Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins.

The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-21. This outbreak has been tentatively associated with a seafood market in Wuhan, China, where the sale of wild animals may be the source of zoonotic infection2. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.

Design of Ultrasound-Driven Charge Interference Therapy for Wound Infection.

Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.

FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Delineation of the phenotypes and genotypes of PIK3CA-related overgrowth spectrum in East asians.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas.

Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas.

Characteristics and Research Waste of Randomized Clinical Trials in Melanoma.

BACKGROUND: Numerous large-scale RCTs have propelled the melanoma treatment strategies. Research waste (RW) presents a significant challenge in translating the outcomes of RCTs into clinical practice. Currently, RW has not yet reported in the melanoma-related RCTs. METHODS: In January 2024, we searched ClinicalTrials.gov for phase 3/4 RCTs registered from January 2000 to December 2023 using "melanoma" as a keyword. We recorded the information listed on the website and searched PubMed and Scopus for the publication and citation status of the RCTs. A completed RCT required at least 47 months of preparation time for publication, hence RCTs completed after December 2019 but not yet published were excluded in the analysis of publication status. RESULTS: A total of 165 RCTs were included in the analysis. Melanoma RCTs primarily studied pharmacological interventions, with the registrations for immunotherapy increasing annually. In the analysis of RW, 103 RCTs were included, of which 41 RCTs (41/103, 39.8%) were unpublished. Of the 62 published RCTs, 19 (19/62, 30.6%) reported insufficiently, and 19 had avoidable design flaws (19/62, 30.6%). Ultimately, 64 (64/103, 62.1%) RCTs were judged to have RW. Registration after 2010, conducting studies in multiple countries, using multiple drug interventions, and having survival as primary outcomes were independent protective factors against RW. Thirty-four RCTs (34/62, 54.8%) were cited by guidelines, and 21 RCTs (21/62, 33.9%) reused their prospective data. CONCLUSIONS: We describe the characteristics of phase III/IV RCTs related to melanoma conducted over the past two decades and identify a substantial degree of RW. The protective factors against RW revealed in this study can provide references for the rational and efficient conduct of new RCTs in the future.

Evaluating research waste and traits among randomized controlled trials of scars over the past 20 years: a cross-sectional study.

PURPOSE: To analyze the changes in the characteristics of randomized controlled trials (RCTs) in the field of scarring over the last two decades, unveil the components of research waste (RW) within these RCTs, and identify targets for improvement. METHODS: A search was conducted on ClinicalTrials.gov for RCTs registered from January 2000 to December 2023, using "scar" as the keyword. The search was carried out in January 2024. RESULTS: 391 RCTs were included in this analysis. The global registration of RCTs in scarring has exhibited a consistent increase annually, with the proportion in Asia gradually rising, while the shares in North America and Europe have demonstrated a declining trend. In the analysis of RW, 232 RCTs were included, of which 96 (41.4%) have been published. Among the published RCTs, 56 (58.3%) were evaluated to have sufficient reporting, while 47 RCTs (48.9%) were identified as having avoidable design flaws. Ultimately, 183 RCTs (78.9%) exhibited at least one form of RW. Multicenter design (OR: 3.324, 95%CI: 1.385-7.975, P = 0.018), non-pharmacological interventions (OR: 2.61, 95%CI: 1.253-5.435, P = 0.010), the absence of external funding (OR: 0.325, 95%CI: 0.144-0.732, P = 0.031), and participant numbers exceeding 50 (OR: 3.269, 95%CI: 1.573-6.794, P = 0.002) were identified as independent protective factors against waste. CONCLUSIONS: This study delineates the changes in the characteristics of scar RCTs globally over the past two decades, uncovering a substantial burden of RW in scarring research. It provides an evidential reference for more rational planning of future scar-related RCTs and for minimizing RW.

Cross-reactive antibody response to Monkeypox virus surface proteins in a small proportion of individuals with and without Chinese smallpox vaccination history.

BACKGROUND: After the eradication of smallpox in China in 1979, vaccination with the vaccinia virus (VACV) Tiantan strain for the general population was stopped in 1980. As the monkeypox virus (MPXV) is rapidly spreading in the world, we would like to investigate whether the individuals with historic VACV Tiantan strain vaccination, even after more than 40 years, could still provide ELISA reactivity and neutralizing protection; and whether the unvaccinated individuals have no antibody reactivity against MPXV at all. RESULTS: We established serologic ELISA to measure the serum anti-MPXV titer by using immunodominant MPXV surface proteins, A35R, B6R, A29L, and M1R. A small proportion of individuals (born before 1980) with historic VACV Tiantan strain vaccination exhibited serum ELISA cross-reactivity against these MPXV surface proteins. Consistently, these donors also showed ELISA seropositivity and serum neutralization against VACV Tiantan strain. However, surprisingly, some unvaccinated young adults (born after 1980) also showed potent serum ELISA activity against MPXV proteins, possibly due to their past infection by some self-limiting Orthopoxvirus (OPXV). CONCLUSIONS: We report the serum ELISA cross-reactivity against MPXV surface protein in a small proportion of individuals both with and without VACV Tiantan strain vaccination history. Combined with our serum neutralization assay against VACV and the recent literature about mice vaccinated with VACV Tiantan strain, our study confirmed the anti-MPXV cross-reactivity and cross-neutralization of smallpox vaccine using VACV Tiantan strain. Therefore, it is necessary to restart the smallpox vaccination program in high risk populations.

Risk predictors of glycaemic control in children and adolescents with type 1 diabetes: A systematic review and meta-analysis.

OBJECTIVES: To conduct systematic evaluation of the risk predictors of glycaemic control in children and adolescents with type 1 diabetes mellitus. METHODS: Cohort studies on risk predictors of glycaemic control in children and adolescents with type 1 diabetes were retrieved from CNKI, PubMed, Web of Science, Embase databases, etc. from the construction of the repository to 3 February 2023. Literature screening was conducted according to inclusion and exclusion criteria, then data extraction of region, sample size, age, follow-up time, risk predictors, outcome indicators, etc., and quality evaluation of The Newcastle-Ottawa Scale were conducted by two researchers while the third researcher makes decisions if there are disagreements. Finally, Revman5.4 and StataMP17 were used for meta-analysis. RESULTS: A total of 29 studies were included, and the results showed that insulin pump [Weighed mean difference (WMD) = -.48, 95% CI (-.73, -.24), p < .01], high-frequency sensor monitoring, early use of insulin pumps, prospective follow-up male, white race, large body mass index-standardised scoring, conscientiousness, agreeableness of mothers, eicosapentaenoic acid, leucine and protein (p < .05) were beneficial for reducing HbA1c levels in children and adolescents with diabetes. Ketoacidosis [WMD = .39, 95% CI (.28, .50), p < .01], selective admission, higher HbA1c level at one time (p < .01), higher glutamate decarboxylase antibody at 1 month after diagnosis, lower socio-economic status, non-living with biological parents, non-two-parent family, family disorder, family history of diabetes and high carbohydrate intake (p < .05) increased HbA1c levels in children and adolescents with diabetes. CONCLUSION: For children and adolescents with type 1 diabetes mellitus, the use of insulin pump, high-frequency sensor monitoring, prospective follow-up, good family support and reasonable diet are conducive to blood glucose control, while selective admission and DKA are not. Disease characteristics and demographic characteristics of children are closely related to subsequent blood glucose control, and the relationship between diagnosis age and blood glucose control needs to be further explored.

Aesthetic Reconstruction of the Sequelae of Large Facial Involuted Infantile Hemangioma with Tissue Expanders.

BACKGROUND: Large involuted infantile hemangioma remains a challenge in facial reconstruction. The characteristic fibrofatty residuum and multiple subunits/tissues involvement contribute significantly to the difficulty of surgical management. Tissue expander plays an important role in facial reconstruction, allowing plastic surgeons to repair skin damaged by both congenital and acquired defects. METHODS: Between 2009 and 2021, 30 patients who underwent tissue expansion surgery were reviewed in a single hospital. The demographic data, lesion characteristics, surgical approaches, complication rate, and aesthetic outcomes were analyzed. RESULTS: Thirty patients (5 men and 25 women) with a mean age of 14.03 ± 7.25 years (range, 4-33 years) were included. The mean follow-up is 35.92 months, ranging from 9 to 75 months. Tissue expansion-related complications include closed infection, 2/30 (6.67%); skin ischemia, 2/30 (6.67%); hematoma, 1/30 (3.33%); flap necrosis, 1/30 (3.33%). CONCLUSION: Large facial involuted infantile hemangiomas have variable patterns of presentation and necessitate tailored therapy. Tissue expansion is a reproducible approach to achieving aesthetic reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Construction of Si-Stereogenic Silanols by Palladium-Catalyzed Enantioselective C-H Alkenylation.

The construction of silicon-stereogenic silanols via Pd-catalyzed intermolecular C-H alkenylation with the assistance of a commercially available L-pyroglutamic acid has been realized for the first time. Employing oxime ether as the directing group, silicon-stereogenic silanol derivatives could be readily prepared with excellent enantioselectivities, featuring a broad substrate scope and good functional group tolerance. Moreover, parallel kinetic resolution with unsymmetric substrates further highlighted the generality of this protocol. Mechanistic studies indicate that L-pyroglutamic acid could stabilize the Pd catalyst and provide excellent chiral induction. Preliminary computational studies unveil the origin of the enantioselectivity in the C-H bond activation step.

25-hydroxycholesterol inhibits human papillomavirus infection in cervical epithelial cells by perturbing cytoskeletal remodeling.

Persistent high-risk human papilloma virus (HR-HPV) infection is the main risk factor for cervical cancer, threatening women's health. Despite growing prophylactic vaccination, annual cervical cancer cases are still increasing and show a trend of younger onset age. However, therapeutic approaches towards HPV infection are still limited. 25-hydrocholesterol (25HC) has a wide-spectrum inhibitory effect on a variety of viruses. To explore efficient interventions to restrict HPV infection at an early time, we applied different pseudoviruses (PsV) to evaluate anti-HPV efficacy of 25HC. We tested PsV inhibition by 25HC in cervical epithelial-derived HeLa and C-33A cells, using high-risk (HPV16, HPV18, HPV59), possibly carcinogenic (HPV73), and low-risk (HPV6) HPV PsVs. Then we established murine genital HPV PsV infection models and applied IVIS to evaluate anti-HPV efficacy of 25HC in vivo. Next, with the help of confocal imaging, we targeted 25HC activity at filopodia upon HPV exposure. After that, we used RNA-seq and Western blot analysis to investigate (1) how 25HC disturbs actin cytoskeleton remodeling during HPV infection and (2) how prenylation regulates the cytoskeletal remodeling signaling pathway. Our findings suggest that 25HC perturbs F-actin rearrangement by reducing small GTPase prenylation. In this way, the phenomenon of HPV virion surfing was restricted, leading to failed infection.

Universal Scaling of Klein Bottle Entropy near Conformal Critical Points.

We show that the Klein bottle entropy [H.-H. Tu, Phys. Rev. Lett. 119, 261603 (2017)PRLTAO0031-900710.1103/PhysRevLett.119.261603] for conformal field theories perturbed by a relevant operator is a universal function of the dimensionless coupling constant. The universal scaling of the Klein bottle entropy near criticality provides an efficient approach to extract the scaling dimension of lattice operators via data collapse. As paradigmatic examples, we validate the universal scaling of the Klein bottle entropy for Ising and Z_{3} parafermion conformal field theories with various perturbations using numerical simulation with continuous matrix product operator approach.

Ethanol Embolotherapy for Cutaneous Erythema of High-Flow Vascular Malformations in the Head and Neck.

BACKGROUND: Cutaneous erythema is one of the most common signs of arteriovenous malformations (AVMs) in the head and neck region, influencing aesthetic appearance. Surgical resection of AVMs may lead to cicatrization of the skin or aggravation of the lesion. Laser treatment, although effective in improving superficial vascular lesions, cannot prevent deep AVMs from further development. OBJECTIVE: The authors propose an absolute ethanol embolization therapy that can effectively and safely eradicate the nidus with a favorable aesthetic outcome. METHODS: The authors conducted a retrospective observational study of 14 AVM patients with distinct cutaneous erythema in the head and neck region undergoing embolotherapy in a single primary care center. Symptoms before and after treatment, complications, and degree of devascularization were recorded and assessed. Changes in cutaneous redness were evaluated using a previously reported quantitative measurement. RESULTS: Complete symptomatic relief was observed in 5 patients, and major improvement was observed in 9 patients. The mean Δ a * value of the color change had a significant reduction of 6.50 ± 4.04, p < .001, indicating a remarkable remission of cutaneous erythema. CONCLUSION: Ethanol embolization is an effective and safe treatment for head and neck AVMs with excellent aesthetic outcomes and might become a potential treatment method for other superficial vascular anomalies.

Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3-kinase catalytic subunit alpha mutation.

We report an unusual case of facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations. In addition to the clinical data and imaging findings, detection of a heterozygous PIK3CA nonhotspot known pathogenic variant C420R in a facial epidermal nevus provided novel insight into the pathogenic effect of somatic PIK3CA mutations.

'On Water'-Promoted Three-Component Tandem Michael Addition/D-A Cycloaddition Reaction to Construct Polycyclic N-Heterocycles Derivatives.

'On Water'-promoted the three-component tandem Michael addition/D-A cycloaddition reaction in 80 °C at 3 h has been developed without employing any catalyst and organic solvent. The process allows facile access to polycyclic N-heterocycles derivatives contain indole and maleimide from easily accessible starting materials in moderate to high yields (up to 91 %). Compared with conventional reaction conditions, this reaction not only improves the reaction efficiency and rate but also minimizes the side reaction.

Updates on Diagnosis and Treatment of PIK3CA-Related Overgrowth Spectrum.

ABSTRACT: Hyperactivation of the PI3K/AKT/mTOR signaling pathway caused by PIK3CA mutations is associated with a category of overgrowth syndromes that are defined as PIK3CA -related overgrowth spectrum (PROS). The clinical features of PROS are highly heterogeneous and usually present as vascular malformations, bone and soft tissue overgrowth, and neurological and visceral abnormalities. Detection of PIK3CA variants is necessary for diagnosis and provides the basis for targeted therapy for PROS. Drugs that inhibit the PI3K pathway offer alternatives to conventional therapies. This article reviews the current knowledge of PROS and summarizes the latest progress in precise treatment, providing new insights into future therapies and research goals.

Treatment of Challenging Extracranial Arteriovenous Malformations: A Single-Center Experience and Literature Review.

ABSTRACT: Extracranial arteriovenous malformation (AVM) is a high-flow congenital vascular malformation, where direct communication between the arteries and veins impedes perfusion of capillary beds and causes disfigurement of the affected tissue. Surgery and endovascular therapy are currently the main treatment for extracranial AVMs. Nevertheless, management of complex cases is sometimes challenging because of severe complications such as refractory ulceration, life-threatening bleeding, and even cardiac insufficiency. Here, we reviewed the development and potential treatment for extracranial AVMs and shared our single-center experiences of diagnosis and treatment of this challenging disease.

Untargeted Lipidomic Profiling Reveals Lysophosphatidylcholine and Ceramide as Atherosclerotic Risk Factors in apolipoprotein E Knockout Mice.

Despite the availability and use of numerous cholesterol-lowering drugs, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality globally. Many researchers have focused their effort on identifying modified lipoproteins. However, lipid moieties such as lysophosphatidylcholine (LPC) and ceramide (CER) contribute to atherogenic events. LPC and CER both cause endothelial mitochondrial dysfunction, leading to fatty acid and triglyceride (TG) accumulation. In addition, they cause immune cells to differentiate into proinflammatory phenotypes. To uncover alternative therapeutic approaches other than cholesterol- and TG-lowering medications, we conducted untargeted lipidomic investigations to assess the alteration of lipid profiles in apolipoprotein E knockout (apoE-/-) mouse model, with or without feeding a high-fat diet (HFD). Results indicated that, in addition to hypercholesterolemia and hyperlipidemia, LPC levels were two to four times higher in apoE-/- mice compared to wild-type mice in C57BL/6 background, regardless of whether they were 8 or 16 weeks old. Sphingomyelin (SM) and CER were elevated three- to five-fold in apoE-/- mice both at the basal level and after 16 weeks when compared to wild-type mice. After HFD treatment, the difference in CER levels elevated more than ten-fold. Considering the atherogenic properties of LPC and CER, they may also contribute to the early onset of atherosclerosis in apoE-/- mice. In summary, the HFD-fed apoE-/- mouse shows elevated LPC and CER contents and is a suitable model for developing LPC- and CER-lowering therapies.