Miracle-dz/UniFAR-FTUs huggingface dataset:
Opioids and Gabapentinoids Utilisation and Their Related-Mortality Trends in the United Kingdom Primary Care Setting, 2010–2019: A Cross-National, Population-Based Comparison Study

Background: There is growing concern over the increasing utilisation trends of opioids and gabapentinoids across but there is lack of data assessing and comparing the utilisation trends across the four United Kingdom countries. We assessed/compared opioids and gabapentinoids utilisation trends across the four United Kingdom countries then evaluated the correlation between their utilisation with related mortality. Methods: This repeated cross-national study used Prescription Cost Analysis (PCA) datasets (2010–2019). Opioids and gabapentinoids utilisation were measured using number of items dispensed/1,000 inhabitants and defined daily doses (DDDs)/1,000 inhabitant/day. Number of Opioids and gabapentinoids-related mortality were extracted from the United Kingdom Office for National Statistics (2010–2018). Data were analysed using descriptive statistics including linear trend analysis; correlation between the Opioids and gabapentinoids utilisation and their related mortality using Pearson correlation coefficient. Results: The results illustrated an overall significant increasing trend in the utilisation of opioids (12.5–14%) and gabapentinoids (205–207%) with substantial variations among the four United Kingdom countries. For opioids, Scotland had the highest level of number of items dispensed/1,000 inhabitant (156.6% higher compared to the lowest level in England), whereas in terms of DDD/1,000 inhabitant/day, NI had the highest level. Utilisation trends increased significantly across the four countries ranging from 7.7% in Scotland to 20.5% in NI (p < 0.001). Similarly, for gabapentinoids, there were significant increasing trends ranging from 126.5 to 114.9% in NI to 285.8–299.6% in Wales (p < 0.001) for number of items/1,000 inhabitants and DDD/1,000 inhabitant/day, respectively. Although the utilisation trends levelled off after 2016, this was not translated into comparable reduction in opioids and gabapentinoids-related mortality as the latter continued to increase with the highest level in Scotland (3.5 times more deaths in 2018 compared to England- 280.1 vs. 79.3 deaths/million inhabitants). There were significant moderate-strong positive correlations between opioids and gabapentinoids utilisation trends and their related mortality. Conclusion: The utilisation trends of opioids and gabapentinoids have increased significantly with substantial variations among the four United Kingdom countries. This coincided with significant increase in their related mortality. Our findings support the call for immediate actions including radical changes in official United Kingdom policies on drug use and effective strategies to promote best clinical practice in opioids and gabapentinoids prescribing.
Leukocyte Immunoglobulin-Like Receptors in Regulating the Immune Response in Infectious Diseases: A Window of Opportunity to Pathogen Persistence and a Sound Target in Therapeutics

Immunoregulatory receptors are essential for orchestrating an immune response as well as appropriate inflammation in infectious and non-communicable diseases. Among them, leukocyte immunoglobulin-like receptors (LILRs) consist of activating and inhibitory receptors that play an important role in regulating immune responses modulating the course of disease progression. On the one hand, inhibitory LILRs constitute a safe-guard system that mitigates the inflammatory response, allowing a prompt return to immune homeostasis. On the other hand, because of their unique capacity to attenuate immune responses, pathogens use inhibitory LILRs to evade immune recognition, thus facilitating their persistence within the host. Conversely, the engagement of activating LILRs triggers immune responses and the production of inflammatory mediators to fight microbes. However, their heightened activation could lead to an exacerbated immune response and persistent inflammation with major consequences on disease outcome and autoimmune disorders. Here, we review the genetic organisation, structure and ligands of LILRs as well as their role in regulating the immune response and inflammation. We also discuss the LILR-based strategies that pathogens use to evade immune responses. A better understanding of the contribution of LILRs to host–pathogen interactions is essential to define appropriate treatments to counteract the severity and/or persistence of pathogens in acute and chronic infectious diseases lacking efficient treatments.
Prediction and action in cortical pain processing

Predicting that a stimulus is painful facilitates action to avoid harm. But does the prediction of upcoming painful events engage the same or different processes than acting to avoid or reduce current pain? In this fMRI experiment, we investigated brain activity as a function of current and predicted painful or nonpainful thermal stimulation, and the ability of voluntary action to affect the duration of the upcoming stimulation. Participants (n = 30) performed a task which involved the administration of a painful or nonpainful stimulus (S1), which predicted an immediately subsequent very painful or nonpainful stimulus (S2). Participants’ task was to press a response button within a short time window upon the presentation of a response cue during S1. On action-effective trials, pressing the button within the specified time window reduced the duration of the upcoming stimulation. On action-ineffective trials, pressing the button had no effect on upcoming stimulation. Predicted pain increased activation in regions including anterior cingulate cortex (ACC), midcingulate cortex (MCC), and insula; however, activation in ACC and MCC depended on whether a meaningful action was performed, with MCC activation showing a direct relationship with motor output. Region-of-interest analyses revealed that insula’s responses for predicted pain were also modulated by potential action consequences, especially in the left hemisphere, albeit without a direct relationship with motor output. Taken together, these findings suggest that cortical pain processing is not specifically tied to the sensory stimulus, but instead depends on the consequences of that stimulus for sensorimotor control of behavior. Significance statement During acute pain, the processing of an acute sensory event likely occurs in parallel with predictive processing about its relevance for current and upcoming voluntary behavior. Here, we temporally separated the functional processes underlying current and predicted pain and found that activation in regions typically implicated in acute pain is modulated both by the noxious nature of upcoming events, as well as by the possibility to affect those events via voluntary action. Specifically, activation in anterior cingulate cortex (ACC), midcingulate cortex (MCC), and insula during the delivery of a painful or nonpainful stimulus was modulated by whether an upcoming stimulus would be painful. Furthermore, ACC/MCC involvement in pain prediction depended on whether a meaningful action was performed, i.e., whether a button-press action would reduce the duration of the upcoming stimulus. Although insula activation was also affected by the possibility of the button-press action to reduce the duration of the upcoming stimulation, only MCC had a direct relationship with motor output.
Confronting Challenges to Enterotoxigenic Escherichia coli Vaccine Development

The enterotoxigenic Escherichia coli (ETEC) are a diverse and genetically plastic pathologic variant (pathovar) of E. coli defined by their production of heat-labile (LT) and heat-stable (ST) enterotoxins. These pathogens, which came to recognition more than four decades ago in patients presenting with severe cholera-like diarrhea, are now known to cause hundreds of millions of cases of symptomatic infection annually. Children in low-middle income regions of the world lacking access to clean water and basic sanitation are disproportionately affected by ETEC. In addition to acute diarrheal morbidity, these pathogens remain a significant cause of mortality in children under the age of five years and have also been linked repeatedly to sequelae of childhood malnutrition and growth stunting. Vaccines that could prevent ETEC infections therefore remain a high priority. Despite several decades of effort, a licensed vaccine that protects against the breadth of these pathogens remains an aspirational goal, and the underlying genetic plasticity of E. coli has posed a fundamental challenge to development of a vaccine that can encompass the complete antigenic spectrum of ETEC. Nevertheless, novel strategies that include toxoids, a more complete understanding of ETEC molecular pathogenesis, structural details of target immunogens, and the discovery of more highly conserved antigens essential for virulence should accelerate progress and make a broadly protective vaccine feasible.
Making Plants Smell Like Moths: Nicotiana benthamiana release moth pheromone alcohol, aldehyde and acetate upon transient expression of biosynthetic genes of different origin

Using genetically modified plants as natural dispensers of insect pheromones may eventually become part of a novel strategy for integrated pest management. In the present study, we first characterized essential functional genes for sex pheromone biosynthesis in the rice stem borer Chilo suppressalis (Walker) by heterologous expression in Saccharomyces cerevisiae and Nicotiana benthamiana, including two desaturase genes CsupYPAQ and CsupKPSE, and a reductase gene CsupFAR2. Subsequently, we co-expressed CsupYPAQ and CsupFAR2 together with the previously characterized moth desaturase AtrΔ11 in N. benthamiana. This resulted in the production of (Z)-11-hexadecenol together with (Z)-11-hexadecenal, the major pheromone component of C. suppressalis. Both compounds were collected from the transformed N. benthamiana headspace volatiles using solid phase microextraction. We finally added the expression of a yeast acetyltransferase gene ATF1 and could then confirm also (Z)-11-hexadecenyl acetate release from the plant. Our results pave the way for stable transformation of plants to be used as biological pheromone sources in different pest control strategies.
Late Jurassic Structural Deformation and Late Cenozoic Reactivation of the Southern Junggar Fold-And-Thrust Belt, NW China

Because of the influence of the far field effect of the collision between Euro-Asian and India plates during the Late Cenozoic, the Tian Shan orogenic belt underwent intense reactivation, forming the Southern Junggar fold-and-thrust belt (SJ-FTB) to the north and the Kuqa fold-and-thrust belt to the south. Most previous research focuses on the deformation features and mechanisms during the Late Cenozoic. However, little research has been done on deformation features and mechanisms during the Late Jurassic. In this paper, we conducted geometric and kinematic analyses of seismic profiles and outcrop data to reveal the Late Jurassic deformation characteristics in SJ-FTB. Furthermore, we carried out sandbox modeling experiments to reproduce the regional structural evolution since the Early Jurassic. Angular unconformity between the Cretaceous and Jurassic is well preserved in the Qigu anticline belt. This unconformity also exists in the Huoerguosi–Manasi–Tugulu (HMT) anticline belt, which is the second fold belt of the SJ-FTB, indicating that the HMT anticline belt started to become active during the Late Jurassic. The Qigu anticline belt reactivated intensively during the Late Cenozoic, and the displacement was transferred to the HMT anticline belt along the Paleogene Anjihaihe Formation mudstone detachment. Therefore, the present-day SJ-FTB forms because of the two-stage compressional deformation from both the Late Jurassic and Late Cenozoic (ca. 24 Ma).
Lifespan Analysis of Dystrophic mdx Fast-Twitch Muscle Morphology and Its Impact on Contractile Function

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast twitch EDL muscles from animals 4-22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost ∼80% of their maximum force after one eccentric contraction of 20% strain, with the greatest loss ∼93% recorded in senescent 22 month old mdx mice. In old age groups there was minimal force recovery ∼24% after 120 minutes, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-stage model where a “tipping point” is reached when branched fibers rupture irrevocably on eccentric contraction. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.
The Mediational Role of Desire for Cultural Tightness on Concern With COVID-19 and Perceived Self-Control

When ecological threats are more severe or prevalent, societies are more likely to tighten their social norms and punishments. Moreover, when people follow clear and tight rules, they are more prone to regulate their behavior (i.e., self-control) in order to avoid punishment. Therefore, we examined the mediating role of people’s endorsement of cultural tightness (i.e., support and desire) on the relationship between concern with COVID-19 threat and personal self-control. Our hypothesis was tested through a mediation model in two studies with a sample of (N=315, 77.1% females, Mage=23.71) university students (Study 1) and with a heterogeneous sample of (N=239, 65.7% females, Mage=36.55) participants (Study 2). Empirical support for the proposed model was found in both studies. Implications of this research will be discussed. The main implication is related to the possibility that people’s desire for strong norms to cope with the COVID-19 threat could promote greater self-regulated preventive behavior in order to protect their health.
Novel Immune Infiltrating Cell Signature Based on Cell Pair Algorithm Is a Prognostic Marker in Cancer

Tumor-infiltrating immune cells (TIICs) have become an important source of markers for predicting the clinical outcomes of cancer patients. However, measurements of cellular heterogeneity vary due to the frequently updated reference genomes and gene annotations. In this study, we systematically collected and evaluated the infiltration pattern of 65 immune cells. We constructed the Immune Cell Pair (ICP) score based on the cell pair algorithm in 3,715 samples and across 12 independent cancer types, among which, the ICP score from six cancer types was further validated in 2,228 GEO samples. An extensive tumorigenic and immunogenomic analysis was subsequently conducted. As a result, the ICP score showed a robust reliability and efficacy in predicting the survival of patients with gliomas, in pan-cancer samples, and six independent cancer types. Notably, the ICP score was correlated with the genomic alteration features in gliomas. Moreover, the ICP score exhibited a remarkable association with multiple immunomodulators that could potentially mediate immune escape. Finally, the ICP score predicted immunotherapeutic responses with a high sensitivity, allowing a useful tool for predicting the overall survival and guiding immunotherapy for cancer patients.
Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats

Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.
Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations

DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56+CD16+ NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19+CD20+ B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.
Molecular Brightness Approach for FRET Analysis of Donor-Linker-Acceptor Constructs at the Single Molecule Level: A Concept

In this report, we have developed a simple approach using single-detector fluorescence autocorrelation spectroscopy (FCS) to investigate the Förster resonance energy transfer (FRET) of genetically encoded, freely diffusing crTC2.1 (mTurquoise2.1–linker–mCitrine) at the single molecule level. We hypothesize that the molecular brightness of the freely diffusing donor (mTurquoise2.1) in the presence of the acceptor (mCitrine) is lower than that of the donor alone due to FRET. To test this hypothesis, the fluorescence fluctuation signal and number of molecules of freely diffusing construct were measured using FCS to calculate the molecular brightness of the donor, excited at 405 nm and detected at 475/50 nm, in the presence and absence of the acceptor. Our results indicate that the molecular brightness of cleaved crTC2.1 in a buffer is larger than that of the intact counterpart under 405-nm excitation. The energy transfer efficiency at the single molecule level is larger and more spread in values as compared with the ensemble-averaging time-resolved fluorescence measurements. In contrast, the molecular brightness of the intact crTC2.1, under 488 nm excitation of the acceptor (531/40 nm detection), is the same or slightly larger than that of the cleaved counterpart. These FCS-FRET measurements on freely diffusing donor-acceptor pairs are independent of the precise time constants associated with autocorrelation curves due to the presence of potential photophysical processes. Ultimately, when used in living cells, the proposed approach would only require a low expression level of these genetically encoded constructs, helping to limit potential interference with the cell machinery.
Management of Patients With Glucocorticoid-Related Diseases and COVID-19

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing’s syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).
Polarisation in Southern Europe: Elites, Party Conflicts and Negative Partisanship

ABSTRACT The article complements our collection of studies of politics in polarised Southern Europe by offering a cross-regional comparison. Following a brief excursion into how polarisation in Southern Europe has been addressed in the existing literature, the focus zooms in on three country case studies. After showing the differential evolution of polarisation in Italy, Greece and Spain over recent decades, the story is brought up to date with an examination of the specific ways in which polarisation played out in the 2019 election cycle. marked by the Catalan conflict in Spain, the Macedonian name question in Greece and the polarising role of Matteo Salvini in Italy. The article concludes with comparative insights into the current polarisation drives in the three countries.