Miracle-dz/UniFAR-FTUs huggingface dataset:
Wildlife in Cameroon harbor diverse coronaviruses, including many closely related to human coronavirus 229E

Abstract Zoonotic spillover of animal viruses into human populations is a continuous and increasing public health risk. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the global impact of emergence. Considering the history and diversity of coronaviruses (CoVs), especially in bats, SARS-CoV-2 will likely not be the last to spillover from animals into human populations. We sampled and tested wildlife in the Central African country Cameroon to determine which CoVs are circulating and how they relate to previously detected human and animal CoVs. We collected animal and ecological data at sampling locations and used family-level consensus PCR combined with amplicon sequencing for virus detection. Between 2003 and 2018, samples were collected from 6,580 animals of several different orders. CoV RNA was detected in 175 bats, a civet, and a shrew. The CoV RNAs detected in the bats represented 17 different genetic clusters, coinciding with alpha (n = 8) and beta (n = 9) CoVs. Sequences resembling human CoV-229E (HCoV-229E) were found in 40 Hipposideridae bats. Phylogenetic analyses place the human-derived HCoV-229E isolates closest to those from camels in terms of the S and N genes but closest to isolates from bats for the envelope, membrane, and RNA-dependent RNA polymerase genes. The CoV RNA positivity rate in bats varied significantly (P < 0.001) between the wet (8.2 per cent) and dry seasons (4.5 per cent). Most sampled species accordingly had a wet season high and dry season low, while for some the opposite was found. Eight of the suspected CoV species of which we detected RNA appear to be entirely novel CoV species, which suggests that CoV diversity in African wildlife is still rather poorly understood. The detection of multiple different variants of HCoV-229E-like viruses supports the bat reservoir hypothesis for this virus, with the phylogenetic results casting some doubt on camels as an intermediate host. The findings also support the previously proposed influence of ecological factors on CoV circulation, indicating a high level of underlying complexity to the viral ecology. These results indicate the importance of investing in surveillance activities among wild animals to detect all potential threats as well as sentinel surveillance among exposed humans to determine emerging threats.
Hemp biochar impacts on selected biological soil health indicators across different soil types and moisture cycles

Application of crop residues and biochar have been demonstrated to improve soil biological and chemical properties in agroecosystems. However, the integrated effect of organic amendments and hydrological cycles on soil health indicators are not well understood. In this study, we quantified the impact of hemp residue (HR), hemp biochar (HB), and hardwood biochar (HA) on five hydrolytic enzymes, soil microbial phospholipid (PLFA) community structure, pH, permanganate oxidizable carbon (POXC) soil organic carbon (SOC), and total nitrogen (TN). We compared two soil types, Piedmont and Coastal Plain soils of North Carolina, under (i) a 30-d moisture cycle maintained at 60% water-filled pore space (WFPS) (D-W1), followed by (ii) a 7-day alternate dry-wet cycle for 42 days (D-W2), or (iii) maintained at 60% WFPS for 42 days (D-W3) during an aerobic laboratory incubation. Results showed that HR and HB significantly increased the geometric mean enzyme activity by 1-2-fold in the Piedmont soil under the three moisture cycles and about 1.5-fold under D-W in the Coastal soil. In the presence of HA, the measured soil enzyme activities were significantly lower than control under the moisture cycles in both soil types. The shift in microbial community structure was distinct in the Coastal soil but not in the Piedmont soil. Under D-W2, HR and HB significantly increased POXC (600–700 mg POXC kg-1 soil) in the Coastal soil but not in the Piedmont soil while HA increased nitrate (8 mg kg-1) retention in the Coastal soil. The differences in amendment effect on pH SOC, TN, POXC, and nitrate were less distinct in the fine-textured Piedmont soil than the coarse-textured Coastal soil. Overall, the results indicate that, unlike HA, HR and HB will have beneficial effects on soil health and productivity, therefore potentially improving soil’s resilience to changing climate.
Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity

Abstract An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.
Four in one—Combination therapy using live Lactococcus lactis expressing three therapeutic proteins for the treatment of chronic non-healing wounds

Diabetes mellitus is one of the major concerns for health care systems, affecting 382 million people worldwide. Among the different complications of diabetes, lower limbs chronic ulceration is a common, severe and costly cause of morbidity. Diabetic foot ulcers are a leading cause of hospitalization in diabetic patients and its rate exceed the ones of congestive heart failure, depression or renal disease. Diabetic non-healing ulcers account for more than 60% of all non-traumatic lower limb amputations and the five-year mortality after amputation is higher than 50%, being equal to several types of advanced cancer. The primary management goals for an existing diabetic foot ulcer are to achieve primary healing as expeditiously as possible and to achieve a reduction of the amputation rate in the patients. Unfortunately, approximately a quarter of patients do not partially or fully respond to the standard of care. Advanced therapies for chronic wounds are existing, however, recent guidelines including the latest reviews and meta-analyses of the scientific and clinical evidence available from current treatment strategies and new therapeutic agents revealed that there is a lack of clinical data and persistent gap of evidence for many of the advanced therapeutic approaches. In addition, no pharmacological wound healing product has gained authority approval for more than 10 years in both US and EU, constituting a highly unmet medical need. In this publication we present data from a live biopharmaceutical product AUP1602-C designed as a single pharmaceutical entity based on the non-pathogenic, food-grade lactic acid bacterium Lactococcus lactis subsp. cremoris that has been genetically engineered to produce human fibroblast growth factor 2,interleukin4 and colony stimulating factor 1. Designed to address different aspects of wound healing (i.e. fibroblast proliferation, angiogenesis and immune cell activation) and currently in phase I clinical study, we show how the combination of the individual components on the wound micro-environment initiates and improves the wound healing in chronic wounds.
Circulating Complement C1q as a Novel Biomarker is Associated with the Occurrence and Development of COPD

Purpose Increasing evidence has shown that the immune response interacts with the chronic inflammatory response and gives rise to the occurrence and development of COPD. Complement component 1q (C1q), as a subcomponent of the C1 complex, could be involved in innate and adaptive immunity. Our study aimed to investigate the relationship between C1q and the clinical characteristics of COPD subjects. Patients and Methods Serum C1q levels were measured in 203 COPD subjects and 191 non-COPD controls. Correlations between C1q and the characteristics of COPD were analyzed using Spearman’s rho. Receiver operating curve (ROC) analysis was used to evaluate the threshold value in differentiating disease status. All 203 COPD subjects were followed up for 1 year for future acute exacerbations. Results There were significant reductions in serum C1q levels in COPD subjects compared to non-COPD controls. Moreover, serum C1q levels were obviously positively correlated with the FEV1/FVC ratio and predicted FEV1% but had a weakly negative correlation with the %LAA-950 and the percentage of neutrophils in peripheral blood. Using a cutoff value of 137.150 mg/l as the boundary in ROC analysis, the sensitivity and specificity were 65.9% and 76.0%, respectively. The 1-year follow-up results showed that C1q levels less than 137.150 mg/l were negatively related to the time to the next severe exacerbation and the time to death. Conclusion Circulating C1q levels may be a novel biomarker not only related to the pulmonary function of COPD but also having great potential to predict the risk of COPD deterioration in the future. However, further prospective trials are needed to clarify the influences of C1q on the pathogenesis of COPD.
Traumatic stress, depression, and non-bereavement grief following non-fatal traffic accidents: Symptom patterns and correlates

Non-fatal traffic accidents may give rise to mental health problems, including posttraumatic stress (PTS) and depression. Clinical evidence suggests that victims may also experience grief reactions associated with the sudden changes and losses caused by such accidents. The aim of this study was to examine whether there are unique patterns of symptoms of PTS, depression, and grief among victims of non-fatal traffic accidents. We also investigated associations of emerging symptom patterns with sociodemographic variables and characteristics of the accident, and with transdiagnostic variables, including self-efficacy, difficulties in emotion regulation, and trauma rumination. Participants (N = 328, Mage = 32.6, SDage = 17.5 years, 66% female) completed self-report measures tapping the study variables. Using latent class analysis (including symptoms of PTS, depression, and grief), three classes were identified: a no symptoms class (Class 1; 59.1%), a moderate PTS and grief class (Class 2; 23.1%), and a severe symptoms class (Class 3; 17.7%). Summed symptom scores and functional impairment were lowest in Class 1, higher in Class 2, and highest in Class 3. Psychological variables were similarly ordered with the healthiest scores in Class 1, poorer scores in Class 2, and the worst scores in Class 3. Different sociodemographic and accident related variables differentiated between classes, including age, education, and time since the accident. In a regression including all significant univariate predictors, trauma rumination differentiated Class 2 from Class 1, all three psychological variables differentiated Class 3 from Class 1, and difficulties with emotion regulation and trauma rumination differentiated Class 3 from Class 2. This study demonstrates that most people respond resiliently to non-fatal traffic accident. Yet, approximately one in three victims experiences moderate to severe mental health symptoms. Increasing PTS coincided with similarly increasing grief, indicating that grief may be considered in interventions for victims of traffic accidents. Trauma rumination strongly predicted class membership and appears a critical treatment target to alleviate distress.
Chemical approach to generating long-term self-renewing pMN progenitors from human embryonic stem cells

Abstract Spinal cord impairment involving motor neuron degeneration and demyelination can cause lifelong disabilities, but effective clinical interventions for restoring neurological functions have yet to be developed. In early spinal cord development, neural progenitors of the motor neuron (pMN) domain, defined by the expression of oligodendrocyte transcription factor 2 (OLIG2), in the ventral spinal cord first generate motor neurons and then switch the fate to produce myelin-forming oligodendrocytes. Given their differentiation potential, pMN progenitors could be a valuable cell source for cell therapy in relevant neurological conditions such as spinal cord injury. However, fast generation and expansion of pMN progenitors in vitro while conserving their differentiation potential has so far been technically challenging. In this study, based on chemical screening, we have developed a new recipe for efficient induction of pMN progenitors from human embryonic stem cells. More importantly, these OLIG2+ pMN progenitors can be stably maintained for multiple passages without losing their ability to produce spinal motor neurons and oligodendrocytes rapidly. Our results suggest that these self-renewing pMN progenitors could potentially be useful as a renewable source of cell transplants for spinal cord injury and demyelinating disorders.
ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration

In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5‐fluorouracil‐induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCRhigh) were enriched within the stem cell fraction at the expense of more proliferative EPCRLow HSCs. These EPCRHigh HSCs were initially more primitive than EPCRLow HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis‐regulatory elements in progenitor cell‐related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY‐dependent histone acetylation promoted differentiation into CD48+ progenitor cells. Collectively, these results indicate that the dynamic control of ACLY‐dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.
Combined ultrasonic/subcritical water hydrolysis pretreatments for agricultural biomass

ABSTRACT In response to the intensification of eco-friendly routes as a strategy to access compounds of interest, extraction based on hydrothermal technologies is an efficient method to obtain high yields of compounds present in lignocellulosic materials. Accordingly, this study investigated the effects of the combination of ultrasonic pretreatments (energy density, 1.23 × 103–37.6 × 103 J/cm3; reaction time, 15 and 60 min) and subcritical water hydrolysis (SWH) (temperature, 220°C; flow rate, 10–30 mL/min; and reaction time, 0.5–15 min) on sugar yield profile from residual biomass of rice, soybean, and pecan. A characterization of the sugars present in the hydrolyzed solutions by high-performance liquid chromatography (HPLC) and a physicochemical evaluation of biomasses by Fourier-transform infrared spectroscopy (FT-IR) was performed. The highest yield reported were 23.8/100 g biomass, 14.4/100 g biomass, and 6.0/100 g biomass for pecan shell, rice shell, and soybean straw, respectively. Cellobiose, glucose, xylose, and arabinose were quantified by the HPLC, as well as inhibitors and organic acids. FT-IR indicated the compositions of the fresh and pretreated samples. Appropriately, the combined application of ultrasonic and SWH methods supported the valorization and optimization of high potential materials generated in agricultural processing. GRAPHICAL ABSTRACT
Investigational New Drug Enabling Nonclinical Safety Pharmacology Assessment of the Iminosugar UV-4, a Broad-Spectrum Host-Targeted Antiviral Agent

UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a broad-spectrum antiviral drug candidate with demonstrated activity in vitro and in vivo against multiple, diverse viruses. Nonclinical safety pharmacology studies were conducted to support the filing of an Investigational New Drug (IND) application. Preliminary in vitro pharmacology testing evaluating potential for binding to “off-target” receptors and enzymes indicated no significant liability for advanced development of UV-4. The safety pharmacology of UV-4 was evaluated in the in vitro human ether-à-go-go-related gene (hERG) assay, in a central nervous system (CNS) study in the mouse (modified Irwin test), in a respiratory safety study in conscious mice using whole body plethysmography, and in a cardiovascular safety study in conscious, radiotelemetry-instrumented beagle dogs. There were no observed adverse treatment-related effects following administration of UV-4 as the hydrochloride salt in the hERG potassium channel assay, on respiratory function, in the CNS study, or in the cardiovascular assessment. Treatment-related cardiovascular effect of decreased arterial pulse pressure after 50 or 200 mg of UV-4/kg was the only change outside the normal range, and all hemodynamic parameters returned to control levels by the end of the telemetry recording period. These nonclinical safety pharmacology assessments support the evaluation of this host-targeted broad-spectrum antiviral drug candidate in clinical studies.
Utilization of a Smart Sock for the Remote Monitoring of Patients With Peripheral Neuropathy: Cross-sectional Study of a Real-world Registry

Background Remote patient monitoring (RPM) devices are increasingly being used in caring for patients to reduce risks of complications. Temperature monitoring specifically has been shown in previous studies to provide a useful signal of inflammation that may help prevent foot ulcers. Objective In this cross-sectional study, we evaluated utilization data for patients who were prescribed smart socks as remote temperature monitoring devices. Methods This study evaluated data from a patient registry from January to July 2021. The utilization data, which were collected starting from the first full month since patients were prescribed the smart socks, were evaluated along with retention over time, the average time that the socks were worn, and the number of days that the socks were worn per month and per week. Results A total of 160 patients wore the smart sock RPM device for 22 to 25 days per month on average. The retention rate was 91.9% (147/160) at the end of the 7-month period; a total of 13 patients were lost to follow-up during this period. The average number of days that the socks were worn per week was 5.8. The percentage of patients with a utilization rate of >15 days ranged from 79.7% (106/133) to 91.9% (125/136) each month. Conclusions This study shows a high level of utilization for a smart sock RPM device and a high compliance rate. A future prospective study on the clinical outcomes after the use of the smart socks may further solidify the idea of conducting temperature monitoring for foot ulcer prevention.
Cooling Effects Occur in Hepatic Microwave Ablation At Low Vascular Flow Rates and in Close Proximity to Liver Vessels – Ex Vivo

Background. The impact of vascular cooling effects in hepatic microwave ablation (MWA) is controversially discussed. The objective of this study was a systematic assessment of vascular cooling effects in hepatic MWA ex vivo. Methods. Microwave ablations were performed in fresh porcine liver ex vivo with a temperature-controlled MWA generator (902-928 MHz) and a non-cooled 14-G-antenna. Energy input was set to 9.0 kJ. Hepatic vessels were simulated by glass tubes. Three different vessel diameters (3.0, 5.0, 8.0 mm) and vessel to antenna distances (5, 10, 20 mm) were examined. Vessels were perfused with saline solution at nine different flow rates (0-500 mL/min). Vascular cooling effects were assessed at the largest cross-sectional ablation area. A quantitative and semi-quantitative/morphologic analysis was carried out. Results. 228 ablations were performed. Vascular cooling effects were observed at close (5 mm) and medium (10 mm) antenna to vessel distances (P < .05). Vascular cooling effects occurred around vessels with flow rates ≥1.0 mL/min (P < .05) and a vessel diameter ≥3 mm (P < .05). Higher flow rates did not result in more distinct cooling effects (P > .05). No cooling effects were measured at large (20 mm) antenna to vessel distances (P > .05). Conclusion. Vascular cooling effects occur in hepatic MWA and should be considered in treatment planning. The vascular cooling effect was mainly affected by antenna to vessel distance. Vessel diameter and vascular flow rate played a minor role in vascular cooling effects.
From paediatric formulations development to access: Advances made and remaining challenges

Developing suitable paediatric formulations and ensuring access to them by the greatest number of the 2.2 billion children worldwide are equally important to provide optimal pharmacotherapy. This review focuses on the progress made over the last two decades with paediatric oral formulations with respect to evidence for acceptability and dosing flexibility of liquid and solid oral dosage forms. It also discusses the clinical needs for, and the access to, paediatric formulations for existing authorised medicines. A significant body of new knowledge now supports the acceptability of solid oral dosage forms in children, resulting in an increasing number of medicines commercialised as multiparticulates, including minitablets that are starting to be brought to market. However, there are gaps with these formulations that deserve more research. Even though efforts have been made to identify medicines in need of age‐appropriate formulations, there is no common priority list shared internationally. Such prioritisation would help to develop paediatric formulations with the greatest potential for providing a health benefit to children worldwide. In addition, available data highlight that paediatric formulation access is fragmented and unequal, with commercialisation of suitable paediatric formulations too often limited to some countries/regions. We propose actions to better align decisions during the development of paediatric formulations and promote a more globalised approach to facilitate registration pathways between different jurisdictions. Furthermore, discussions about alignment between approval, pricing and reimbursement processes should also happen, leaving working in siloes behind us. It is time for adults to start thinking outside the box for children.