Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in Cannabis extracts. Mechanic studies have indicated that CBD has high affinity on a series of receptors, including type 1 cannabinoid receptor (CB1), type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV), peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptor, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anti-cancer properties. Recently, according to some initial studies, CBD’s anti-inflammatory properties could be applied for treat or prevent COVID-19. CBD has gained increased attention in recent years because of its great potential to treat various human diseases. This review provides a current overview of CBD’s applications in human diseases, from mechanism of action to clinical trials.

Background and Purpose: Parkinson’s disease (PD) is clinically defined by the presence of the cardinal motor symptoms, which are associated with a loss of dopaminergic nigrostriatal neurons in the substantia nigra pars compacta (SNpc). While SNpc neurons serve as the prototypical cell-type to study cellular vulnerability in PD, there is an unmet need to extent our efforts to other neurons at risk. The noradrenergic locus coeruleus (LC) represents one of the first brain structures affected in Parkinson’s disease (PD) and plays not only a crucial role for the evolving non-motor symptomatology, but it is also believed to contribute to disease progression by efferent noradrenergic deficiency. Experimental Approach: Therefore, we sought to characterized the electrophysiological properties of LC neurons in two distinct PD models: (1) in an in vivo mouse model of focal α-synuclein overexpression; and (2) in an in vitro rotenone-induced PD model. Key Results: Despite the fundamental differences of these two PD models, α-synuclein overexpression as well as rotenone exposure led to an accelerated autonomous pacemaker frequency of LC neurons, accompanied by severe alterations of the afterhyperpolarization amplitude. On the mechanistic side, we identified small-conductance Ca2+-activated K+ (SK) channels as crucial mediators of the increased LC neuronal excitability and demonstrate that pharmacological activation of these channels is sufficient to prevent increased LC pacemaking and subsequent neurodegeneration following in vitro rotenone exposure. Conclusion and Implications: These findings highlight the important role of SK channels in PD by linking α-synuclein- and rotenone-induced LC pathology to SK channel dysfunction.

Background and Purpose: Diethyldithiocarbamate(DDC) alleviates hepatic inflammation and fibrosis of methionine- and choline-deficient(MCD) diet-induced non-alcoholic steatohepatitis(NASH) in mice. Interestingly, increased macrovesicular steatosis replace the ballooning of hepatocytes by DDC. The therapeutic mechanism of DDC on NASH remains unclear. Experimental Approach: C57BL/6 mice received choline-deficient, L-amino acid-defined(CDAA) diet to induce NASH with or without DDC treatment. Lipidomic and microarray analyses were used to find the lipid metabolites and genes regulated by DDC. RNAscope and immunoblotting were used to detect perilipin 5(Plin5) in the liver. Peridroplet mitochondria(PDM) were isolated from liver tissues, stained and observed by confocal microscope. Mixture of Oleic and palmitic acid were used to treat C3A cells. The effect of DDC on Plin5, mitochondria-LD contact and mitochondrial function were analyzed. Key Results: DDC alleviated hepatic inflammation and fibrosis, whereas steatosis increased in CDAA-diet induced NASH. Triglyceride content and genes related to LDs and mitochondrial function increased by DDC. Plin5 which can promote the expansion of LD and formation of PDM was upregulated in the liver by DDC. PDM were observed in steatotic liver and have enhanced mitochondrial function relative to cytoplasm mitochondria. DDC increased the size of LDs and the number of PDM, and improved mitochondrial function both in vivo and in vitro. Conclusion and Implications: PDM promote triglyceride synthesis and reduce lipotoxicity-induced liver injury, inflammation and fibrosis. PDM regulated by Plin5 contribute to the therapeutic effect of DDC on NASH. The regulation of PDM may represent an attractive pharmacological target for NAFLD.

Here, we study the dynamics of the singularly perturbed logistic difference equation with two different continuous arguments. First of all, local stability of the fixed points is investigated by analyzing the corresponding characteristic equations of the linearized equations. Secondly, we illustrate that the considered system exhibits Hopf bifurcation. A discretized analogue of the original system is obtained using the method of steps. Local stability and bifurcation analysis of the discretized system are investigated. Explicit conditions for the occurrence of a variety of complex dynamics such as fold and Neimark-Sacker bifurcations are reached. We compare the results with those of the associated difference equation with continuous argument when the perturbation parameter $\epsilon \longrightarrow 0$ and with those of the logistic delay differential equation with two different delays when $\epsilon \longrightarrow 1$. Finally, numerical simulations including Lyapunov exponent, bifurcation diagrams and phase portraits are carried out to confirm the theoretical analysis obtained and to illustrate more complex dynamics of the system.

The plant bug, Pachypeltis micranthus Mu et Liu (Hemiptera: Miridae), is a potential biological control agent for Mikania micrantha H.B.K. (Asteraceae; one of the most invasive weeds worldwide). To date, only a few studies have investigated plant bugs. Here, we performed a chromosome-level genome assembly of P. micranthus using MGISEQ-2000 short-read, Nanopore, PacBio long-read, and high-throughput chromosome conformation capture (Hi-C) techniques. The assembled genome was 712.72 Mb in size, with a contig N50 of 16.84 Mb. Using the Hi-C technique, 71 scaffolds were assembled into 15 chromosomes, accounting for 99.96%. We predicted 11,746 protein-coding genes in P. micranthus with 96.20% complete benchmarking universal single-copy orthologs. Phylogenomic analysis showed that P. micranthus and two other Miridae bugs (Apolygus lucorum and Nesidiocoris tenuis) diverged from the common ancestor approximately 200.01 million years ago. Chromosome synteny analysis between P. micranthus and A. lucorum indicated high-level synteny. Many gene families including chemosensory genes and digestive and detoxification enzyme genes—were significantly expanded in the P. micranthus genome. These expanded gene families may indicate the bug to adapt to the single host plant. This high-quality chromosome-level genome assembly provides an invaluable resource for further molecular and evolutionary research on mirid bugs and also provides a basis for further research on biological control mechanisms for M. micrantha.

The canine distemper virus is a major threat to the already endangered wild dogs. We propose an evidence-based mathematical model of canine distemper in the wild to predict the rate and possibility of disease spread under a different scenario. We find the endemic and disease-free equilibrium points and the condition for their stability from the model. The bifurcation analysis of the model shows how the endemic equilibrium can be transformed into the disease-free equilibrium through parameters that represent fundamental ecological properties. The sensitivity of these parameters to the secondary disease spread points out the specific interaction rates and a birth rate that should be targeted to reduce the CDV outbreak. We suggest target parameters for controlling the disease outbreak considering the plausibility of manipulating them in terms of implications besides the sensitivity of the parameters. Finally, this article proposes two specific control strategies based on this modeling framework: isolation and birth-control-reintroduction. Since the isolation strategy may be cost-intensive, we modify our model to quantify the isolation rate necessary to reduce the disease outbreak. We suggest that the birth-control-reintroduction strategy based on the proposed model is cost-effective for a small contaminated area.

Abstract: Background: Emergency department employees are exposed to a significant number of sick patients and a wide range of dangerous situations in a congested emergency and trauma department with a high patient turnover. Their understanding of occupational dangers particular to their professions, as well as administrative processes for mitigating such risks, is important to their safety. As a result, the goal of this research is to look into an e-Training material for healthcare workers about emergency room dangers. This research was founded on Recognizing Hazard theory and E-learning theory. Methods: The Fuzzy Delphi Method (FDM) was used in the study, which was performed among 16 experts to select a list of material on the e-training content of risks. The basic content elements were established by a survey of literature and interviews with specialists. The items were chosen based on their replies to an FDM survey questionnaire according to a seven-Likert linguist scale. The ‘threshold’ value (d) was used to determine the expert’ consensus for the questionnaire, whereas defuzzification (Amax) values recorded the experts’ recommendations. Results: Only 14 contents were accepted based on expert consensus. This resulted in the conclusion that the content finding demonstrated a high degree of acceptability among experts, and the finding suggested the necessity of undertaking curriculum design. Conclusion: Further research can concentrate on additional online training implementation curriculum packages that might be designed for unique learner needs, such as post-natural disaster training, rookie health care worker training, and others.

Climate oscillations may drive the divergence of ancestral species through habitat isolation, species distribution patterns, and the cessation of gene flow. However, traditional ecological niche models lack the consideration for the genetic adaptation of species, thus it’s difficult to understand how climate oscillations affect species divergence by changing their climatic suitability and historical demography. We analyzed the impact of climate change on the divergence of two langur species, François’ langur and White-headed langur, using Maxent, Genotype–Environment Association (GEA) models and genomic data. Our results indicate that 1) Climatic suitability for François’ langur and White-headed langur has separated from the Last Interglacial (LIG, 120,000-140,000 years ago) to the Last Glacial Maximum (LGM); 2) Although the effective population size for both species decreased between the LIG and the LGM, the effective population size of François’ langur increased more quickly than that of White-headed langur from the LGM to the present; 3) Historical patterns of climate change have resulted in periods of expanded and contracted climatic suitability, with each species experiencing periods of interspecific genetic isolation and periods of interspecific genetic exchange; and 4) Human activities and future climate change have contracted the range of François’ langur (in China) and White-headed langur. Climate oscillation, population isolation, and in situ evolution in refugia from the LIG to the LGM appear to have played a critical role in langur speciation and adaptive evolution. Overall, our results demonstrate how climatic oscillations and historical demography drive speciation, providing a new perspective on species divergence and conservation.

Background: Severe congenital neutropenia (SCN) is an autoimmune disease clinically characterized by persistent and severe neutropenia. It is typically caused by a heterozygous mutation in the ELANE gene, which encodes neutrophil elastase. Procedure: Using one 3-year-old male diagnosed with severe congenital neutropenia, we aimed to assess the clinical and genetic characteristics of SCN caused by ELANE mutations and test whether the mutation can be corrected by CRISPR/Cas9-mediated gene editing. The proband underwent extensive clinical assessments, with exome sequencing and bioinformatics analysis to identify pathogenic genes. In addition, Sanger sequencing was used to verify the pedigrees. The cell line, 293-ELANE, harboring ELANE mutation was generated by lentiviral transduction and selection with puromycin from HEK-293. And the mutation was corrected by CRISPR/Cas9-mediated homology-directed repair (HDR). Results: The ELANE gene test in the proband unveiled a heterozygous de novo missense mutation: c. 248T>A (p.V83D), which is not detected in his asymptomatic parents with peripheral blood samples. Surprisingly, we found that 46.01% of his father’s sperm cells had the same mutation. These results demonstrated that the proband inherited the ELANE mutation from his father, who had a normal neutrophil count but was germline mosaic. In this study, the highest repair efficiency of CRISPR/Cas9-mediated HDR for 293-ELANE is 4.43%. Conclusions: We identified a missense mutation (p.V83D) in ELANE causing SCN, the first report on paternal semen mosaicism of an ELANE mutation. Our study also paves the way for preimplantation genetic diagnosis (PGD) based on ELANE mutation prevention and clinical treatment of congenital disabilities.

Objectives: The aim of this study was to identify if there was a change in the incidence of epistaxis attendances following initiation of the COVID-19 vaccination programme. Design: A retrospective, cohort study. Setting: A large university teaching hospital with an emergency department (ED). Participants: A study group consisting of adults attending the emergency department for epistaxis over a 2-month period in 2021 and a control group consisting of adults attending the emergency for epistaxis over a 2-month period in 2019. Main outcome measures: The comparison of emergency department admission data with vaccination data between the control and study groups. Results: 187 (0.8% of total ED attendances) epistaxis attendances occurred in 2021 compared to 174 (0.6% of total ED attendances) epistaxis attendances in 2019 (p=0.002). No significant differences in platelet count were observed between the vaccinated (250.52 x109/L) and unvaccinated patients (214 x109/L) in the study group (p=0.117). The mean time between vaccination and presentation with epistaxis was 36 days ± 23.5 (n=102). Conclusion: The COVID-19 vaccine may be responsible for an increased proportion of epistaxis attendances to our emergency department. No evidence of thrombocytopenia was observed amongst patients presenting with epistaxis after vaccine administration. The mean time between vaccination and presentation with epistaxis was over five weeks.

This study light the influences of activation energy, mixed convection, magnetohydyo-dynamic, hall current on blood motion of Seminal nanofluid in a vertical symmetric channel. Viscosity of fluid is supposed to be various with temperature, also variable velocity slip and variable thermal jump is considered. Governing equations of presented model found to be having a high degree of non-linearity. Consequently, we use an accurate combined numerical technique with help of Mathematica 12.2. Pade' approximant and differential transform techniques are combined together to obtain a highly accurate semi-numerical techniques called Pad'-DTM. The results of proposed system of partial differential equations is computed semi-numerically using Pade'-DTM method and influences of physical parameters on the flow characteristics have been figured and scrutinized. The paramount outcome show that the activation energy parameter gives fluid nanoparticles more heat enabling them move more and more freely in the cervix of the woman canal. All computed results approve that the Pade'-DTM technique is an effective computational method for solving peristaltic flow problems of non-Newtonian fluids.

Hyperleukocytosis in leukaemia causes leukostasis, which can lead to thrombosis of arterial systems of various organs and cause renal and retinal thrombosis, acute limb ischemia and myocardial infarction. We report a case of an eight-year-old male child who had pericardial thrombus formation consequential to hyperleukocytosis. Keywords Hyperleukocytosis, Leukostasis, Pericardial thrombus, Leukemia

Introduction: Transesophageal cardiac electrophysiological study can identify the type of supraventricular tachycardia and may find some special electrophysiological phenomena. Case presentation: This paper reported a 1-month-old infant who underwent transesophageal cardiac electrophysiological study and was induced atrioventricular nodal reentrant tachycardia and atrial flutter. The type of narrow QRS tachycardia in the infant was defined, which showed great value for the selection of medications to terminate tachycardia in the near future and the long-term radiofrequency ablation therapy. Conclusion: Transesophageal cardiac electrophysiological study is viable，safe and non-invasive, additionally can help to find some important ECG phenomena. It is especially suitable for infants who are temporarily inaccessible to receive radiofrequency ablation.

Massive pulmonary artery aneurysms, while extremely rare, might require surgical intervention. Most previous cases have been repaired either by pulmonary artery plication or synthetic graft replacement. We report a case of massive pulmonary artery aneurysm that was successfully repaired using an ‘overlapping-plasty’ technique with the help of 3D image simulation. The ‘overlapping-plasty’ technique might support pressure resistance without the need for synthetic material. This specially designed procedure might be useful as a surgical option for pulmonary artery aneurysms.

Water resource vulnerability in ecologically vulnerable karst areas is a key issue for regional sustainable development and the sustainable use of water resources. In this study, geographical information system (GIS) and remote sensing (RS) technology were employed to explore the vulnerability characteristics and spatial distribution of water resources in Guiyang City. The water resource vulnerability indicator in Guiyang ranged from 0.10 to 0.59, with an average value of 0.26. Yanglongsi Town, in Xifeng County, in the northern and main central urban area exhibited the highest water resource vulnerability, whereas Huaxi District in the south, and regions around Hongfeng Lake and Baihua Lake, in Qingzhen City, exhibited the lowest water resource vulnerability. Water resource vulnerability was predominantly mild, accounting for 35.85% of the total land area, followed by moderate (28.99%), with some non-vulnerable areas (13.60%) and very few extremely vulnerable areas (3.20%). Compared with traditional methods, the proposed index selection and assessment method, based on GIS/RS, are both scientific and intuitive. In addition, the results are presented in detail, accurately reflecting the actual situation of water resource system vulnerability.

Objective: Provide normative data on intrauterine placental size and placental size relative to fetal size (placental to fetal ratio). Design: Prospective study. Setting: Akershus University Hospital, Norway. From April 2017 to May 2018. Population: 107 unselected singleton pregnancies recruited at routine antenatal care. Method: The pregnancies were examined by magnetic resonance imaging (MRI) at gestational week 27 and 37. Based on the estimated volumes of the placenta and the fetus, we calculated median and percentiles at the gestational weeks 27 and 37, and we assumed linear growth in the intermediate interval. Main outcome measures: Median placental volume (cm3) and placental to fetal ratio (placental volume cm3/fetal volume cm3). Results: Median placental volume at gestational week 27 was 513 cm3 (Inter Quartile Range (IQR) 182 cm3), and it was 831cm3 (IQR 252 cm3) at week 37. Median placental to fetal ratio was 0.54 (IQR 0.18) at gestational week 27 and 0.31 (IQR 0.08) at week 37. The 10th – 90th percentiles included placental volumes between 392-717 cm3 at gestational week 27, and 631-1087 cm3 at week 37. The corresponding 10th-90th percentiles included placental to fetal ratios between 0.43-0.73 and 0.25-0.39. Conclusions: This study provides normative data about intrauterine placental volume and placental volume relative to fetal volume. Such data are important for the diagnostics of abnormal growth. Funding: The South-Eastern Norway Regional Health Authority (grant number 277901 and 2020013) and the Strategic Research Funding at Akershus University Hospital (grant number 269903). Keywords: Placenta, placental to fetal ratio MRI, pregnancy, percentiles

Heat exchanger network is one of the major technique of energy conservation. This article synthesizes the heat exchange network, through adjusting the bypass of the heat exchanger, the flexibility of the heat exchange network and the redundancy of the control system can be effectively improved, which is conducive to forming a closed-loop control of the final heat exchange temperature, thereby improving the quality of the heat exchange network and the stability of the system. The matching relationship is selected effectively through the qualitative analysis of operating characteristics and coupling relationship of control loops, which reduces the coupling degree between the control loops effectively in the engineering design stage. The concepts and discrimination methods of resonance coupling are proposed, the design process of control loop variable matching is optimized, and the selection and matching rules of adjusting variables are supplemented and perfected.

Background The aim of this study was to create a patient-derived slice model by combining cryopreservation technique with precision-cut slice culture method and explore its effectivity of predicting anti-cancer drug sensitivity in vitro. Methods We prepared 0.3 mm thick tissue slices by a microtome and maintain its cell viability by cryopreservation technique. Slices were cultured individually in the presence or absence of regorafenib (REG) for 72 hours. Alterations in morphology and gene expression was assessed by histological and genetic analysis. Overall viability was also analyzed in tissue slices by CCK-8 quantification assay and fluorescent staining. Tissue morphology and cell viability could be evaluated to quantify drug effects. Results Histological and genetic analysis showed that no significant alterations in morphology and gene expression were induced by vitrification‑based cryopreservation. The viability of warmed HCC tissues was up to 90% of the fresh tissues. The viability and proliferation could be retained for at least four days in filter culture system. The positive drug responses in precision-cut slice culture in vitro were evaluated by tissue morphology and cell viability. Conclusions In summary, the successful application of precision-cut HCC slice culture combining cryopreservation technique in a systematic drug screen demonstrates the feasibility and utility of slice culture method for drug response.

Acute graft versus host disease (aGvHD) remains one of the most serious complications, occurring in about 30-70%, of allogeneic hematopoietic stem cell transplantation (HSCT) recipients. While about 40-60% of these recipients will respond to steroids as first line, there is no consensus on second line agents. The management of steroid-refractory (SR) and steroid dependent (SD) GVHD after HSCT continues to be challenging. In the absence of clinical trials, treatment in most cases is based on individual physician or center experience. Herein, we present our institutional experience with the use of bortezomib, a first-generation reversible proteasome inhibitor, in SD aGvHD.

Subcutaneous-ICD for more and Transvenous-ICD for few?! Amr Abdin1 and Suleman Aktaa21 Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany2Leeds Institute for Data Analytics, University of Leeds, UK; Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK; Department of Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

This paper is devoted to the geometry of vector fields and timelike flows in terms of anholonomic coordinates in three dimensional Lorentzian space. We discuss eight parameters which are related by three partial differential equations. Then, it is seen that the curl of tangent vector field does not include any component in the direction of principal normal vector field. This implies the existence of a surface which contains both s-lines and b-lines. Moreover, we examine a normal congruence of timelike surfaces containing the s-lines and b-lines . Considering the compatibility conditions, we obtain the Gauss-Mainardi-Codazzi equations for this normal congruence of timelike surfaces in the case of the abnormality of normal vector field is zero. Intrinsic geometric properties of this normal congruence of timelike surfaces are obtained. We have deal with important results on these geometric properties.

Dermatophytic pathogens are a source of disturbance to the host microbiome, but the temporal progression of these disturbances is unclear. Here, we determined how Snake Fungal Disease progression resulted in disturbance to the host microbiome. To assess disease effects, 22 Common Watersnakes (Nerodia sipedon) were collected and half inoculated with O. ophidiicola. Epidermal swabs were collected weekly for use in microbiome and pathogen load characterization. For the inoculated treatment only, we found a significant effect of time on richness and Shannon diversity. When accounting for differences in assemblage richness, we found that microbial assemblages becoming more dissimilar across time in the inoculated but not the control group. Accounting for richness, average microbiome composition differed between treatments, but there was no interaction between treatment and time. These results suggest that changes in composition of the microbiome associated with disease occur due to disease-associated changes in microbial richness.

Objective: To compare the mental well-being of French women who were and were not pregnant during the first COVID-19 pandemic lockdown. Design: Survey. Setting: France. Population: Women between 18 and 45 years of age during the second and third weeks of global lockdown (March 25–April 07, 2020) during the COVID-19 pandemic. Methods: Nationwide online quantitative survey. Main Outcome Measures: Mental well-being measured by the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). Results: This study analysed 275 responses from pregnant women and compared them with those from a propensity score–matched sample of 825 non-pregnant women. The median WEMWBS score was 49.0 and did not differ by pregnancy status. Women living in urban areas reported better well-being, while those with sleep disorders or who spent more than an hour a day watching the news reported poorer well-being. Conclusion: During the first lockdown in France, women had relatively low mental well-being scores, with no significant difference between pregnant and non-pregnant women. More than ever, health-care workers need to find a way to maintain their support for women’s well-being. Minor daily annoyances of pregnancy, such as insomnia, should not be trivialised because they are a potential sign of poor well-being.

We investigated the evolutionary history of the grey reef shark (Carcharhinus amblyrhynchos) in the Indo-Pacific (IP) by harnessing the power of thousands of RAD-seq loci sequenced in 175 individuals across its range. We bring strong evidences of the occurrence of a range expansion (RE) originating close to the Indo-Australian Archipelago (IAA) from which two stepping-stone waves (east and westward) started, colonizing almost the entire IP. Consequently, the demographic history of C. amblyrhynchos is best explained by a meta-population model, for which we estimated a homogenous connectivity throughout its range (Nm~10 per generation) by means of coalescent modeling coupled with an Approximate Bayesian Computation framework. An isolation by distance model further highlights the absence of either genetic barriers or preferential migration corridors, despite the dependency of C. amblyrhynchos from coral reefs occurrence. This is consistent with the long-distance swims observed, suggesting that the strong genetic structure at the IP scale (FST~0.56 between its ends) is rather the consequence of its large current distribution. We contrasted these results with those previously obtained for the sympatric but strictly lagoon-associated Carcharhinus melanopterus, a species well known for its restricted dispersal ability. While C. melanopterus exhibits a similar RE dynamic, it is characterized by stronger genetic structure and a non-homogeneous connectivity largely dependent on local coral reefs availability. The comparison between the two species sheds new light on shark evolution, emphasizing the role of IAA as source of biodiversity and of dispersal ability in shaping the extent of population structure and genetic diversity.