Miracle-dz/UniFAR-FTUs huggingface dataset:
The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.
Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these “no-option” patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described.
The Role of Creatine in the Development and Activation of Immune Responses

The use of dietary supplements has become increasingly common over the past 20 years. Whereas supplements were formerly used mainly by elite athletes, age and fitness status no longer dictates who uses these substances. Indeed, many nutritional supplements are recommended by health care professionals to their patients. Creatine (CR) is a widely used dietary supplement that has been well-studied for its effects on performance and health. CR also aids in recovery from strenuous bouts of exercise by reducing inflammation. Although CR is considered to be very safe in recommended doses, a caveat is that a preponderance of the studies have focused upon young athletic individuals; thus there is limited knowledge regarding the effects of CR on children or the elderly. In this review, we examine the potential of CR to impact the host outside of the musculoskeletal system, specifically, the immune system, and discuss the available data demonstrating that CR can impact both innate and adaptive immune responses, together with how the effects on the immune system might be exploited to enhance human health.
Does Surgical Margin Width Remain a Challenge for Triple-Negative Breast Cancer? A Retrospective Analysis

Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm (range 0–5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23–126.166), there were 5 local recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our study supports a safe “no ink on tumor” approach for TNBC patients treated with BCS.
Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury

Traumatic brain injury (TBI) affects over 3 million individuals every year in the U.S. There is growing appreciation that TBI can produce systemic modifications, which are in part propagated through blood–brain barrier (BBB) dysfunction and blood–brain cell interactions. As such, platelets and leukocytes contribute to mechanisms of thromboinflammation after TBI. While these mechanisms have been investigated in experimental models of contusion brain injury, less is known regarding acute alterations following mild closed head injury. To investigate the role of platelet dynamics and bioenergetics after TBI, we employed two distinct, well-established models of TBI in mice: the controlled cortical impact (CCI) model of contusion brain injury and the closed head injury (CHI) model of mild diffuse brain injury. Hematology parameters, platelet-neutrophil aggregation, and platelet respirometry were assessed acutely after injury. CCI resulted in an early drop in blood leukocyte counts, while CHI increased blood leukocyte counts early after injury. Platelet-neutrophil aggregation was altered acutely after CCI compared to sham. Furthermore, platelet bioenergetic coupling efficiency was transiently reduced at 6 h and increased at 24 h post-CCI. After CHI, oxidative phosphorylation in intact platelets was reduced at 6 h and increased at 24 h compared to sham. Taken together, these data demonstrate that brain trauma initiates alterations in platelet-leukocyte dynamics and platelet metabolism, which may be time- and injury-dependent, providing evidence that platelets carry a peripheral signature of brain injury. The unique trend of platelet bioenergetics after two distinct types of TBI suggests the potential for utilization in prognosis.
Pathophysiology of sepsis

Purpose of review To provide a current overview of sepsis pathophysiology. Recent findings The emphasis on sepsis pathophysiology has moved away from the pathogen - the initiating factor - and instead is focussed upon the abnormal and exaggerated host response. Instead of targeted eradication of the infection, the host response activates or suppresses multiple downstream pathways, leading to multiple organ dysfunction. Summary Sepsis represents a dysregulated host response to infection leading to organ dysfunction. Here, the pathogen triggers an initial exaggerated inflammatory-immune response that leads to activation or suppression of multiple endothelial, hormonal, bioenergetic, metabolic, immune, and other pathways. These, in turn, produce the circulatory and metabolic perturbations resulting in organ dysfunction. This review will provide an overview of underlying mechanisms and propose that these processes, whereas superficially viewed as dysfunctional, may actually be adaptive/protective in the first instance, though spilling over into maladaptation/harm depending on the magnitude of the host response.
Properties of transparent zinc‐stannate conducting films prepared by radio frequency magnetron sputtering

Highly transparent and conductive amorphous zinc‐stannate thin films were prepared by rf magnetron sputtering using a target with a Zn/(Zn+Sn) content of 33 at. %. The resistivity distribution of the zinc‐stannate films having a composition near ZnSnO3 and deposited on the surface of substrates placed parallel to the target surface was successfully controlled by optimizing both the sputter gas pressure and oxygen partial pressure. A uniform distribution with a resistivity of 4–5×10−3 Ω cm and an average transmittance above 80% in the visible range was obtained for undoped zinc‐stannate films deposited on substrates from room temperature to 300 °C. The zinc‐stannate films were found to be thermally and chemically more stable than undoped SnO2 and ZnO films.
Relationship between Bone Quality, Egg Production and Eggshell Quality in Laying Hens at the End of an Extended Production Cycle (105 Weeks)

Simple Summary Nowadays, the industry aims to extend egg laying until hens are 100 weeks old or longer (from 65 to 70 weeks currently) to make egg production more sustainable. However, intensive egg production challenges hen health and particularly bone metabolism as eggshell formation mobilizes large amounts of calcium from the skeleton, inducing a severe form of osteoporosis and bone fractures. In this study, bone quality was compared in old hens (100 weeks) having different egg production and eggshell quality. Hens with a high egg production and good eggshell quality had poorer bone quality than hens with lower production and/or bad eggshell quality. This is due to a greater calcium mobilization capacity that decreases bone mineral reserves in the form of medullary bone. However, no clear relationship could be found between measured bone quality and egg production/eggshell quality parameters, suggesting that both bone and egg quality can be improved independently through genetic selection and optimum nutrition. Abstract (1) Background: Nowadays the industry aims to improve lay persistency for extended cycles (100 weeks or longer) to make egg production more sustainable. However, intensive egg production challenges hen health, inducing severe osteoporosis and the incidence of bone fractures. In this study, the relationship between bone quality and egg production, and/or eggshell quality, was evaluated at the end of an extended laying cycle of 100 weeks, comparing groups of hens with different production and eggshell quality parameters; (2) Methods: Quality parameters of egg (as weight, egg white height), eggshell (as thickness, weight, breaking strength, elasticity and microstructure) and tibiae bone (weight, diameter, cortical thickness, ash weight, breaking strength, medullary bone) were determined; (3) Results: Hens from groups with a high egg production and good eggshell quality have poorer bone quality (lower ash weight and lesser amount of medullary bone). However, Pearson’s correlation analysis shows no clear relationship between bone and egg/eggshell parameters. (4) Conclusions: Bone and egg production/eggshell quality are independent and can be improved separately. Medullary bone has an important contribution to bone mechanical properties, being important to accumulate enough bone medullary bone early in life to maintain skeletal integrity and eggshell quality in old hens.
Myopathy-Sensitive G-Actin Segment 227-235 Is Involved in Salt-Induced Stabilization of Contacts within the Actin Filament

Formation of stable actin filaments, critically important for actin functions, is determined by the ionic strength of the solution. However, not much is known about the elements of the actin fold involved in ionic-strength-dependent filament stabilization. In this work, F-actin was destabilized by Cu2+ binding to Cys374, and the effects of solvent conditions on the dynamic properties of F-actin were correlated with the involvement of Segment 227-235 in filament stabilization. The results of our work show that the presence of Mg2+ at the high-affinity cation binding site of Cu-modified actin polymerized with MgCl2 strongly enhances the rate of filament subunit exchange and promotes the filament instability. In the presence of 0.1 M KCl, the filament subunit exchange was 2–3-fold lower than that in the MgCl2-polymerized F-actin. This effect correlates with the reduced accessibility of the D-loop and Segment 227-235 on opposite filament strands, consistent with an ionic-strength-dependent conformational change that modulates involvement of Segment 227-235 in stabilization of the intermonomer interface. KCl may restrict the mobility of the α-helix encompassing part of Segment 227-235 and/or be bound to Asp236 at the boundary of Segment 227-235. These results provide experimental evidence for the involvement of Segment 227-235 in salt-induced stabilization of contacts within the actin filament and suggest that they can be weakened by mutations characteristic of actin-associated myopathies.
Nocturnal One-Hour Lighting Stimulates Gonadal Development and Lowers Fat Deposition in Male Mule Ducks

Simple Summary Photoperiods can affect sexual maturity, body weight, and body composition. In this work, we provided male mule ducks with a one-hour lighting from 20:00 to 21:00, in addition to the natural photoperiod, and evaluated its effects on their body weight, organ mass, gonadal function, and plasma levels of metabolites. The results indicate that the nocturnal lighting stimulated gonadal development and function and reduced fat deposition. This implies that nocturnal lighting is able to shorten the feeding period for the marketing of mature ducks. Abstract In this study, the effects of a nocturnal light pulse on body weight, organ mass, gonadal function, and plasma levels of metabolites were determined in male mule ducks. In total, 32 15-week-old mule ducks were randomly allocated to either Group C (control group) or L+ (lighting group). Group C was exposed to the natural photoperiod, whereas Group L+ was provided with a 1-h lighting over 20:00–21:00 every day, in addition to the natural photoperiod. At the end of the 42-day experiment, Group L+ had significantly lower relative weights (% of live weight) of the digestive tract and abdominal fat and higher relative weights of the breast meat and testes than Group C. Moreover, Group L+ had significantly higher plasma testosterone and lower plasma glucose levels. However, no between-group differences were observed in the triacylglycerol and uric acid levels. Histological examination demonstrated that the seminiferous tubule diameter was larger in Group L+ than in Group C. Moreover, the meiosis stage in spermatogenesis had begun in Group L+ but not in Group C. In conclusion, the supplemented 1-h lighting at 20:00 stimulated gonadal development and function and reduced fat deposition.
Model for electronic transport in Cu(In,Ga)Se2 solar cells

Temperature-dependent measurements of the current–voltage characteristics and of the junction admittance of ZnO/CdS/Cu(In,Ga)Se2 heterojunction solar cells are presented, together with numerical modelling of these experimental results. We explain the cross-over between dark and illuminated current–voltage characteristics currently observed for this type of device by the impact of the defect chalcopyrite layer at the surface of the Cu(In,Ga)Se2 absorber. Our model assumes an illumination-dependent voltage drop across a defect layer with a thickness of 15 nm to explain the cross-over. The voltage drop results from the electrical dipole made up of donor-like states at the interface between the defect layer and CdS and deep acceptor states in the defect layer itself. The illumination dependence of this voltage drop is explained by photogenerated holes trapped by the deep acceptor states in the defect layer. Numerical simulations have been carried out using the program SCAPS-1D in order to verify our model assumptions. From our model, indirect conclusions are derived concerning the maximum conduction band offsets between CdS and the defect layer and between CdS and ZnO. Copyright © 1998 John Wiley & Sons, Ltd.
Fully Flexible Textile Antenna-Backed Sensor Node for Body-Worn UWB Localization

A mechanically flexible textile antenna-backed sensor node is designed and manufactured, providing accurate personal localization functionality by application of Decawave’s DW1000 Impulse Radio Ultra-Wideband (IR-UWB) Integrated Circuit (IC). All components are mounted on a flexible polyimide foil, which is integrated on the backplane of a wearable cavity-backed slot antenna designed for IR-UWB localization in Channels 2 and 3 of the IEEE 802.15. 4-2011 standard (3744 MHz–4742.4 MHz). The textile antenna’s radiation pattern is optimized to mitigate body effects and to minimize absorption by body tissues. Furthermore, its time-domain characteristics are measured to be adequate for localization. By combining the antenna and the bendable Printed Circuit Board (PCB), a mechanically supple sensor system is realized, for which the performance is validated by examining it as a node used in a complete localization system. This shows that six nodes around the body must be deployed to provide system coverage in all directions around the wearer. Even without using sleep mode functionalities, the measurements indicate that the system’s autonomy is 13.3 h on a 5 V 200 mAh battery. Hence, this system acts as a proof of concept for the joining of localization electronics and other sensors with a full-textile antenna into a mechanically flexible sensor system.
Demographic inference from multiple whole genomes using a particle filter for continuous Markov jump processes

Demographic events shape a population’s genetic diversity, a process described by the coalescent-with-recombination model that relates demography and genetics by an unobserved sequence of genealogies along the genome. As the space of genealogies over genomes is large and complex, inference under this model is challenging. Formulating the coalescent-with-recombination model as a continuous-time and -space Markov jump process, we develop a particle filter for such processes, and use waypoints that under appropriate conditions allow the problem to be reduced to the discrete-time case. To improve inference, we generalise the Auxiliary Particle Filter for discrete-time models, and use Variational Bayes to model the uncertainty in parameter estimates for rare events, avoiding biases seen with Expectation Maximization. Using real and simulated genomes, we show that past population sizes can be accurately inferred over a larger range of epochs than was previously possible, opening the possibility of jointly analyzing multiple genomes under complex demographic models. Code is available at https://github.com/luntergroup/smcsmc.
Rare severe hypofibrinogenemia induced by tissue plasminogen activator in stroke patients

Abstract Rationale: Severe hypofibrinogenemia after intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is rare and easily overlooked, but hypofibrinogenemia increases the risk of major bleeding. However, it is unclear when hypofibrinogenemia reaches the peak and when hypofibrinogenemia is resolved. Patient concerns: Case 1 was of a 66-year-old man who was hospitalized due to sudden onset of vague speech and right hemiplegia for 4 hours. Case 2 was of an 84-year-old woman who was hospitalized for sudden onset of left hemiplegia and vague speech for 4 hours. In case 1, fibrinogen levels decreased from normal values to <0.25 g/L within 4.5 hours after commencing IVT and returned to normal at 35 hours later. In case 2, fibrinogen levels decreased from 1.1 to <0.25 g/L within 2 hours after commencing IVT and normalized 36.5 hours later. Diagnoses: Both patients were diagnosed with rt-PA-related hypofibrinogenemia. Interventions: No antiplatelet or symptomatic treatment was administered during the period of hypofibrinogenemia. Outcomes: Fibrinogen levels gradually recovered. In case 1, the patient did not experience cerebral hemorrhage during hypofibrinogenemia. His symptoms improved significantly within 1 week. In case 2, repeat computed tomography revealed minor cerebral hemorrhage, but no deterioration in her condition was noted until she was discharged. Lessons: Rapid, severe, and prolonged hypofibrinogenemia may occur after IVT with rt-PA, which may increase the risk of massive hemorrhage and affect the related therapy. Prompt diagnosis of hypofibrinogenemia is important for preventing complications. We recommend checking the fibrinogen levels routinely after IVT. Fibrinogen replacement therapy and platelet transfusion are the main management routes for rt-PA-related symptomatic intracranial hemorrhage.
Knockdown of lncRNA H19 suppresses endometriosis in vivo

The long noncoding RNA (lncRNA) H19 is involved in the pathogenesis of endometriosis by modulating the proliferation and invasion of ectopic endometrial cells in vitro, but related in vivo studies are rare. This study aimed to investigate the role of lncRNA H19 in a nude mouse model of endometriosis. Ectopic endometrial stromal cells (ecESCs) were isolated from ectopic endometrium of patients with endometriosis and infected with lentiviruses expressing short hairpin RNA (shRNA) negative control (LV-NC-shRNA) or lncRNA-H19 shRNA (LV-H19-shRNA). The ecESCs infected with LV-NC-shRNA and LV-H19-shRNA were subcutaneously implanted into forty 6- to 8-week-old female nude mice. The size and weight of the endometriotic implants were measured at 1, 2, 3, and 4 weeks after implantation and compared, and lncRNA H19 levels in endometriotic implants were evaluated using real-time polymerase chain reaction (RT-PCR). All nude mice survived the experimental period, and no significant differences in body weight were observed between the experimental group and the control group. All nude mice developed histologically confirmed subcutaneous endometriotic lesions with glandular structures and stroma after 1 week of implantation. The subcutaneous lesions in the LV-NC-shRNA group after 1, 2, 3, and 4 weeks of implantation were larger than those in the LV-H19-shRNA group, and lncRNA H19 levels in subcutaneous lesions in the LV-NC-shRNA group were significantly higher than those in the LV-H19-shRNA group. Knockdown of lncRNA H19 suppresses endometriosis in vivo. Further study is required to explore the underlying mechanism in the future.