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Abstract The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Abstract Background Carcinoid tumors are rare neuroendocrine malignancies presenting in an increasing number in our center. The incidence of carcinoid tumors is approximatively between 2.5 and 5 cases per 100,000 people of whom about 50% develop carcinoid syndrome. Once the carcinoid syndrome has developed, a carcinoid cardiomyopathy can occur. Carcinoid heart disease (CaHD) remains a serious and rare complication associated with a significant increase in morbidity and mortality. Although carcinoid tumors have been known and studied for several years, there are still scarce data on the anesthetic management and the peri operative period. Case presentation We describe a case of a Caucasian 44-year-old woman with an unusual presentation of left CaHD with an ileal neuroendocrine tumor and liver metastases. Our preoperative somatostatin administration protocol, limit the cardiac damage. The maintenance of stable hemodynamics, the use of balanced anesthetic technique, all along with a good understanding of the pathology, played a major role in the successful management of anesthesia. This case report allows us to introduce our decision algorithm for the management of this type of pathology in our tertiary hospital, Cliniques Universitaires Saint-Luc. Conclusion Despite the paucity of data, anesthetic management of patients with carcinoid tumor can be safely performed with effective hemodynamic monitoring and a good understanding of the pathophysiology. Knowledge and application of a clear institutional algorithm for octreotide administration and multidisciplinary consultation at a referral center are essential for the management of these patients.

Pregnancy is a fascinating immunological phenomenon because it allows allogeneic fetal and placental tissues to survive inside the mother. As a component of innate immunity with high inflammatory potential, the complement system must be tightly regulated during pregnancy. Dysregulation of the complement system plays a role in pregnancy complications including pre-eclampsia and intrauterine growth restriction. Complement components are also used as biomarkers for pregnancy complications. However, the mechanisms of detrimental role of complement in pregnancy is poorly understood. C5a is the most potent anaphylatoxin and generates multiple immune reactions via two transmembrane receptors, C5aR1 and C5aR2. C5aR1 is pro-inflammatory, but the role of C5aR2 remains largely elusive. Interestingly, murine NK cells have been shown to express C5aR2 without the usual co-expression of C5aR1. Furthermore, C5aR2 appears to regulate IFN-γ production by NK cells in vitro. As IFN-γ produced by uterine NK cells is one of the major factors for the successful development of a vital pregnancy, we investigated the role anaphylatoxin C5a and its receptors in the establishment of pregnancy and the regulation of uterine NK cells by examinations of murine C5ar2–/– pregnancies and human placental samples. C5ar2–/– mice have significantly reduced numbers of implantation sites and a maternal C5aR2 deficiency results in increased IL-12, IL-18 and IFN-γ mRNA expression as well as reduced uNK cell infiltration at the maternal-fetal interface. Human decidual leukocytes have similar C5a receptor expression patterns showing clinical relevance. In conclusion, this study identifies C5aR2 as a key contributor to dNK infiltration and pregnancy success.

The soil mantle of the tropical karst landscapes of southern Mexico was a key resource for ancient Maya agriculture and experienced deep transformation due to long-term human impacts under changing environmental conditions. We conducted a comparative analysis of three compound soil toposequences in mountainous (Sierra de Chiapas/Middle Usumacinta Valley, Busiljá, and Chinikihá archaeological sites) and platform (NE Yucatán Peninsula, Yalahau region) karst landscapes to reconstruct general tendencies and regional variations in pedodiversity development and soil–human interactions since the Early Preclassic Period. Toposequence characterization is based on macro- and micromorphological observations, accompanied by a suite of laboratory data. Calcareous upland geoforms of all toposequences have similar soil combinations consisting of shallow Rendzina and deep red clayey Terra Rossa types of profiles. We argue that Rendzinas, now dominant in the upland soil cover, in most cases, are not a product of incipient pedogenesis on limestone; they have developed from the residues of Terra Rossa soils after their advanced erosion. Pedosediments generated by ancient soil erosion have been found in the piedmont and depression positions in the mountainous landscapes of Chiapas, as a result of lateral downslope soil removal, and in the subsurface karstic cavities in the platform of NE Yucatán, indicating vertical “soil piping.” The soils of the lowland domains show contrasting differences between the toposequences: gleyic clay–rich soils and humic alluvial soils prevail in Chinikihá and Busiljá, whereas hydromorphic carbonate soils have formed in Yalahau karstic depressions. These differences in the lowland soil properties led to divergent ancient Maya land use strategies; in Chinikihá and Busiljá, the major agricultural domain was developed in the lowlands, implying largescale artificial drainage. On the contrary, in Yalahau, mostly upland Rendzinas were cultivated, implying “precision agriculture” and “container gardening.”

Purpose: Bariatric and metabolic surgery is increasing in Asia to address the growing obesity epidemic. Literature is scarce regarding this surgery in vegetarian patients. We aim to survey surgeons regarding their practices and experiences with the vegetarian population. Materials and methods: The regional bariatric and metabolic surgery society distributed a multi-national electronic questionnaire to surgeon members. The questionnaire was in the English and Chinese languages. Results: Fifty-six bariatric and metabolic surgeons responded to the questionnaire (response rate 40.6%). Twenty-two respondents (48.9%) have vegetarian patients in their case volume. Patients mostly consume a vegetarian diet for religious (66.7%) and health (66.7%) reasons. More than 60% of surgeons are unsure of micronutrient deficiency status amongst these patients. Over half of the respondents (58.8%) reported that their vegetarian patients do not take multivitamins or vitamin supplements. Significant proportions of respondents (44.4–61.1%) were unsure of the iron, vitamin B12, vitamin D, zinc, and folic acid deficiency status of these patients. Only 38.9% of respondents routinely prescribe multivitamin supplementation. Conclusions: Vegetarian bariatric patients in East and South-East Asia are an under-recognized patient cohort at risk of micronutrient deficiencies. There is a knowledge gap among regional surgeons in long-term nutritional assessment and management.

Background and Aims: Zenker's diverticulum is a false diverticulum through Killian's dehiscence. Symptoms include halitosis, dysphagia, regurgitation, cough, and aspiration pneumonia. Treatment options include open transcervical cricopharyngeal myotomy, trans-oral rigid endoscopic stapling, and minimally invasive endoscopic myotomy. Although open surgical techniques have historically been the criterion standard for treatment, endoscopic options have become increasingly used. We propose the use of flexible endoscopy in the management of Zenker's diverticulum. Methods: We present a retrospective case series of 9 patients undergoing endoscopic cricopharyngeal myotomy from 2014 to 2018 using our endoscopic technique. Results: We demonstrate that endoscopic technique provided adequate symptomatic relief in 7 of 9 patients, with no operative adverse events. Conclusions: Cricopharyngeal myotomy using flexible endoscopy is a safe and effective technique for the management of Zenker's diverticulum. Potential benefits of this approach include shorter operative times, shorter postoperative admissions, and earlier progression of diet. Initial treatment with endoscopic technique does not preclude future open repairs.

Summary: Aberrant hyperphosphorylation of the protein phosphatase 2A catalytic subunit (PP2Ac) at Tyr307 has been associated with aggressive disease and poor clinical outcome in multiple cancers. However, the study of reversible phosphorylation at this site has relied entirely upon the use of antibodies—most prominently, the clone E155. Here, we provide evidence that the E155 and F-8 phospho-Tyr307 antibodies cannot differentiate between phosphorylated and unphosphorylated forms of PP2Ac. The form of PP2Ac bound by these antibodies in H358 cells is unphosphorylated at the C-terminal tail. Furthermore, these antibodies are sensitive to additional protein modifications that occur near Tyr307, including Thr304 phosphorylation and Leu309 methylation, when these post-translational modifications are present. Thus, studies that used these antibodies to report PP2Ac hyperphosphorylation require reinterpretation, as these antibodies cannot be reliably used as readouts for a single PP2Ac post-translational modification (PTM) change. : Inhibitory hyperphosphorylation of the PP2A catalytic subunit in cancer has been correlated with poor prognosis in numerous studies. Mazhar et al. show that the phospho-Tyr307-specific antibodies commonly used to detect this inhibitory mark are in fact agnostic to their intended target, binding unphosphorylated PP2A with equal affinity. Keywords: antibody validation, PP2A, phospho-Tyr307 PP2Ac, phospho-specific antibody

Researchers have related the manufacturing technique of plasters and stucco in the Maya area with their period of production but not with their architectural function. In this paper, we establish a relationship between those three features (manufacturing technique, age, and architectural function) in the plasters of the Maya site of Dzibanché in southern Quintana Roo. Dzibanché has abundant remains of stuccos and plasters found mainly in three buildings (Plaza Pom, Pequeña Acrópolis, and Structure 2). We used thin sections, SEM and XRD, and archaeomagnetic dating processes. The pictorial layer of Structure 2 was the earliest (AD 274–316 and the stuccoes and plasters of the other two buildings were dated to the Middle Classic (AD 422–531), but we obtained different archaeomagnetic dates for the red pigment layers found in the buildings of the Pequeña Acrópolis and thus we were able to determine their chronological order of construction. The raw materials and proportions were carefully chosen to fulfil the mechanical necessities of the architectonic function: different proportions were found in plasters of floors, in the external walls, and inside the buildings; differences between earlier and later plasters were also detected.

Pregnancy is a fascinating immunological phenomenon because it allows allogeneic fetal and placental tissues to survive inside the mother. As a component of innate immunity with high inflammatory potential, the complement system must be tightly regulated during pregnancy. Dysregulation of the complement system plays a role in pregnancy complications including pre-eclampsia and intrauterine growth restriction. Complement components are also used as biomarkers for pregnancy complications. However, the mechanisms of detrimental role of complement in pregnancy is poorly understood. C5a is the most potent anaphylatoxin and generates multiple immune reactions via two transmembrane receptors, C5aR1 and C5aR2. C5aR1 is pro-inflammatory, but the role of C5aR2 remains largely elusive. Interestingly, murine NK cells have been shown to express C5aR2 without the usual co-expression of C5aR1. Furthermore, C5aR2 appears to regulate IFN-γ production by NK cells in vitro. As IFN-γ produced by uterine NK cells is one of the major factors for the successful development of a vital pregnancy, we investigated the role anaphylatoxin C5a and its receptors in the establishment of pregnancy and the regulation of uterine NK cells by examinations of murine C5ar2-/- pregnancies and human placental samples. C5ar2-/- mice have significantly reduced numbers of implantation sites and a maternal C5aR2 deficiency results in increased IL-12, IL-18 and IFN-γ mRNA expression as well as reduced uNK cell infiltration at the maternal-fetal interface. Human decidual leukocytes have similar C5a receptor expression patterns showing clinical relevance. In conclusion, this study identifies C5aR2 as a key contributor to dNK infiltration and pregnancy success. [ABSTRACT FROM AUTHOR]