Changes of B cell subsets in different types of diabetes and its effect on the progression of latent autoimmune diabetes in adults.

PURPOSE: Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters. METHODS: A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method. RESULTS: We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of ß-cell in patients with diabetes. CONCLUSIONS: This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients.

Fast Water Transport in UTSA-280 via a Knock-Off Mechanism.

Water and other small molecules frequently coordinate within metal-organic frameworks (MOFs). These coordinated molecules may actively engage in mass transfer, moving together with the transport molecules, but this phenomenon has yet to be examined. In this study, we explore a unique water transfer mechanism in UTSA-280, where an incoming water molecule can displace a coordinated molecule for mass transfer. We refer to this process as the "knock-off" mechanism. Despite UTSA-280 possessing one-dimensional channels, the knock-off transport enables water movement along the other two axes, effectively simulating a pseudo-three-dimensional mass transfer. Even with a relatively narrow pore width, the knock-off mechanism enables a high water flux in the UTSA-280 membrane. The knock-off mechanism also renders UTSA-280 superior water/ethanol diffusion selectivity for pervaporation. To validate this unique mechanism, we conducted 1 H and 2 H solid-state NMR on UTSA-280 after the adsorption of deuterated water. We also derived potential energy diagrams from the density functional theory to gain atomic-level insight into the knock-off and the direct-hopping mechanisms. The simulation findings reveal that the energy barrier of the knock-off mechanism is marginally lower than the direct-hopping pathway, implying its potential role in enhancing water diffusion in UTSA-280.

Host biomarkers other than interferon gamma in QFT-TB supernatants for identifying active tuberculosis.

Interferon gamma release assays (IGRAs) for tuberculosis (TB) remain limited in their ability to discriminate between active TB (ATB) and latent TB infection (LTBI). The objective of our study was to evaluate the value of additional cytokines/chemokines other than interferon gamma (IFN-γ) as biomarkers to identify different TB infection status. A total of 128 subjects were enrolled to detect the quantification of IL-2, IP-10, MCP-1 and RANTES in the supernatants of QuantiFERON®-TB (QFT-TB). Area under the curve (AUC) was used to evaluate the diagnostic efficiency. Notably, Mycobacterium tuberculosis (Mtb) induced cytokines/chemokines of ATB patients were significantly higher than those of the LTBI, other lung related diseases (ORD) and healthy controls (HC). Moreover, ROC analysis indicated that all cytokine/chemokine parameters detected were more capable of distinguishing ATB from LTBI than IFN-γ, especially IL-2. The diagnostic model including TB specific IL-2 and RANTES improved the performance in distinguishing ATB from LTBI, which was superior to single cytokines/chemokines in QFT-TB supernatants. Our results suggest that the combination of Mtb specific cytokines/chemokines has great prospects in the diagnosis of ATB, and the diagnostic model based on IL-2 and RANTES can be used as an alternative to distinguish ATB from LTBI.

Cost-effectiveness analysis of nivolumab plus cabozantinib versus sunitinib as first-line therapy in advanced renal cell carcinoma.

Aim: To evaluate the cost-effectiveness of first-line treatment for advanced renal cell carcinoma with nivolumab plus cabozantinib versus sunitinib from a US payer perspective. Methods: Economic outcomes were estimated with Markov and partitioned survival models. Efficacy, safety and other data were taken from the CheckMate 9ER trial. Costs and utilities were gathered from published sources. Sensitivity analyses addressed model uncertainties. Results: The incremental cost-effectiveness ratio of nivolumab plus cabozantinib versus sunitinib was US$555,663 and $531,748 per quality-adjusted life year in the Markov and partitioned survival models, respectively, exceeding the willingness-to-pay threshold (US$150,000 per quality-adjusted life-year). Sensitivity analyses showed robust outcomes. Conclusion: From a US payer perspective, first-line nivolumab plus cabozantinib for advanced renal cell carcinoma is not cost effective.

Renal cell carcinoma (RCC) is a common cancer in the USA. Up to 30% of patients with RCC are in an advanced stage of disease at diagnosis. RCC is difficult to cure, with an 11% chance of survival after 5 years for patients with advanced RCC. A recent clinical study showed that nivolumab plus cabozantinib (NC) had a greater benefit in patients with advanced RCC than sunitinib. The US FDA approved NC for advanced RCC, but NC is relatively expensive. This study explored the cost­effectiveness of NC for advanced RCC versus sunitinib for a US payer using two cost­effectiveness models developed based on the results of the aforementioned clinical study. The results showed that to gain an additional year in perfect health, NC costs an average of US$555,663 or $531,748 more versus sunitinib, which is more than a US payer is willing to pay for an additional year in perfect health ($150,000). Therefore, NC for advanced RCC is not cost-effective versus sunitinib for a US payer at current prices.

Evaluating the diversity of circulating natural killer cells between active tuberculosis and latent tuberculosis infection.

Tuberculosis (TB) is a leading global public health problem; however, the mechanisms underlying the immunopathology of TB progression are not well understood. It is currently believed that Mycobacterium tuberculosis (Mtb) infection can modify natural killer (NK) cell phenotypic signatures. Hence, our study was designed to investigate the diversity of circulating NK cells in patients with different TB infection status. NK subsets, as well as their expression of activating and inhibitory receptors between active TB (ATB) and latent TB infection (LTBI) were evaluated. There were significant differences in NK cell phenotypes between ATB, LTBI and healthy controls. Notably, the proportion of KLRG1 in NK cells (P = 0.036), as well as in their subsets CD56DimCD16+ (P = 0.046) and CD27+ (P = 0.027) NK cells, increased significantly in LTBI group than in ATB group; while Mtb specific IFN-γ+CD56BrightCD16Dim NK cells expressed higher KLRG1 in ATB than in LTBI (P = 0.027). However, the expression of activating receptor NKG2D in NK subsets showed no significant difference among the study groups. Our results suggest that different TB infection status are coupled with the diversity of NK cell compartments, and the expression of KLRG1 in NK cells may be a specific phenotype that modulates the progression of TB from latent to active.

Direct investigation of the reorientational dynamics of A-site cations in 2D organic-inorganic hybrid perovskite by solid-state NMR.

Limited methods are available for investigating the reorientational dynamics of A-site cations in two-dimensional organic-inorganic hybrid perovskites (2D OIHPs), which play a pivotal role in determining their physical properties. Here, we describe an approach to study the dynamics of A-site cations using solid-state NMR and stable isotope labelling. 2H NMR of 2D OIHPs incorporating methyl-d3-ammonium cations (d3-MA) reveals the existence of multiple modes of reorientational motions of MA. Rotational-echo double resonance (REDOR) NMR of 2D OIHPs incorporating 15N- and ¹³C-labeled methylammonium cations (13C,15N-MA) reflects the averaged dipolar coupling between the C and N nuclei undergoing different modes of motions. Our study reveals the interplay between the A-site cation dynamics and the structural rigidity of the organic spacers, so providing a molecular-level insight into the design of 2D OIHPs.

Semen quality and sperm DNA methylation in relation to long-term exposure to air pollution in fertile men: A cross-sectional study.

Some studies have examined the association between air pollution and semen quality. While it is less of evidence on the sperm quality after long-term air pollution exposure, especially the co-exposure of different air pollution components. Additionally, the role of DNA methylation in it hasn't been confirmed. This study aimed to investigate whether long-term exposure to air pollution was associated with semen quality, as well as to explore the effect of sperm DNA methylation in such association. From 2014 to 2016, 1607 fertile men were enrolled to evaluate 14 parameters of semen quality. Exposure window was defined as one-year before semen sampling. Multivariable linear regression and weighted quantile sum (WQS) regression model were used to investigate the association between six air pollutants co-exposure and semen quality. Sensitivity analysis regarding at the normal semen quality group was also conducted. Semen samples were randomly selected from 200 participants to detect the genomic 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5-hmC) levels in sperm. In the total population, PM10, PM2.5, SO2, and NO2 were negatively associated with sperm total motility (PM10: ß = -2.67, P = 0.009; PM2.5: ß = -2.86, P = 0.004; SO2: ß = -2.32, P = 0.011; NO2: ß = -2.21, P = 0.012). Results of the normal semen quality group were consistent with those from the whole population. WQS regression results indicated significant decreasing sperm total motility after the co-exposure of the six air pollutants (ß = -1.64, P = 0.003) in whole participants. Wherein, PM10 accounted for largest proportion (43.4%). The 5-hmC level was positively associated with PM10 exposure (ß = 0.002, P < 0.001). Long-term exposure to PM10, PM2.5, SO2, and NO2, as well as co-exposure to six air pollutants, reduced semen quality in fertile men. As the most significant contributor of air pollutant, PM10 exposure decreased sperm DNA methylation.

Association between Exercise and Blood Pressure in Hypertensive Residents: A Meta-Analysis.

BACKGROUND: Exercise is recommended as an effective lifestyle behaviour for adults to prevent and treat hypertension. In this study, a randomized-effect meta-analysis was used to analyse the influence of exercise interventions on blood pressure in patients with hypertension. METHODS: Candidate papers were retrieved from PubMed, Web of Science, Embase, and Cochrane Library electronic databases, and 46 studies were finally included and analysed. RESULTS: It was shown that preplanned walking (systolic blood pressure (SBP): WMD (weighted mean difference) = -5.94, 95% CI: -8.57, -3.30; diastolic blood pressure (DBP): WMD = -2.66, 95% CI: -3.66, -1.67), yoga (SBP: WMD = -5.09, 95% CI: -9.28, -0.89; DBP: WMD = -3.06, 95% CI: -5.16, -0.96), aquatic sports (SBP WMD = -7.53, 95% CI: -11.40, -3.65; DBP: WMD = -5.35, 95% CI: -9.00, -1.69), and football (SBP: WMD = -6.06, 95% CI: -9.30, -2.82; DBP: WMD = -5.55, 95% CI: -8.98, -2.13) had significant effects on blood pressure reduction. However, Tai Chi (SBP: WMD = -8.31, 95% CI: -20.39, 3.77; DBP: WMD = -3.05, 95% CI: -6.96, 0.87) and Qigong (SBP: WMD = -4.34, 95% CI: -13.5, 4.82; DBP: WMD = -3.44, 95% CI: -7.89, 1.01) did not significantly reduce blood pressure. The heterogeneity of the meta-analysis was high. CONCLUSION: Walking, yoga, aquatic sports, and football were feasible and independent lifestyle interventions, and they were effective options for treating hypertension. More scientifically designed randomized controlled trials are needed in the future to further compare different forms of exercise for the treatment of hypertension.

Keyword extraction and structuralization of medical reports.

PURPOSE: In recent years, patients usually accept more accurate and detailed examinations because of the rapid advances in medical technology. Many of the examination reports are not represented in numerical data, but text documents written by the medical examiners based on the observations from the instruments and biochemical tests. If the above-mentioned unstructured data can be organized as a report in a structured form, it will help doctors to understand a patient's status of the various examinations more efficiently. Besides, further association analysis on the structuralized data can be performed to identify potential factors that affect a disease. METHODS: In this paper, from the pathology examination reports of renal diseases, we applied the POS tagging results of natural language analysis to automatically extract the keyword phrases. Then a medical dictionary for various examination items in an examination report is established, which is used as the basic information for retrieving the terms to construct a structured form of the report. Moreover, a topical probability modeling method is applied to automatically discover the candidate keyword phrases of the examination items from the reports. Finally, a system is implemented to generate the structured form for the various examination items in a report according to the constructed medical dictionary. RESULTS AND CONCLUSION: The results of the experiments showed that the methods proposed in this paper can effectively construct a structural form of examination reports. Furthermore, the keywords of the popular examination items can be extracted correctly. The above techniques will help automatic processing and analysis of medical text reports.

Biophysical characterization and modulation of Transthyretin Ala97Ser.

OBJECTIVE: Ala97Ser (A97S) is the major transthyretin (TTR) mutation in Taiwanese patients of familial amyloid polyneuropathy (FAP), characterized by a late-onset but rapidly deteriorated neuropathy. Tafamidis can restore the stability of some mutant TTR tetramers and slow down the progression of TTR-FAP. However, there is little understanding of the biophysical features of A97S-TTR mutant and the pharmacological modulation effect of tafamidis on it. This study aims to delineate the biophysical characteristics of A97S-TTR and the pharmacological modulation effect of tafamidis on this mutant. METHOD: The stability of TTR tetramers was assessed by urea denaturation and differential scanning calorimetry. Isothermal titration calorimetry (ITC) was used to measure the binding constant of tafamidis to TTR. Nuclear magnetic resonance spectroscopy (NMR) titration experiment was used to map out the tafamidis binding site. RESULTS: Chemical and thermal denaturation confirmed the destabilization effect of A97S. Consistent with other the amyloidogenic mutant, A97S-TTR has slightly lower conformational stability. NMR revealed the binding site of A97S-TTR with tafamidis is at the thyroxine binding pocket. The ITC experiments documented the high affinity of the binding which can effectively stabilize the A97S-TTR tetramer. INTERPRETATION: This study confirmed the structural modulation effect of tafamidis on A97S-TTR and implied the potential therapeutic benefit of tafamidis for A97S TTR-FAP. This approach can be applied to investigate the modulation effect of tafamidis on other rare TTR variants and help to make individualized choices of available treatments for FAP patients.

Membrane Charging and Swelling upon Calcium Adsorption as Revealed by Phospholipid Nanodiscs.

Direct binding of calcium ions (Ca2+) to phospholipid membranes is an unclarified yet critical signaling pathway in diverse Ca2+-regulated cellular phenomena. Here, high-pressure-liquid-chromatography, small-angle X-ray scattering (SAXS), UV-vis absorption, and differential refractive index detections are integrated to probe Ca2+-binding to the zwitterionic lipid membranes in nanodiscs. The responses of the membranes upon Ca2+-binding, in composition and conformation, are quantified through integrated data analysis. The results indicate that Ca2+ binds specifically into the phospholipid headgroup zone, resulting in membrane charging and membrane swelling, with a saturated Ca2+-lipid binding ratio of 1:8. A Ca2+-binding isotherm to the nanodisc is further established and yields an unexpectedly high binding constant K = 4260 M-1 and a leaflet potential of ca. 100 mV based on a modified Gouy-Chapman model. The calcium-lipid binding ratio, however, drops to 40% when the nanodisc undergoes a gel-to-fluid phase transition, leading to an effective charge capacity of a few µF/cm2.

Optimization of the Production of Covalently Circularized Nanodiscs and Their Characterization in Physiological Conditions.

Lipid nanodiscs are widely used platforms for studying membrane proteins in a near-native environment. Lipid nanodiscs made with membrane scaffold proteins (MSPs) in the linear form have been well studied. Recently, a new kind of nanodisc made with MSPs in the circular form, referred to as covalently circularized nanodiscs (cNDs), has been reported to have some possible advantages in various applications. Given the potential of nanodisc technology, researchers in the field are very interested in learning more about this new kind of nanodisc, such as its reproducibility, production yield, and the possible pros and cons of using it. However, research on these issues is lacking. Here, we report a new study on nanodiscs made with circular MSPs, which are produced from a method different from the previously reported method. We show that our novel production method, detergent-assisted sortase-mediated ligation, can effectively avoid high-molecular-weight byproducts and also significantly improve the yield of the target proteins up to around 80% for larger circular MSP constructs. In terms of the application of circular MSPs, we demonstrate that they can be used to assemble nanodiscs using both synthetic lipids and native lipid extract as the source of lipids. We also show that bacteriorhodopsin can be successfully incorporated into this new kind of cND. Moreover, we found that cNDs have improved stability against both heat and high-concentration-induced aggregations, making them more beneficial for related applications.

New insights into Keggin-type 12-tungstophosphoric acid from 31P MAS NMR analysis of absorbed trimethylphosphine oxide and DFT calculations.

The acid and transport properties of the anhydrous Keggin-type 12-tungstophosphoric acid (H(3)PW(12)O(40); HPW) have been studied by solid-state (31)P magic-angle spinning NMR of absorbed trimethylphosphine oxide (TMPO) in conjunction with DFT calculations. Accordingly, (31)P NMR resonances arising from various protonated complexes, such as TMPOH(+) and (TMPO)(2)H(+) adducts, could be unambiguously identified. It was found that thermal pretreatment of the sample at elevated temperatures (≥423 K) is a prerequisite for ensuring complete penetration of the TMPO guest probe molecule into HPW particles. Transport of the TMPO absorbate into the matrix of the HPW adsorbent was found to invoke a desorption/absorption process associated with the (TMPO)(2)H(+) adducts. Consequently, three types of protonic acid sites with distinct superacid strengths, which correspond to (31)P chemical shifts of 92.1, 89.4, and 87.7 ppm, were observed for HPW samples loaded with less than three molecules of TMPO per Keggin unit. Together with detailed DFT calculations, these results support the scenario that the TMPOH(+) complexes are associated with protons located at three different terminal oxygen (O(d)) sites of the PW(12)O(40)(3-) polyanions. Upon increasing the TMPO loading to >3.0 molecules per Keggin unit, abrupt decreases in acid strength and the corresponding structural variations were attributed to the change in secondary structure of the pseudoliquid phase of HPW in the presence of excessive guest absorbate.

31P chemical shift of adsorbed trialkylphosphine oxides for acidity characterization of solid acids catalysts.

A comprehensive study has been made to predict the adsorption structures and (31)P NMR chemical shifts of various trialkylphosphine oxides (R3PO) probe molecules, viz., trimethylphosphine oxide (TMPO), triethylphosphine oxide (TEPO), tributylphosphine oxide (TBPO), and trioctylphosphine oxide (TOPO), by density functional theory (DFT) calculations based on 8T zeolite cluster models with varied Si-H bond lengths. A linear correlation between the (31)P chemical shifts and proton affinity (PA) was observed for each of the homologous R3PO probe molecules examined. It is found that the differences in (31)P chemical shifts of the R3POH(+) adsorption complexes, when referring to the corresponding chemical shifts in their crystalline phase, may be used not only in identifying Brønsted acid sites with varied acid strengths but also in correlating the (31)P NMR data obtained from various R3PO probes. Such a chemical shift difference therefore can serve as a quantitative measure during acidity characterization of solid acid catalysts when utilizing (31)P NMR of various adsorbed R3PO, as proposed in our earlier report (Zhao; et al. J. Phys. Chem. B 2002, 106, 4462) and also illustrated herein by using a mesoporous H-MCM-41 aluminosilicate (Si/Al = 25) test adsorbent. It is indicative that, with the exception of (TMPO), variations in the alkyl chain length of the R3PO (R = C(n)H(2n+1); n > or = 2) probe molecules have only negligible effect on the (31)P chemical shifts (within experimental error of ca. 1-2 ppm) either in their crystalline bulk or in their corresponding R3POH(+) adsorption complexes. Consequently, an average offset of 8 +/- 2 ppm was observed for (31)P chemical shifts of adsorbed R3PO with n > or = 2 relative to TMPO (n = 1). Moreover, by taking the value of 86 ppm predicted for TMPO adsorbed on 8T cluster models as a threshold for superacidity (Zheng; et al. J. Phys. Chem. B 2008, 112, 4496), a similar threshold (31)P chemical shift of ca. 92-94 ppm was deduced for TEPO, TBPO, and TOPO.