A reply to "TCR+/BCR+ dual-expressing cells and their associated public BCR clonotype are not enriched in type 1 diabetes".

We have recently identified a novel lymphocyte that is a dual expresser (DE) of TCRαß and BCR. DEs in T1D patients are predominated by a public BCR clonotype (clone-x) that encodes a potent autoantigen that cross-activates insulin-reactive T cells. Betts and colleagues were able to detect DEs but alleged to not detect high DE frequency, clone-x, or similar clones in T1D patients. Unfortunately, the authors did not follow our methods and when they did, their flow cytometric data at two sites were conflicting. Moreover, contrary to their claim, we identified clones similar to clone-x in their data along with clones bearing the core motif (DTAMVYYFDYW). Additionally, their report of no increased usage of clone-x VH/DH genes by bulk B cells confirms rather than challenges our results. Finally, the authors failed to provide data verifying purity of their sorted DEs, making it difficult to draw reliable conclusion of their repertoire analysis. This Matters Arising Response paper addresses the Japp et al. (2021) Matters Arising paper, published concurrently in Cell.

A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

A mutagenesis study of autoantigen optimization for potential T1D vaccine design.

A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to HLA-DQ8, supporting its strong role in CD4+ T cell activation. In this work, we probed HLA-X-idiotype-TCR binding and designed enhanced-reactive pHLA-TCR antigens using an in silico mutagenesis approach which we functionally validated by cell proliferation assays and flow cytometry. From a combination of single, double, and swap mutations, we identified antigen-binding sites p4 and p6 as potential mutation sites for HLA binding affinity enhancement. Site p6 is revealed to favor smaller but more hydrophobic residues than the native tyrosine, such as valine (Y6V) and isoleucine (Y6I), indicating a steric mechanism in binding affinity improvement. Meanwhile, site p4 methionine mutation to hydrophobic residues isoleucine (M4I) or leucine (M4L) modestly increases HLA binding affinity. Select p6 mutations to cysteine (Y6C) or isoleucine (Y6I) exhibit favorable TCR binding affinities, while a swap p5-p6 tyrosine-valine double mutant (V5Y_Y6V) and a p6-p7 glutamine-glutamine double mutant (Y6Q_Y7Q) exhibit enhanced HLA binding affinity but weakened TCR affinity. This work holds relevance to potential T1D antigen-based vaccine design and optimization.

An analysis of the stability and bifurcation of a discrete-time predator-prey model with the slow-fast effect on the predator.

In many environments, predators have significantly longer lives and meet several generations of prey, or the prey population reproduces rapidly. The slow-fast effect can best describe such predator-prey interactions. The slow-fast effect ε can be considered as the ratio between the predator's linear death rate and the prey's linear growth rate. This paper examines a slow-fast, discrete predator-prey interaction with prey refuge and herd behavior to reveal its complex dynamics. Our methodology employs the eigenvalues of the Jacobian matrix to examine the existence and local stability of fixed points in the model. Through the utilization of bifurcation theory and center manifold theory, it is demonstrated that the system undergoes period-doubling bifurcation and Neimark-Sacker bifurcation at the positive fixed point. The hybrid control method is utilized as a means of controlling the chaotic behavior that arises from these bifurcations. Moreover, numerical simulations are performed to demonstrate that they are consistent with analytical conclusions and to display the complexity of the model. At the interior fixed point, it is shown that the model undergoes a Neimark-Sacker bifurcation for larger values of the slow-fast effect parameter by using the slow-fast effect parameter ε as the bifurcation parameter. This is reasonable since a large ε implies an approximate equality in the predator's death rate and the prey's growth rate, automatically leading to the instability of the positive fixed point due to the slow-fast impact on the predator and the presence of prey refuge.

Climate change effects and their implications for the financial markets: Evidence from the United Kingdom.

This study aims to examine how the climate affects the behaviour of the stock market. To achieve this, we have drawn on daily data from Jan 2005 to Jan 31, 2023 and several environmental factors (e.g., temperature, humidity, cloud cover and visibility) to account for extreme weather conditions using the 21-day moving average and its standard deviation. The empirical analysis has revealed three key findings regarding the impact of weather on the stock market's behaviour. First, various forms of extreme weather conditions consistently lead to influence stock behaviour. Second, results provide valuable insights into market behaviour and help investors to make more informed investment decisions. Third, the weather conditions have new information about the climate risk and investors should react to it swiftly in light of our findings. The saliency theory can help reconcile the theoretical conflicts between the real options and risk-shifting theories when it comes to investing in uncertain and extreme climate conditions.

Financial sanctions and environmental, social, and governance (ESG) performance: A comparative study of ownership responses in the Chinese context.

This study conducts a comprehensive examination of the relationships between strategic investors, financial sanctions, and ESG performance in non-financial Chinese firms from 2011 to 2022. Using data from ASSET4 and the Global Sanction Database (GSDB), the study reveals that government and foreign investors significantly promote ESG performance, while family investors have a negative impact. Moreover, the findings show distinct responses among government, foreign, and family investors when confronted with financial sanctions. Specifically, both foreign and family investors demonstrate an increased engagement in CSR activities during these periods. Conversely, government investors are linked to a decrease in ESG performance amidst financial sanctions. The results make significant contributions to the fields of ownership literature, agency theory, and sanctions literature. Additionally, they provide practical implications for diverse stakeholders, including investors, managers, and policymakers.

Risk modelling of ESG (environmental, social, and governance), healthcare, and financial sectors.

Climate change poses enormous ecological, socio-economic, health, and financial challenges. A novel extreme value theory is employed in this study to model the risk to environmental, social, and governance (ESG), healthcare, and financial sectors and assess their downside risk, extreme systemic risk, and extreme spillover risk. We use a rich set of global daily data of exchange-traded funds (ETFs) from 1 July 1999 to 30 June 2022 in the case of healthcare and financial sectors and from 1 July 2007 to 30 June 2022 in the case of ESG sector. We find that the financial sector is the riskiest when we consider the tail index, tail quantile, and tail expected shortfall. However, the ESG sector exhibits the highest tail risk in the extreme environment when we consider a shock in the form of an ETF drop of 25% or 50%. The ESG sector poses the highest extreme systemic risk when a shock comes from China. Finally, we find that ESG and healthcare sectors have lower extreme spillover risk (contagion risk) compared to the financial sector. Our study seeks to provide valuable insights for developing sustainable economic, business, and financial strategies. To achieve this, we conduct a comprehensive risk assessment of the ESG, healthcare, and financial sectors, employing an innovative approach to risk modelling in response to ecological challenges.

Assessing the environmental impacts of renewable energy sources: A case study on air pollution and carbon emissions in China.

This study investigates the impact of renewable and non-renewable energy sources on carbon emissions in the context of China's 14th Five-Year Plan (2021-2025). The plan emphasises a "Dual-control" strategy of simultaneously setting energy consumption limits and reducing energy intensity for GDP (gross domestic product) in order to meet the targets of the five-year plan. Using a comprehensive dataset of Chinese energy and macroeconomic information spanning from 1990 to 2022, we conduct a Granger causality analysis to explore the relationship between energy sources and the level of air pollution. Our findings reveal a unidirectional link, wherein renewable energy contributes to a reduction in air pollution, while non-renewable energy sources lead to an increase. Despite the government's investment in renewable energy, our results show that China's economy remains heavily reliant on traditional energy sources (e.g., fossil fuels). This research is the first systematic examination of the interplay between energy usage and carbon emissions in the Chinese context. Our findings provide valuable insights for policy and market strategies aimed at promoting carbon neutrality and driving technological advancements in both government and industries.

Radiological risk assessment from the Gamma spectrometry of soil samples in the vicinity of a research centre in Nilore, Pakistan.

Measurements of radionuclides' activities in air, water, and soil give clues about the anthropogenic activities in the region, and imperative to assess the overall radiological risk for individuals. Such an investigation was carried out to characterize the soil activities in the region hosting a research center, and to calculate the associated elements of radiological risk in terms of radiation doses and hazard indices. The soil samples were collected within the radius of 10 km in local area, Nilore, and analysed for activity using a high-purity germanium (HPGe) gamma spectrometric system. In all samples, only the basic nuclides, contributing to terrestrial activity, i.e., 40 K, 232Th, 226Ra, and 137Cs, were observed within the detectable limits of activity. The distribution of the data set and the correlation between the measured activities were studied with the use of the principal component analysis (PCA). The measured average specific activities of 226Ra, 232Th, 40 K, and 137Cs were 40.65 ± 9.84 Bq/kg, 59.31 ± 16.53 Bq/kg, 528.24 ± 131.18 Bq/kg, and 5.16 ± 4.56 Bq/kg respectively. The corresponding dose rate in air was found to be 76.63 ± 18.39 nGy/h, which is slightly higher than the world median value of 51 nGy/h calculated from concentration of terrestrial radionuclides in soil but falls within the world average value range of outdoor external exposure of 18-93 nGy/h obtained through direct measurement, and therefore not harmful for the living species. The standard hazard indices for all soil samples such as radium equivalent activity ([Formula: see text]), external hazard index (Hex), and internal hazard index (Hin) were also found within safe limits for the soil to be used as construction of building material. This investigation led to conclusion that the soil activities are consistent with the usual background level of terrestrial activities, and their associated dose rates are well within the safe limits for public.

Expression of unique gene signature distinguishes TCRαß+ /BCR+ dual expressers from CD3+ CD14+ doublets.

Increasing evidence shows pathophysiological significance of rare immune cells, necessitating the need for reliable and proper methods for their detection and analysis. We have recently identified a new lymphocyte that coexpresses lineage markers of T- and B-cells including T cell receptor and B cell receptor (called dual expressers, DEs). Because of the peculiar phenotype of DEs, we used multiple techniques to authenticate their identity (fluorescence-activated cell sorting [FACS], scRNAseq, EBV cell lines, and imaging flow cytometry). In an recent article published in this journal, Burel and colleagues successfully detected DEs using FACS and imaging microscopy. Yet they claimed, based on the profile of what they called naturally occurring CD3+ CD14+ T cell/monocyte complexes that the scRNAseq signature of DEs resembles that of cell-cell complexes. Serious flaws in their analysis, however, invalidate their conclusions. Unlike the CD3+ CD14+ complexes, DEs have a distinct identity due to expression of a unique set of signature genes. Without a clear explanation, Burel and colleagues excluded these genes from their analysis, thereby effectively stripped DEs from their identity. Inclusion of these genes as described in this communication restores the identity of DEs. Moreover, contrary to the claim of Burel and colleagues, B- and T-cell specific genes are similarly expressed in DE cells.

The Association Between Preoperative Opioid Exposure and Prolonged Postoperative Use.

OBJECTIVE: To determine the effect of nonchronic, periodic preoperative opioid use on prolonged opioid fills after surgery. BACKGROUND: Nonchronic, periodic opioid use is common, but its effect on prolonged postoperative opioid fills is not well understood. We hypothesize greater periodic opioid use before surgery is correlated with persistent postoperative use. METHODS: We used a national private insurance claims database, Optum's de-identifed Clinformatics Data Mart Database, to identify adults undergoing general, gynecologic, and urologic surgical procedures between 2008 and 2015 (N = 191,043). We described patterns of opioid fills based on dose, recency, duration, and continuity to categorize preoperative opioid exposure. Patients with chronic use were excluded. Our primary outcome was persistent postoperative use, defined as filling an opioid prescription between 91- and 180-days post-discharge. The association between preoperative opioid use and persistent use was determined using multivariable logistic regression, controlling for clinical covariates. RESULTS: In the year before surgery, 41% of patients had nonchronic, periodic opioid fills. Compared with other risk factors, patterns of preoperative fills were most strongly correlated with persistent postoperative opioid use. Patients with recent intermittent use were significantly more likely to have prolonged fills after surgery compared with opioid-naïve patients [minimal use: odds ratio (OR): 2.0, 95% confidence interval (CI) 1.89-2.03; remote intermittent: OR 4.7, 95% CI 4.46-4.93; recent intermittent: OR 12.2, 95% CI 11.49-12.90]. CONCLUSIONS: Patients with nonchronic, periodic opioid use before surgery are vulnerable to persistent postoperative opioid use. Identifying opioid use before surgery is a critical opportunity to optimize care after surgery.

Detection of lead in soil implying sample heating and laser-induced breakdown spectroscopy.

The emission line intensities enhancement and sensitivity of laser-induced breakdown spectroscopy (LIBS) has been a subject of great interest for the last several years to improve the detection of the trace elements in soil and other environmental samples. Among several other methodologies, LIBS of the heated targets is emerging as one of the effective techniques to achieve the objective. We have investigated the effect of target heating (room temperature, 100°C, and 200°C) on the emission enhancement and plasma parameters of the laser-produced plasma on the soil sample containing 80 ppm lead. In addition, the limit of detection (LOD) of lead in soil has been determined at a fixed target temperature (200°C) and with varying lead concentration (20 ppm, 80 ppm, and 100 ppm) in the soil samples. With increasing the target temperature, not only do the emission line intensities, the excitation temperature, and electron number density increase, but also the spectral lines of Pb emerge, which were absent in the soil spectra recorded at room temperature. The limit of detection of lead in LIBS of the heated soil target has been determined as 3.8 ppm. This study reveals the potential application of the LIBS of a pre-heated target for the detection of lead with an improved LOD in the environmental sample.

Carbon neutrality: The role of banks in optimal environmental management strategies.

This study explores the ecological ambitions of banks by studying the coincidence of economic realities with environmental management strategies. We address this question by studying the environmental performance of US banks and its impact on their tail risk as US is not committed to carbon neutrality in COP 21. We proxy economic reality with tail risk of banks and employ a novel extreme value theory to measure this. We use Asset4 ESG data for environmental performance score and test our hypothesis with a sample of 256 US banks. The results indicate that the US banks are ecologically ambitious and their environmental strategies are likely to reduce their tail risk. This provides evidence that better environmental strategies do coincide with the economic realities. We test the consistency of our results by using alternate proxies for tail risk and find our results robust. Our results are also not driven by endogeneity concerns. Finally, our additional results show that the nature of relationship differs with corporate governance levels, CSR committee existence, institutional ownership presence and crisis period.

Real-time simulation of accidental passive transport of radioactive pollutant from a proposed nuclear power plant.

Power plant's site selection is a complex task and involves through analyses of multi-disciplinary processes which are interlinked with each other. The site selection for nuclear power plants additionally requires an assessment of radiation doses to the environment and public during normal operation and in the case of an accident. This demands the problem of radioactive particles' dispersion in atmosphere to be analysed in real time for a comprehensive set of radioactive release scenarios in prevailing meteorological conditions in the plant surroundings. In this study, a local scale atmospheric dispersion problem, considering a hypothetical accidental release (1 Bq s-1of I-131) from a nuclear power plant is simulated with a combination of weather forecasting and particle dispersion codes on a multiprocessor computer system. The meteorological parameters are predicted with a weather research and forecasting (WRF) model and used in Lagrangian particle dispersion model based code FLEXPART to calculate the trajectory of released particles, and thereby, the estimation of spatial I-131 dose distribution. The concentration of particles and radiation doses were calculated for release heights of 10, 57, and 107 m and found in a reasonable agreement with the observed data and better than an earlier investigation done with regional atmospheric modelling system (RAMS) code. A comparison between the results of WRF and RAMS for various meteorological parameters revealed that better space-time predictions of wind speeds and directions by WRF had a profound effect on tracing the trajectories of particles and thereby the spatial dose distribution. The particles followed the changes in wind direction predicted by WRF that were known to prevail in the region.

The impact of carbon emissions on country risk: Evidence from the G7 economies.

This paper empirically investigates the effect of carbon emissions on sovereign risk? To answer this question, we use fixed effects model by using annual data from G7 advanced economies, which includes Canada, France, Germany, Italy, Japan, UK and USA, for the period from 1996 to 2014. We employ a novel extreme value theory to measure sovereign risk. The results indicate that climate change (carbon emissions) are likely to increase sovereign risk significantly. We also expand our analysis to some specific sectors, as some of the sectors emit more carbon than others. Specifically, we take top three polluting sectors namely: transportation, electricity and industry and show that they are more likely to increase the sovereign risk. Our results are robust to change in risk measures, estimation in differences and dynamic version of econometric models. Therefore, we have robust consideration that the carbon emissions significantly explain the sovereign risk.

Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

IL-17 and limits of success.

Interleukin-17 (IL-17) is a potent proinflammatory cytokine that protects a host against fungal and extracellular bacterial infections. On the other hand, excessive or dysregulated production of IL-17 underlines susceptibility to autoimmune disease. Consequently, blocking IL-17 has become an effective strategy for modulating several autoimmune diseases, including multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA). Notably, however, IL-17 blockade remains ineffective or even pathogenic against important autoimmune diseases such as inflammatory bowel disease (IBD). Furthermore, the efficacy of IL-17 blockade against other autoimmune diseases, including type 1 diabetes (T1D) is currently unknown and waiting results of ongoing clinical trials. Coming years will determine whether the efficacy of IL-17 blockade is limited to certain autoimmune diseases or can be expanded to other autoimmune diseases. These efforts include new clinical trials aimed at testing second-generation agents with the goal of increasing the efficiency, spectrum, and ameliorating side effects of IL-17 blockade. Here we briefly review the roles of IL-17 in the pathogenesis of selected autoimmune diseases and provide updates on ongoing and recently completed trials of IL-17 based immunotherapies.

Survey of physician attitudes towards psychogenic nonepileptic seizures and driving.

BACKGROUND: Physicians from various disciplines encounter patients presenting with psychogenic nonepileptic seizures (PNES) as part of their routine clinical practice. Recommendations towards assessing fitness to drive and reporting are clearer for conditions such as neurocognitive disorders and epilepsy, but such guidelines do not exist for patients with PNES. Here, we assess physicians' attitudes towards driving for patients diagnosed with PNES. METHODS: Electronic questionnaires were sent to Neurology and Family Medicine physicians practicing at Creighton University Medical Center and Psychiatry physicians practicing at Creighton-Nebraska Psychiatry Residency Program to assess their opinion regarding driving risk when encountering PNES. RESULTS: The survey request was sent to 125 physicians, of which close to 60% completed the survey. Eighty-eight percent of participants encountered PNES in their clinical practice, and 69.1% agreed it was a difficult problem to assess, with only 8.3% endorsing a belief that these patients should drive without restrictions. Ninety-three percent felt having guidelines would help them assess the driving risk in this population. CONCLUSION: Psychogenic nonepileptic seizures are common across neurology, psychiatry, and primary care, and most physicians find assessing driving risk in such individuals highly warranted yet difficult. Developing such assessment guidelines and recommendations is of great need for clinicians.

Elemental composition analysis of granite rocks using LIBS and LA-TOF-MS.

Qualitative and quantitative analysis of the raw granite rocks acquired from deposits in the Hunza district, Gilgit area of Pakistan were studied using laser-induced breakdown spectroscopy (LIBS) and laser ablation time-of-flight mass spectrometry (LA-TOF-MS). The optical emission spectra of the granite rocks used in artificial jewelry and for flooring tiles show the emission lines of (Si, Ca, K, Fe, Mg, Al, Na, and Li) and (Si, Ca, K, Fe, Mg, Al, Ti, Na, Ba, and Li), respectively. The mass spectra of these granite rocks were also studied with the LA-TOF-MS, revealing analogous elemental compositions. The results obtained using LIBS and LA-TOF-MS for the raw granite samples display their ability as powerful and complementary tools for the compositional analysis of the geological samples.

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.