Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphatidylserine exposure promotes increased adhesion in Dictyostelium Copine A mutants

The phospholipid phosphatidylserine (PS) is a key signaling molecule and binding partner for many intracellular proteins. PS is normally found on the inner surface of the cell membrane, but PS can be flipped to the outer surface in a process called PS exposure. PS exposure is important in many cell functions, yet the mechanisms that control PS exposure have not been extensively studied. Copines (Cpn), found in most eukaryotic organisms, make up a family of calcium-dependent phospholipid binding proteins. In Dictyostelium, which has six copine genes, CpnA strongly binds to PS and translocates from the cytosol to the plasma membrane in response to a rise in calcium. Cells lacking the cpnA gene (cpnA-) have defects in adhesion, chemotaxis, membrane trafficking, and cytokinesis. In this study we used both flow cytometry and fluorescent microscopy to show that cpnA- cells have increased adhesion to beads and bacteria and that the increased adhesion was not due to changes in the actin cytoskeleton or cell surface proteins. We found that cpnA- cells bound higher amounts of Annexin V, a PS binding protein, than parental cells and showed that unlabeled Annexin V reduced the increased cell adhesion property of cpnA- cells. We also found that cpnA- cells were more sensitive to Polybia-MP1, which binds to external PS and induces cell lysis. Overall, this suggests that cpnA- cells have increased PS exposure and this property contributes to the increased cell adhesion of cpnA- cells. We conclude that CpnA has a role in the regulation of plasma membrane lipid composition and may act as a negative regulator of PS exposure.
Efficacy of Neoadjuvant Single or Dual Anti-HER-2 Therapy Combined with Chemotherapy in Patients with HER-2-Positive Breast Cancer: A Single-Center Retrospective Study

Background: Studies have shown that neoadjuvant anti-HER-2 therapy and chemotherapy can increase pathologic complete response (pCR) rate in HER-2-positive breast cancer patients and improve prognosis. However, data from Chinese patients are limited. Therefore, we conducted a single-center retrospective study to evaluate the effects of neoadjuvant single or dual anti-HER-2 therapy and chemotherapy in Chinese HER-2-positive breast cancer patients and to explore the prognostic indicators of pCR and progression-free survival (PFS). Methods: We included patients with HER-2-positive breast cancer treated with neoadjuvant anti-HER-2 therapy and chemotherapy at the First Affiliated Hospital of Chongqing Medical University in China from January 2016 to July 2020. We analyzed the relationship between patient characteristics and the pCR rate or PFS. Results: Forty-seven patients with HER-2-positive breast cancer receiving neoadjuvant anti-HER-2 therapy and chemotherapy were included. Univariate analysis suggested that compared with patients receiving neoadjuvant single anti-HER-2 therapy, patients receiving neoadjuvant dual anti-HER-2 therapy tended to have a higher pCR rate and better PFS. Patients who achieved pCR also tended to have longer PFS. Multivariate analysis indicated that patients with greater systemic inflammation response index (SIRI) reduction (>0.54) during neoadjuvant treatment (NAT) and patients with a lower T stage were more likely to achieve pCR. Patients aged ≤60 years with lower Ki-67 had longer PFS. Conclusion: Greater SIRI reduction during NAT was an independent influencing factor for pCR. Patients receiving neoadjuvant dual anti-HER-2 therapy and chemotherapy tended to have higher pCR rates and longer PFS. Patients who achieved pCR also tended to have longer PFS.
Determinants of Self-Rated Health Among Middle-Aged and Elderly Patients with COPD: The China Health and Retirement Longitudinal Study

This study aimed to assess self-rated health (SRH) status and its determinants in patients with chronic obstructive pulmonary disease (COPD). Participants aged at least 45 years were included from a nationally representative investigation in 2015. The SRH assessment was divided into two groups: “good” and “not good. ” Independent samples t-tests, chi-square tests, and Fisher’s exact tests were used to determine differences in patient characteristics between the two groups. Multiple logistic models were used to determine factors influencing SRH. A total of 1,215 patients with COPD were included in the final analysis, of whom 21.2% reported favorable SRH status. The results indicated that female gender, non-smoking, and elevated peak expiratory flow correlated with better SRH, while nighttime sleep duration less than 7 hours, asthma, and disability, negatively impacted SRH. Our findings provide new evidence for the development of effective health promotion programs for the well-being of patients with COPD.
Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide: an international collaborative study

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.
Bronchial angiogenesis in horses with severe asthma and its response to corticosteroids

Abstract Background Severe asthma in horses is characterized by structural changes that thicken the lower airway wall, a change that is only partially reversible by current treatments. Increased vascularization contributes to the thickening of the bronchial wall in humans with asthma and is considered a potential new therapeutic target. Objective To determine the presence of angiogenesis in the bronchi of severely asthmatic horses, and if present, to evaluate its reversibility by treatment with corticosteroids. Animals Study 1: Bronchial samples from asthmatic horses in exacerbation (7), in remission (7), and aged‐matched healthy horses. Study 2: Endobronchial biopsy samples from asthmatic horses in exacerbation (6) and healthy horses (6) before and after treatment with dexamethasone. Methods Blinded, randomized controlled study. Immunohistochemistry was performed using collagen IV as a marker for vascular basement membranes. Number of vessels, vascular area, and mean vessel size in the bronchial lamina propria were measured by histomorphometry. Reversibility of vascular changes in Study 2 was assessed after 2 weeks of treatment with dexamethasone. Results The number of vessels and vascular area were increased in the airway walls of asthmatic horses in exacerbation (P = .01 and P = .02, respectively) and in remission (P = .02 and P = .04, respectively) when compared to controls. In Study 2, the differences observed between groups disappeared after 2 weeks of treatment with corticosteroids because of the increased number of vessels in healthy horses. Conclusions and Clinical Importance Angiogenesis contributes to thickening of the airway wall in asthmatic horses and was not reversed by a 2‐week treatment with corticosteroids.
Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy

ABSTRACT Introduction: CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has the potential to increase the fraction of patients that respond to established immunotherapies. Areas covered: This article reviews current as well as emerging CD40 agonist therapies with a focus on antibody-based therapies, including next generation bispecific CD40 agonists. The scientific rationale for different design criteria, binding epitopes, and formats are discussed. Expert opinion: The ability of CD40 agonists to activate dendritic cells and enhance antigen cross-presentation to CD8+ T cells provides an opportunity to elevate response rates of cancer immunotherapies. While there are many challenges left to address, including optimal dose regimen, CD40 agonist profile, combination partners and indications, we are confident that CD40 agonists will play an important role in the challenging task of reprogramming the immune system to fight cancer.
Perspectives of nurses’ role in interprofessional pharmaceutical care across 14 European countries: A qualitative study in pharmacists, physicians and nurses

Objectives To understand healthcare professionals’ experiences and perceptions of nurses’ potential or ideal roles in pharmaceutical care (PC). Design Qualitative study conducted through semi-structured in-depth interviews. Setting Between December 2018 and October 2019, interviews were conducted with healthcare professionals of 14 European countries in four healthcare settings: hospitals, community care, mental health and long-term residential care. Participants In each country, pharmacists, physicians and nurses in each of the four settings were interviewed. Participants were selected on the basis that they were key informants with broad knowledge and experience of PC. Data collection and analysis All interviews were conducted face to face. Each country conducted an initial thematic analysis. Consensus was reached through a face-to-face discussion of all 14 national leads. Results 340 interviews were completed. Several tasks were described within four potential nursing responsibilities, that came up as the analysis themes, being: 1) monitoring therapeutic/adverse effects of medicines, 2) monitoring medicines adherence, 3) decision making on medicines, including prescribing 4) providing patient education/information. Nurses’ autonomy varied across Europe, from none to limited to a few tasks and emergencies to a broad range of tasks and responsibilities. Intended level of autonomy depended on medicine types and level of education. Some changes are needed before nursing roles can be optimised and implemented in practice. Lack of time, shortage of nurses, absence of legal frameworks and limited education and knowledge are main threats to European nurses actualising their ideal role in PC. Conclusions European nurses have an active role in PC. Respondents reported positive impacts on care quality and patient outcomes when nurses assumed PC responsibilities. Healthcare professionals expect nurses to report observations and assessments. This key patient information should be shared and addressed by the interprofessional team. The study evidences the need of a unique and consensus-based PC framework across Europe.
A Bayesian Inference Model for Metamemory

The dual-basis theory of metamemory suggests that people evaluate their memory performance based on both processing experience during the memory process and their prior beliefs about overall memory ability. However, few studies have proposed a formal computational model to quantitatively characterize how processing experience and prior beliefs are integrated during metamemory monitoring. Here, we introduce a Bayesian inference model for metamemory (BIM) which provides a theoretical and computational framework for the metamemory monitoring process. BIM assumes that when people evaluate their memory performance, they integrate processing experience and prior beliefs via Bayesian inference. We show that BIM can be fitted to recall or recognition tasks with confidence ratings on either a continuous or discrete scale. Results from data simulation indicate that BIM can successfully recover a majority of generative parameter values, and demonstrate a systematic relationship between parameters in BIM and previous computational models of metacognition such as the stochastic detection and retrieval model (SDRM) and the meta-d′ model. We also show examples of fitting BIM to empirical data sets from several experiments, which suggest that the predictions of BIM are consistent with previous studies on metamemory. In addition, when compared with SDRM, BIM could more parsimoniously account for the data of judgments of learning (JOLs) and memory performance from recall tasks. Finally, we discuss an extension of BIM which accounts for belief updating, and conclude with a discussion of how BIM may benefit metamemory research.
DNA and modified vaccinia Ankara prime–boost vaccination generates strong CD8+ T cell responses against minor histocompatibility antigen HA‐1

Allogeneic immune responses underlie the graft‐versus‐leukaemia effect of stem cell transplantation, but disease relapse occurs in many patients. Minor histocompatibility antigen (mHAg) peptides mediate alloreactive T cell responses and induce graft‐versus‐leukaemia responses when expressed on patient haematopoietic tissue. We vaccinated nine HA‐1‐negative donors against HA‐1 with a ‘prime–boost’ protocol of either two or three DNA ‘priming’ vaccinations prior to ‘boost’ with modified vaccinia Ankara (MVA). HA‐1‐specific CD8+ T cell responses were observed in seven donors with magnitude up to 1·5% of total CD8+ T cell repertoire. HA‐1‐specific responses peaked two weeks post‐MVA challenge and were measurable in most donors after 12 months. HA‐1‐specific T cells demonstrated strong cytotoxic activity and lysed target cells with endogenous HA‐1 protein expression. The pattern of T cell receptor (TCR) usage by HA‐1‐specific T cells revealed strong conservation of T cell receptor beta variable 7‐9 (TRBV7‐9) usage between donors. These findings describe one of the strongest primary peptide‐specific CD8+ T cell responses yet recorded to a DNA–MVA prime–boost regimen and this may reflect the strong immunogenicity of mHAg peptides. Prime–boost vaccination in donors or patients may prove of substantial benefit in boosting graft‐versus‐leukaemia responses.
CG11426 gene product negatively regulates glial population size in the Drosophila eye imaginal disc

Glial cells play essential roles in the nervous system. Although glial populations are tightly regulated, the mechanisms regulating the population size remain poorly understood. Since Drosophila glial cells are similar to the human counterparts in their functions and shapes, rendering them an excellent model system to understand the human glia biology. Lipid phosphate phosphatases (LPPs) are important for regulating bioactive lipids. In Drosophila, there are three known LPP‐encoding genes: wunen, wunen‐2, and lazaro. The wunens are important for germ cell migration and survival and septate junction formation during tracheal development. Lazaro is involved in phototransduction. In the present study, we characterized a novel Drosophila LPP‐encoding gene, CG11426. Suppression of CG11426 increased glial cell number in the eye imaginal disc during larval development, while ectopic CG11426 expression decreased it. Both types of mutation also caused defects in axon projection to the optic lobe in larval eye–brain complexes. Moreover, CG11426 promoted apoptosis via inhibiting ERK signaling in the eye imaginal disc. Taken together, these findings demonstrated that CG11426 gene product negatively regulates ERK signaling to promote apoptosis for proper maintenance of the glial population in the developing eye disc.
Modelling maternal and perinatal risk factors to predict poorly controlled childhood asthma

Asthma is the most common non-communicable pulmonary condition, affecting prepubertal boys more often than girls. This study explored how maternal and perinatal risk factors are linked to poorly controlled childhood asthma in a sex dependent manner. This single centre study was performed at a metropolitan teaching hospital in Western Sydney, Australia, using electronical obstetric records from 2000 to 2017 and electronical pediatric records from 2007 to 2018. The data of 1694 children with complete entries were retrospectively analysed. Risk factors for multiple hospital admission for asthma were selected by backward-eliminated Poisson regression modelling. Selection stability of these parameters was independently confirmed using approximated exhaustive search. Sex-specific regression models indicated that most notably parity (RR[95%CI] for parity = 3; 1.85[1.22–2.81]), birth length z-score (1.45[1.23–1.70]) and birth weight z-score (0.77[0.65–0.90]) contributed to multiple asthma admissions in girls, while boys were affected most prominently by maternal BMI (e.g. BMI 35–39.9; 1.92[1.38–2.67]) and threatened preterm labor (1.68[1.10–2.58]). Allergic status was a risk factors for both boys and girls (1.47[1.18–1.83] and 1.46[1.13–1.89]). Applying ROC analysis, the predictive modelling of risk factors for hospital admissions showed an incremental increase with an AUC of 0.84 and 0.75 for girls and boys respectively for >3 hospital admissions. Multiple hospital admissions for asthma are associated with maternal and perinatal risk factors in a sex and birth order dependent manner. Hence, prospective risk stratification studies aiming to improve childhood asthma control are warranted to test the clinical utility of these parameters. Furthermore, the influence of the early in utero environment on male-female differences in other communicable and non-communicable respiratory conditions should be considered.
Pulsed high magnetic field-induced reversible blood-brain barrier permeability to enhance brain-targeted drug delivery

ABSTRACT The present study aimed to select an effective Pulsed High Magnetic Field (PHMF) stimulation protocol that would induce the Blood-Brain Barrier’s (BBB) reversible permeability to enhance brain-targeted drug delivery. PHMF was applied to the skull over the right hemisphere of 60 Wistar rats. The sham group contained other 10 rats that did not receive PHMF stimulation. The investigated parameters were repetition frequencies (0.25, 1, and 4 Hz as well as the effective low frequency combined with 10 Hz) and numbers of pulses in each train. Evans Blue Dye (EBD) uptake within the brain parenchyma was measured to select an effective PHMF stimulation protocol. BBB reversibility was evaluated by measuring EBD uptake and Gadobutrol retention, through MRI signal intensity enhancement, within brain parenchyma after exposure to the effective PHMF stimulation protocol at different time points including 0.5, 1, and 24 hours. The obtained results showed that the PHMF stimulation increased the BBB’s reversible permeability; this increase was more significant for 28 pulses with 1 Hz frequency (P < .0001). Changes in EBD uptake and MRI signal intensity in the exposed side (right hemisphere) peaked within 0.5–1 hour and returned to normal levels 24 hours after exposure to the effective protocol of PHMF stimulation (28 pulses with 1 Hz frequency). The Contrast-Enhanced MRI (CE-MRI) signal intensity confirmed the changes in EBD concentration. PHMF stimulation can be used as an effective protocol for enhancing the permeability reversibly of BBB, hence considered a potential clinical approach to brain-targeted drug delivery.
Comparative molecular dynamics simulations identify a salt-sensitive loop responsible for the halotolerant activity of GH5 cellulases

Abstract Halotolerant glycoside hydrolases (GH) have broad application potentials in biorefinery industries. Elucidating the structure-activity relationship underlying the halotolerant catalysis is essential to design superior biocatalysts. Here, we performed molecular dynamics simulations to investigate the structural dynamics of two GH5 cellulases, namely the halotolerant Cel5R and non-halotolerant TfCel5A. Through characterizing the physical properties at different salt concentrations, the results revealed that the overall structures of Cel5R and TfCel5A were marginally affected by the increase in salt concentrations. However, a salt-sensitive loop was identified from both Cel5R and TfCel5A based on its significantly increased flexibility at high salt concentrations. Importantly, compared to TfCel5A the salt-sensitive loop of Cel5R engaged more sodium ions and water molecules around the active site of the enzyme. Besides, the unique residue motif of the salt-sensitive loop in Cel5R formed more intramolecular hydrogen bonds, stabilizing the active architecture of Cel5R at high salt concentrations. Collectively, the structural and dynamic differences may contribute to the various catalytic halotolerance of Cel5R and TfCel5A. These findings provide mechanistic insight into the halotolerant catalysis and will guide the ration design of GH5 cellulases with improved catalytic properties. Communicated by Ramaswamy H. Samy Graphical Abstract
Development and evaluation of a new non-competitive Luminex immunoassay detecting antibodies against human papillomavirus types 6, 11, 16 and 18.

Serum antibody levels can be used to measure the humoral immune response against human papillomaviruses (HPV). We developed and validated a rapid, technically simple and relatively inexpensive multiplex non-competitive Luminex-based immunoassay (ncLIA) to measure total IgG antibody levels against four HPV types. For the assay's solid phase, virus-like particles (VLPs) of HPV6, 11, 16 and 18 were bound to heparin-coated beads. HPV serum antibody levels binding to the VLPs were quantified using a phycoerithrin-conjugated secondary polyclonal donkey anti-human IgG antibody. Standardization and validation of the ncLIA were performed using 96 paired serum and genital samples from participants in the HITCH cohort study, including young women (aged 18-24 years) and their male sexual partners (aged 18+) in Montreal, Canada. Results from the ncLIA were compared to a validated Luminex immunoassay from PPD laboratories using Pearson's correlation coefficients, receiver operating characteristic curves and logistic regression. Our assay had good inter- and intra-assay variability. The correlation of serum antibody levels between the ncLIA and validation assay was highest for HPV16 and HPV11 (r=0.90), followed by HPV6 (r=0.86) and HPV18 (r=0.67). The ncLIA was better able to predict HPV DNA positivity in genital samples than the validation assay for HPV16 [area under the curve (AUC) 0.65 versus 0.52, P=0.001] and HPV18 [AUC 0.71 versus 0.57, P=0.024]. AUCs for HPV6 and HPV11 were similar between the two assays (0.70 versus 0.71, P=0.59, and 0.88 versus 0.96, P=0.08, respectively). The developed ncLIA is useful for measuring total IgG antibody response following natural infection or vaccination against four HPV VLPs included in the quadrivalent vaccine.
Association of liver stiffness and steatosis with hepatocellular carcinoma development in patients with hepatitis C virus infection who received direct‐acting antiviral therapy and achieved sustained virological response

The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with chronic hepatitis C virus who receive direct‐acting antiviral therapy and achieve sustained virological response. This study investigated two risk factors for HCC in these patients; specifically, hepatic fibrosis and steatosis.