Tag: nevin manimala

PLoS One. 2022 Jan 18;17(1):e0262104. doi: 10.1371/journal.pone.0262104. eCollection 2022.

ABSTRACT

Renal clinical chemistry only detects kidney dysfunction after considerable damage has occurred and is imperfect in predicting long term outcomes. Consequently, more sensitive markers of early damage and better predictors of progression are being urgently sought, to better support clinical decisions and support shorter clinical trials. Transglutaminase 2 (TG2) is strongly implicated in the fibrotic remodeling that drives chronic kidney disease (CKD). We hypothesized that urinary TG2 and its ε-(γ-glutamyl)-lysine crosslink product could be useful biomarkers of kidney fibrosis and progression. Animal models: a rat 4-month 5/6th subtotal nephrectomy model of CKD and a rat 8-month streptozotocin model of diabetic kidney disease had 24-hour collection of urine, made using a metabolic cage, at regular periods throughout disease development. Patients: Urine samples from patients with CKD (n = 290) and healthy volunteers (n = 33) were collected prospectively, and progression tracked for 3 years. An estimated glomerular filtration rate (eGFR) loss of 2-5 mL/min/year was considered progressive, with rapid progression defined as > 5 mL/min/year. Assays: TG2 was measured in human and rat urine samples by enzyme-linked immunosorbent assay (ELISA) and ε-(γ-glutamyl)-lysine by exhaustive proteolytic digestion and amino acid analysis. Urinary TG2 and ε-(γ-glutamyl)-lysine increased with the development of fibrosis in both animal model systems. Urinary TG2 was 41-fold higher in patients with CKD than HVs, with levels elevated 17-fold by CKD stage 2. The urinary TG2:creatinine ratio (UTCR) was 9 ng/mmol in HV compared with 114 ng/mmol in non-progressive CKD, 1244 ng/mmol in progressive CKD and 1898 ng/mmol in rapidly progressive CKD. Both urinary TG2 and ε-(γ-glutamyl)-lysine were significantly associated with speed of progression in univariate logistic regression models. In a multivariate model adjusted for urinary TG2, ε-(γ-glutamyl)-lysine, age, sex, urinary albumin:creatinine ratio (UACR), urinary protein:creatinine ratio (UPCR), and CKD stage, only TG2 remained statistically significant. Receiver operating characteristic (ROC) curve analysis determined an 86.4% accuracy of prediction of progression for UTCR compared with 73.5% for UACR. Urinary TG2 and ε-(γ-glutamyl)-lysine are increased in CKD. In this pilot investigation, UTCR was a better predictor of progression in patients with CKD than UACR. Larger studies are now warranted to fully evaluate UTCR value in predicting patient outcomes.

PMID:35041708 | DOI:10.1371/journal.pone.0262104

PLoS Negl Trop Dis. 2022 Jan 18;16(1):e0010090. doi: 10.1371/journal.pntd.0010090. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth disease caused by enterovirus 71 (EV71-HFMD). In this context, we explored the influence of gene methylation and polymorphism on EV71-HFMD.

METHODOLOGY/PRINCIPAL FINDINGS: 60 healthy controls and 120 EV71-HFMD patients, including 60 mild EV71-HFMD and 60 severe EV71-HFMD patients, were enrolled. First, MiSeq was performed to explore the methylation of CpG islands in the DDX58 and IFIH1 promoter regions. Then, DDX58 and IFIH1 expression were detected in PBMCs using RT-qPCR. Finally, imLDR was used to detect DDX58 and IFIH1 single-nucleotide polymorphism (SNP) genotypes. Severe EV71-HFMD patients exhibited higher DDX58 promoter methylation levels than healthy controls and mild EV71-HFMD patients. DDX58 promoter methylation was significantly associated with severe HFMD, sex, vomiting, high fever, neutrophil abundance, and lymphocyte abundance. DDX58 expression levels were significantly lower in mild patients than in healthy controls and lower in severe patients than in mild patients. Binary logistic regression analysis revealed statistically significant differences in the genotype frequencies of DDX58 rs3739674 between the mild and severe groups. GeneMANIA revealed that 19 proteins displayed correlations with DDX58, including DHX58, HERC5, MAVS, RAI14, WRNIP1 and ISG15, and 19 proteins displayed correlations with IFIH1, including TKFC, IDE, MAVS, DHX58, NLRC5, TSPAN6, USP3 and DDX58.

CONCLUSIONS/SIGNIFICANCE: DDX58 expression and promoter methylation were associated with EV71 infection progression, especially in severe EV71-HFMD patients. The effect of DDX58 in EV71-HFMD is worth further attention.

PMID:35041675 | DOI:10.1371/journal.pntd.0010090

PLoS One. 2022 Jan 18;17(1):e0257178. doi: 10.1371/journal.pone.0257178. eCollection 2022.

ABSTRACT

Sialyltransferase, an enzyme responsible for attaching sialic acid to the cell surface, is reported to play a key role in cancer, making sialyltransferase a potential therapeutic target in drug development. Several methods have been developed to quantify sialic acids in biological samples however limitations exists and quantification in complex cell matrices lack investigation. Hence, this paper outlines a simple method to detect and quantify sialic acids in cancer cells for evaluating sialyltransferase activity of potential therapeutic compounds. An efficient method was developed using a reverse-phase ion-pairing HPLC-UV using triisopropanolamine as the ion-pairing agent with a C18 column. Neu5Ac was successfully eluted with the retention time 6.344 min with a flow rate of 0.4 mL/min. The proposed method was validated appropriately according to the AOAC guidelines (2013). This work demonstrates that the proposed method is not only relatively simple but also cost and time effective compared to pre-existing methods to successfully determine both free and protein-bound Neu5Ac in a complex cancer cell matrix. Furthermore, by applying the proposed method, a statistically significant decrease was observed for both HeLa and HuCCT1 cell lines with the application of deoxycholic acid-a known sialyltransferase inhibitor. Hence, the proposed method seems promisingly applicable to evaluate the effectiveness of potential sialyltransferase inhibitors.

PMID:35041670 | DOI:10.1371/journal.pone.0257178

PLoS One. 2022 Jan 18;17(1):e0262024. doi: 10.1371/journal.pone.0262024. eCollection 2022.

ABSTRACT

Analysis of population genetic data often includes a search for genomic regions with signs of recent positive selection. One of such approaches involves the concept of extended haplotype homozygosity (EHH) and its associated statistics. These statistics typically require phased haplotypes, and some of them necessitate polarized variants. Here, we unify and extend previously proposed modifications to loosen these requirements. We compare the modified versions with the original ones by measuring the false discovery rate in simulated whole-genome scans and by quantifying the overlap of inferred candidate regions in empirical data. We find that phasing information is indispensable for accurate estimation of within-population statistics (for all but very large samples) and of cross-population statistics for small samples. Ancestry information, in contrast, is of lesser importance for both types of statistic. Our publicly available R package rehh incorporates the modified statistics presented here.

PMID:35041674 | DOI:10.1371/journal.pone.0262024

PLoS Comput Biol. 2022 Jan 18;18(1):e1009490. doi: 10.1371/journal.pcbi.1009490. Online ahead of print.

ABSTRACT

Lévy flight is a type of random walk that characterizes the behaviour of many natural phenomena studied across a multiplicity of academic disciplines; within biology specifically, the behaviour of fish, birds, insects, mollusks, bacteria, plants, slime molds, t-cells, and human populations. The Lévy flight foraging hypothesis states that because Lévy flights can maximize an organism’s search efficiency, natural selection should result in Lévy-like behaviour. Empirical and theoretical research has provided ample evidence of Lévy walks in both extinct and extant species, and its efficiency across models with a diversity of resource distributions. However, no model has addressed the maintenance of Lévy flight foraging through evolutionary processes, and existing models lack ecological breadth. We use numerical simulations, including lineage-based models of evolution with a distribution of move lengths as a variable and heritable trait, to test the Lévy flight foraging hypothesis. We include biological and ecological contexts such as population size, searching costs, lifespan, resource distribution, speed, and consider both energy accumulated at the end of a lifespan and averaged over a lifespan. We demonstrate that selection often results in Lévy-like behaviour, although conditional; smaller populations, longer searches, and low searching costs increase the fitness of Lévy-like behaviour relative to Brownian behaviour. Interestingly, our results also evidence a bet-hedging strategy; Lévy-like behaviour reduces fitness variance, thus maximizing geometric mean fitness over multiple generations.

PMID:35041659 | DOI:10.1371/journal.pcbi.1009490

J Bone Joint Surg Am. 2022 Jan 18. doi: 10.2106/JBJS.21.00785. Online ahead of print.

ABSTRACT

BACKGROUND: Next-generation DNA sequencing (NGS) detects bacteria-specific DNA corresponding to the 16S ribosomal RNA gene and can identify bacterial presence with greater accuracy than traditional culture methods. The clinical relevance of these findings is unknown. The purpose of the present study was to compare the results from bacterial culture and NGS in order to characterize the potential use of NGS in orthopaedic trauma patients.

METHODS: A prospective cohort study was performed at a single academic, level-I trauma center. Three patient groups were enrolled: (1) patients undergoing surgical treatment of acute closed fractures (presumed to have no bacteria), (2) patients undergoing implant removal at the site of a healed fracture without infection, and (3) patients undergoing a first procedure for the treatment of a fracture nonunion who might or might not have subclinical infection. Surgical site tissue was sent for culture and NGS. The proportions of culture and NGS positivity were compared among the groups. The agreement between culture and NGS results was assessed with use of the Cohen kappa statistic.

RESULTS: Bacterial cultures were positive in 9 of 111 surgical sites (110 patients), whereas NGS was positive in 27 of 111 surgical sites (110 patients). Significantly more cases were positive on NGS as compared with culture (24% vs. 8.1%; p = 0.001), primarily in the acute closed fracture group. No difference was found in terms of the percent positivity of NGS when comparing the acute closed fracture, implant removal, and nonunion groups. With respect to bacterial identification, culture and NGS agreed in 73% of cases (κ = 0.051; 95% confidence interval, -0.12 to 0.22) indicating only slight agreement compared with expected chance agreement of 50%.

CONCLUSIONS: NGS identified bacterial presence more frequently than culture, but with only slight agreement between culture and NGS. It is possible that the increased frequency of bacterial detection with molecular methods is reflective of biofilm presence on metal or colonization with nonpathogenic bacteria, as culture methods have selection pressure posed by restrictive, artificial growth conditions and there are low metabolic activity and replication rates of bacteria in biofilms. Our data suggest that NGS should not currently substitute for or complement conventional culture in orthopaedic trauma cases with low suspicion of infection.

LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

PMID:35041629 | DOI:10.2106/JBJS.21.00785

Neuromodulation. 2022 Jan;25(1):53-63. doi: 10.1111/ner.13460.

ABSTRACT

OBJECTIVE: The objective of this preclinical study was to examine the responses of the brain to noxious stimulation in the presence and absence of different modes of spinal cord stimulation (SCS) using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI).

MATERIALS AND METHODS: Sprague-Dawley rats were randomized to groups based on the mode of SCS delivered which included tonic stimulation (n = 27), burst stimulation (n = 30), and burst-cycle stimulation (n = 29). The control (sham) group (n = 28) received no SCS. The SCS electrode was inserted between T10 and T12 spinal levels prior to fMRI session. The experimental protocol for fMRI acquisition consisted of an initial noxious stimulation phase, a treatment phase wherein the SCS was turned on concurrently with noxious stimulation, and a residual effect phase wherein the noxious stimulation alone was turned on. The responses were statistically analyzed through paired t-test and the results were presented as z-scores for the quantitative analysis of the fMRI data.

RESULTS: The treatment with different SCS modes attenuated the BOLD brain responses to noxious hindlimb stimulation. The tonic, burst, and burst-cycle SCS treatment attenuated BOLD responses in the caudate putamen (CPu), insula (In), and secondary somatosensory cortex (S2). There was little to no corresponding change in sham control in these three regions. The burst and burst-cycle SCS demonstrated greater attenuation of BOLD signals in CPu, In, and S2 compared to tonic stimulation.

CONCLUSION: The high-resolution fMRI study using a rat model demonstrated the potential of different SCS modes to act on several pain-matrix-related regions of the brain in response to noxious stimulation. The burst and burst-cycle SCS exhibited greater brain activity reduction in response to noxious hindlimb stimulation in the caudate putamen, insula, and secondary somatosensory cortex compared to tonic stimulation.

PMID:35041588 | DOI:10.1111/ner.13460

IEEE Trans Neural Syst Rehabil Eng. 2022 Jan 18;PP. doi: 10.1109/TNSRE.2022.3144169. Online ahead of print.

ABSTRACT

Deep sleep staging networks have reached top performance on large-scale datasets. However, these models perform poorer when training and testing on small sleep cohorts due to data inefficiency. Transferring well-trained models from large-scale datasets (source domain) to small sleep cohorts (target domain) is a promising solution but still remains challenging due to the domain-shift issue. In this work, an unsupervised domain adaptation approach, domain statistics alignment (DSA), is developed to bridge the gap between the data distribution of source and target domains. DSA adapts the source models on the target domain by modulating the domain-specific statistics of deep features stored in the Batch Normalization (BN) layers. Furthermore, we have extended DSA by introducing cross-domain statistics in each BN layer to perform DSA adaptively (AdaDSA). The proposed methods merely need the well-trained source model without access to the source data, which may be proprietary and inaccessible. DSA and AdaDSA are universally applicable to various deep sleep staging networks that have BN layers. We have validated the proposed methods by extensive experiments on two state-of-the-art deep sleep staging networks, DeepSleepNet+ and U-time. The performance was evaluated by conducting various transfer tasks on six sleep databases, including two large-scale databases, MASS and SHHS, as the source domain, four small sleep databases as the target domain. Thereinto, clinical sleep records acquired in Huashan Hospital, Shanghai, were used. The results show that both DSA and AdaDSA could significantly improve the performance of source models on target domains, providing novel insights into the domain generalization problem in sleep staging tasks.

PMID:35041607 | DOI:10.1109/TNSRE.2022.3144169

Neuromodulation. 2022 Jan;25(1):128-136. doi: 10.1111/ner.13400.

ABSTRACT

OBJECTIVES: In patients with chronic pain, a relative lower parasympathetic activity is suggested based on heart rate variability measurements. It is hypothesized that spinal cord stimulation (SCS) is able to influence the autonomic nervous system. The aim of this study is to further explore the influence of SCS on the autonomic nervous system by evaluating whether SCS is able to influence skin conductance, blood volume pulse, heart rate, and respiration rate.

MATERIALS AND METHODS: Twenty-eight patients with Failed Back Surgery Syndrome (FBSS), who are being treated with SCS, took part in this multicenter study. Skin conductance and cardiorespiratory parameters (blood volume pulse, heart rate, and respiration rate) were measured during on and off states of SCS. Paired statistics were performed on a 5-min recording segment for all parameters.

RESULTS: SCS significantly decreased back and leg pain intensity scores in patients with FBSS. Skin conductance level and blood volume pulse were not altered between on and off states of SCS. Heart rate and respiration rate significantly decreased when SCS was activated.

CONCLUSIONS: Parameters that are regulated by the sympathetic nervous system were not significantly different between SCS on and off states, leading to the hypothesis that SCS is capable of restoring the dysregulation of the autonomic nervous system by primarily increasing the activity of the parasympathetic system in patients with FBSS.

PMID:35041582 | DOI:10.1111/ner.13400

Soc Indic Res. 2022 Jan 13:1-22. doi: 10.1007/s11205-021-02870-w. Online ahead of print.

ABSTRACT

Life expectancy at birth has attracted interest in various fields, as a health indicator that measures the quality of life. Its appeal relies on the ability to enclose and summarize all the factors affecting longevity. However, more granular information, provided by social indicators such as cause-of-death mortality rates, plays a crucial role in defining appropriate policies for governments to achieve well-being and sustainability goals. Unfortunately, their availability is not always guaranteed. Exploiting the relationship between life expectancy at birth and cause-of-death mortality rates, in this paper we propose an indirect model to produce estimates of death rates due to specific causes using the summary indicator of life expectancy at birth, thus the general levels of the observed mortality. By leveraging on a constrained optimization procedure, we ensure a robust framework where the cause-specific mortality rates are coherent to the aggregate mortality. The main advantage is that indirect estimations allow us to overcome the data availability problem: very often the cause-specific mortality data are incomplete, whereas data on the aggregate mortality are not. Using data from the Human Cause-of-Death Database, we show a numerical application of our model to two different countries, Russia and Spain, which have experienced a different evolution of life expectancy and different leading causes of death. In Spain, we detected the impact of several public health policies on the lowered levels of cancer deaths and related life expectancy increases. As regards the Russia, our results catch the effects of the anti-alcohol campaign of 1985-1988 on longevity changes.

PMID:35039708 | PMC:PMC8756417 | DOI:10.1007/s11205-021-02870-w