatient admission.

ER-positive breast tumors represent ∼70% of all breast cancer cases. Although their treatment with endocrine therapies is effective in the adjuvant or recurrent settings, the development of resistance compromises their effectiveness. The binding of estrogen to ERα, a transcription factor, triggers the regulation of the target genes (genomic pathway). Additionally, a cytoplasmic fraction of estrogen-bound ERα activates oncogenic signaling pathways such as PI3K/AKT/mTOR (nongenomic pathway). The upregulation of the estrogenic and the PI3K/AKT/mTOR signaling pathways are frequently associated with a poor outcome. To better characterize the connection between these two pathways, we performed a phosphoproteome analysis of ER-positive MCF7 breast cancer cells treated with estrogen or estrogen and the mTORC1 inhibitor rapamycin. Many proteins were identified as estrogen-regulated mTORC1 targets and among them, DEPTOR was selected for further characterization. DEPTOR binds to mTOR and inhibits the kinase activity of both mTOR complexes mTORC1 and mTORC2, but mitogen-activated mTOR promotes phosphorylation-mediated DEPTOR degradation. Although estrogen enhances the phosphorylation of DEPTOR by mTORC1, DEPTOR levels increase in estrogen-stimulated cells. We demonstrated that DEPTOR accumulation is the result of estrogen-ERα-mediated transcriptional upregulation of DEPTOR expression. Consequently, the elevated levels of DEPTOR partially counterbalance the estrogen-induced activation of mTORC1 and mTORC2. These results underscore the critical role of estrogen-ERα as a modulator of the PI3K/AKT/mTOR signaling pathway in ER-positive breast cancer cells. Additionally, these studies provide evidence supporting the use of dual PI3K/mTOR or dual mTORC1/2 inhibitors in combination with endocrine therapies as a first-line treatment option for the patients with ER-positive advanced breast cancer.

We conducted a large cohort study to investigate the association between work-related wrist movements and carpal tunnel syndrome (CTS).

Autophagy maintains cellular homeostasis by degrading organelles, proteins, and lipids in lysosomes. Autophagy is involved in the innate and adaptive immune responses to a variety of pathogens. Some viruses can hijack host autophagy to enhance their replication. However, the role of autophagy in porcine reproductive and respiratory syndrome virus (PRRSV) infection is unclear. Here, we show that N-Myc downstream-regulated gene 1 (NDRG1) deficiency induced autophagy, which facilitated PRRSV replication by regulating lipid metabolism. NDRG1 mRNA is expressed ubiquitously in most porcine tissues and most strongly in white adipose tissue. PRRSV infection downregulated the expression of NDRG1 mRNA and protein, while NDRG1 deficiency contributed to PRRSV RNA replication and progeny virus assembly. NDRG1 deficiency reduced the number of intracellular lipid droplets (LDs), but the expression levels of key genes in lipogenesis and lipolysis were not altered. Our results also show that NDRG1 deficiency promoted autophagy and increased the subsequent yields of hydrolyzed free fatty acids (FFAs). The reduced LD numbers, increased FFA levels, and enhanced PRRSV replication were abrogated in the presence of an autophagy inhibitor. Overall, our findings suggest that NDRG1 plays a negative role in PRRSV replication by suppressing autophagy and LD degradation.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-positive-stranded RNA virus, causes acute respiratory distress in piglets and reproductive failure in sows. It has led to tremendous economic losses in the swine industry worldwide since it was first documented in the late 1980s. Vaccination is currently the major strategy used to control the disease. However, conventional vaccines and other strategies do not provide satisfactory or sustainable prevention. Therefore, safe and effective strategies to control PRRSV are urgently required. The significance of our research is that we demonstrate a previously unreported relationship between PRRSV, NDRG1, and lipophagy in the context of viral infection. Furthermore, our data point to a new role for NDRG1 in autophagy and lipid metabolism. Thus, NDRG1 and lipophagy will have significant implications for understanding PRRSV pathogenesis for developing new therapeutics.

Background: Type II diabetes mellitus (T2DM), a persistent metabolic disorder, is primarily characterized by insulin resistance, relative insulin deficiency and dyslipidemia. Here, we aimed to investigate whether different doses of atorvastatin (ATV) affect rats with T2DM. A total of 110 Sprague-Dawley rats were successfully established as T2DM models. Methods: First, the total cholesterol, triglyceride (TG), high-/low-/very-low-density lipoprotein cholesterol (HDL-c/LDL-c/VLDL-c), alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), apolipoprotein Al (ApoA1) and apolipoprotein B (ApoB) levels in rat serum were analyzed. In addition, cholesteryl ester transfer protein (CETP) and retinol-binding protein 4 (RBP4) were also measured. Then, the incidence of adverse reactions was noted. Finally, the pathological study of liver and pancreatic tissues was performed. Results: Rats administered ATV at the doses of 40 and 80 mg/(kg·day) showed down-regulated TG, LDL-c, ApoB, CETP and RBP4 levels yet up-regulated HDL-c and ApoAl levels. Rats administered ATV at a dose of 80 mg/(kg·day) exhibited a higher incidence of adverse reactions and higher ALT and AST levels but lower BUN and Cr levels, which might affect liver and kidney function. Rats administered ATV at the doses of 40 and 80 mg/(kg·day) demonstrated significantly improved liver injury and pancreatic injury induced by T2DM. Conclusion: These data revealed that ATV could improve the lipid metabolism in T2DM rats and 40 mg/(kg·day) may serve as the optimal dose for the reduction of lipid levels and the incidence of adverse effects.

Laryngeal carcinoma is one of the most common malignant tumors of the head, neck, and respiratory tract. The aim of the present study is to explore the biological function of SRY-related HMG-box 18 (SOX18) in laryngeal carcinoma cells and study the molecular mechanism involved. Initial findings indicate that the expression of SOX18 was increased in laryngeal carcinoma cell lines and tissues. The effect of SOX18 on laryngeal carcinoma cell proliferation, cell cycle, apoptosis, invasion, and migration was also identified. The results indicated that down-regulation of SOX18 significantly inhibited cell proliferation, migration, and invasion, and induced cell-cycle arrest in G0/G1 phase and apoptosis of laryngeal carcinoma cells. However, overexpression of SOX18 promoted cell proliferation, invasion, and migration, and inhibited cell apoptosis. The expression of cyclin D1, active-caspase-3, N-cadherin, MTA1, MMP-2, and MMP-7 was also regulated by the overexpression of siSOX18 or SOX18. In addition, it was found that SOX18 could also accelerate the phosphorylation of JAK2/STAT3 signaling in laryngeal carcinoma cells. Furthermore, our study indicated that SOX18 could stimulate cell proliferation, migration, and invasion of laryngeal carcinoma cells via regulation of JAK2/STAT3 signaling, which could provide a new strategy for laryngeal carcinoma diagnosis and molecular therapies.

Currently, there is a lack of effective therapeutic approaches to the treatment of chronic kidney disease (CKD) with irreversible deterioration of renal function. This study aimed to investigate the ability of mutant FGF1 (FGF1ΔHBS, which has reduced mitogenic activity) to alleviate CKD and to study its associated mechanisms. We found that FGF1ΔHBS exhibited much weaker mitogenic activity than wild-type FGF1 (FGF1WT) in renal tissues. RNA-seq analysis revealed that FGF1ΔHBS inhibited oxidative stress and inflammatory signals in mouse podocytes challenged with high glucose. These antioxidative stress and anti-inflammatory activities of FGF1ΔHBS prevented CKD in two mouse models: a diabetic nephropathy model and an adriamycin-induced nephropathy model. Further mechanistic analyses suggested that the inhibitory effects of FGF1ΔHBS on oxidative stress and inflammation were mediated by activation of the GSK-3β/Nrf2 pathway and inhibition of the ASK1/JNK signaling pathway, respectively. An in-depth study demonstrated that both pathways are under control of PI3K/AKT signaling activated by FGF1ΔHBS. This finding expands the potential uses of FGF1ΔHBS for the treatment of various kinds of CKD associated with oxidative stress and inflammation.

An increased surface level of CIE (clathrin-independent endocytosis) proteins is a new feature of malignant neoplasms. CD147 is a CIE glycoprotein highly up-regulated in hepatocellular carcinoma (HCC). The ability to sort out the early endosome and directly target the recycling pathway confers on CD147 a prolonged surface half-life. However, current knowledge on CD147 trafficking to and from the cell-surface is limited. In this study, an MSP (membrane and secreted protein)-cDNA library was screened against EpoR/LR-F3/CD147EP-expressed cells by MAPPIT (mammalian protein-protein interaction trap). CD147 co-expressing with the new binder was investigated by GEPIA (gene expression profiling interactive analysis). The endocytosis, ER-Golgi trafficking and recycling of CD147 were measured by confocal imaging, flow cytometry, and biotin-labeled chase assays, respectively. Rab GTPase activation was checked by GST-RBD pull-down and MMP activity was measured by gelatin zymography. HCC malignant phenotypes were determined by cell adhesion, proliferation, migration, Transwell motility, and invasion assays. An ER-Golgi-resident transmembrane protein YIPF2 was identified as an intracellular binder to CD147. YIPF2 correlated and co-expressed with CD147, which is a survival predictor for HCC patients. YIPF2 is critical for CD147 glycosylation and trafficking functions in HCC cells. YIPF2 acts as a Rab-GDF (GDI-displacement factor) regulating three independent trafficking steps. First, YIPF2 recruits and activates Rab5 and Rab22a GTPases to the endomembrane structures. Second, YIPF2 modulates the endocytic recycling of CD147 through distinctive regulation on Rab5 and Rab22a. Third, YIPF2 mediates the mature processing of CD147 via the ER-Golgi trafficking route. Decreased YIPF2 expression induced a CD147 efficient delivery to the cell-surface, promoted MMP secretion, and enhanced the adhesion, motility, migration, and invasion behaviors of HCC cells. Thus, YIPF2 is a new trafficking determinant essential for CD147 glycosylation and transport. Our findings revealed a novel YIPF2-controlled ER-Golgi trafficking signature that promotes CD147-medated malignant phenotypes in HCC.

The Kenya-Belgium data collection includes about 111,800 biotic observations on benthos, algae, fish, zooplankton, phytoplankton, birds and mangroves which cover more than 400 unique locations that were sampled between 1873 and 1999. The scope of this data digitization project was to recover data in theses and reports resulting from marine and coastal research activities in the Eastern African region conducted between 1984 and 1999. Data were digitized and quality checked in the frame of the Belgian LifeWatch project. The dataset provides a better insight into the different types of research conducted between 1985 and 1996 in frame of the Kenya-Belgium cooperation in marine sciences (KBP) project and can facilitate further coastal biodiversity research in Kenya.

Tissue architecture and cell-extracellular matrix (cell-ECM) interaction determine the organ specificity; however, the influences of these factors on anticancer drugs preclinical studies are highly neglected. For considering such aspects, three-dimensional (3D) cell culture models are relevant tools for accurate analysis of cellular responses to chemotherapy. Here we compared the MCF-7 breast cancer cells responses to cisplatin in traditional two-dimensional (2D) and in 3D-reconstituted basement membrane (3D-rBM) cell culture models. The results showed a substantial increase of cisplatin resistance mediated by 3D microenvironment. This phenotype was independent of p53 status and autophagy activity and was also observed for other cellular models, including lung cancer cells. Such strong decrease on cellular sensitivity was not due to differences on drug-induced DNA damage, since similar levels of γ-H2AX and cisplatin-DNA adducts were detected under both conditions. However, the processing of these cisplatin-induced DNA lesions was very different in 2D and 3D cultures. Unlike cells in monolayer, cisplatin-induced DNA damage is persistent in 3D-cultured cells, which, consequently, led to high senescence induction. Moreover, only 3D-cultured cells were able to progress through S cell cycle phase, with unaffected replication fork progression, due to the upregulation of translesion (TLS) DNA polymerase expression and activation of the ATR-Chk1 pathway. Co-treatment with VE-821, a pharmacological inhibitor of ATR, blocked the 3D-mediated changes on cisplatin response, including low sensitivity and high TLS capacity. In addition, ATR inhibition also reverted induction of REV3L by cisplatin treatment. By using REV3L-deficient cells, we showed that this TLS DNA polymerase is essential for the cisplatin sensitization effect mediated by VE-821. Altogether, our results demonstrate that 3D-cell architecture-associated resistance to cisplatin is due to an efficient induction of REV3L and TLS, dependent of ATR. Thus co-treatment with ATR inhibitors might be a promising strategy for enhancement of cisplatin treatment efficiency in breast cancer patients.

Despite an increasing concern of consequences of using vast amounts of glyphosate-based herbicides in agroecosystems, their potential effects on non-target soil organisms and soil functioning are mostly unknown. It has also been argued that fields in northern latitudes should be under special surveillance as the short active period of decomposers may restrict glyphosate degradation. We investigated the effects of a glyphosate-based herbicide, Roundup, on the abundance of enchytraeids and nematodes, both essential groups in decomposer food webs, and plant litter mass loss and soil availability of mineral N in a two-year agricultural field setting in south-west Finland. Our experiment consisted of (1) non-treated weed plots, (2) plots, where weeds were killed by hoeing, and (3) plots treated with both Roundup and hoeing. We found that killing plants by hoeing had drastic effects on soil fauna and functioning, and apparently, distinguishing these effects from direct glyphosate effects is profoundly important when evaluating glyphosate risks in soils. In contrast, the effects of Roundup on soil fauna and functioning were minor and transient and no glyphosate remains were found in the soil at the end of the experiment. These results suggest that side-effects can be minor and glyphosate degradation effective also in soil under northern climatic conditions.

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.

Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease.

Complex conformational dynamics are essential for function of the dimeric molecular chaperone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimerization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90.

Genetic isolation of populations over evolutionary time leads to the formation of independent species. We examined a pair of shorebirds - the Kentish Plover Charadrius alexandrinus and the enigmatic White-faced Plover C. dealbatus - which display strong plumage differentiation, yet show minimal genetic divergence based on previous mitochondrial and microsatellite work. Two scenarios may lead to this situation: (1) they represent clinal or poorly diverged populations with limited genomic differentiation despite substantial plumage variation, or (2) they are diverging taxa at the cusp of speciation, with ongoing limited gene flow obliterating signals of differentiation in traditional genetic markers. We compared the genotypes of 98 plovers (59 Kentish Plovers, 35 White-faced Plovers and 4 genomic hybrids) sampled in eastern Asia and Europe using ddRADSeq to harvest over 8000 genome-wide SNPs. In contrast to previous studies, our analyses revealed two well defined genomic clusters, with limited hybridization and a narrow contact zone. We also uncovered significant differences in bill length and further sex-specific differences in size, which may signal differences in mate choice between Kentish and White-faced Plovers. Our results support the hypothesis that this shorebird duo is on the verge of speciation.