Use of TC-325 Hemostatic Powder as a Rescue Monotherapy for Management of Rectal Variceal Bleed.

The use of the endoscopic hemostatic powder TC-325 as a rescue monotherapy or as an adjunct agent in achieving hemostasis has been studied in upper gastrointestinal variceal bleeds and nonvariceal lower gastrointestinal bleeds with promising results. In this report, we describe a case of a successful use of TC-325 as rescue monotherapy to manage rectal variceal bleeding in a patient with alcohol-related cirrhosis with no report of bleeding recurrence and no side effects within the first 7 days, 30 days, or 6 months.

Coxsackievirus-Induced Myocarditis With Acute Onset of Heart Failure With Pleural Effusion.

This is a case of a 45-year-old Caucasian female with coxsackievirus-induced myocarditis. Myocarditis is an inflammation of the heart muscles, which can be difficult to diagnose at times because its symptoms overlap with other cardiovascular diseases. At times, when the patient presents, the full impact of the etiology would have either improved or resolved. In this case, the patient presented with symptoms closely resembling that of acute coronary syndrome but did not fit the typical age category. After lab and imaging workup, the coxsackievirus panel was positive, complicated with a new diagnosis of systolic heart failure with an ejection fraction of 30%-35% along with pericardial effusion.

A Recurrent Case of Mesothelial Pericardial Cyst.

This is a case of a 37-year-old female patient with past medical history of mitral valve prolapse and benign mesothelial pericardial cyst status post laparoscopic resection who presented to the emergency department with a chief complaint of right-sided sharp non-radiating chest pain due to recurrent case of benign mesothelial pericardial cyst. Though this is not a common pathology, it does overlap with common cardiovascular symptoms/conditions; not limited to but including chest pain, dyspnea, palpitations, pericardial effusions, infections and arrhythmias. It is crucial to have appropriate history and physical exam and appropriate evaluation to rule out pericardial cysts as well as their locations and their potential lethal mechanical implication on crucial nearby structures. This is significant in order to avoid uncommon but lethal cardiac complications in this condition such as cardiac arrhythmias, cardiac tamponade, right ventricular outflow tract and even sudden cardiac death.

Genotypic study of Chlamydia trachomatis for lymphogranuloma venereum diagnosis in rectal specimens from men who have sex with men: a cost-effectiveness analysis.

PURPOSE: The significant proportion of asymptomatic patients and the scarcity of genotypic analysis of lymphogranuloma venereum (LGV), mainly among men who have sex with men (MSM), triggers a high incidence of underdiagnosed patients, highlighting the importance of determining the most appropriate strategy for LGV diagnosis, at both clinical and economical levels. MATERIALS AND METHODS: We conducted L1-L3 serovar detection by molecular biology in stored Chlamydia trachomatis-positive samples from MSM patients with HIV, another STI or belonging to a Pre-exposure prophylaxis program, to make a cost effectiveness study of four diagnostic strategies with a clinical, molecular, or mixed approach. RESULTS: A total of 85 exudates were analyzed: 35urethral (31 symptomatic/4 positive) and 50 rectal (22 symptomatic/25 positive), 70/85 belonging to MSM with associated risk factors. The average cost per patient was €77.09 and €159.55 for clinical (Strategy I) and molecular (Strategy IV) strategies respectively. For molecular diagnosis by genotyping of all rectal exudate samples previously positive for CT (Strategy II), the cost was €123.84. For molecular diagnosis by genotyping of rectal and/or urethral exudate samples from all symptomatic patients (proctitis or urethritis) with a previous positive result for CT (Strategy III), the cost was €129.39. The effectiveness ratios were 0.80, 0.95, 0.91, and 1.00 for each strategy respectively. The smallest ICER was €311.67 for Strategy II compared to Strategy I. CONCLUSIONS: With 30% asymptomatic patients, the most cost-effective strategy was based on genotyping all rectal exudates. With less restrictive selection criteria, thus increasing the number of patients with negative results, the most sensitive strategies tend to be the most cost-effective, but with a high incremental cost-effectiveness ratio.

Trends in suicide mortality in Spain from 1998 to 2021 and its relationship with the COVID-19 pandemic: A joinpoint regression analysis.

In the European Union, a rate of 11.9 cases per 100,000 was estimated in 2019.In Spain, suicide is the leading cause of external death. Social crises can have an impact on suicide rates. We analyzed changes in suicide mortality trends in Spain following the COVID-19 pandemic. We used statistical data from the National Institute of Statistics of Spain (1998-2021). We calculated age-specific rates, age and sex-adjusted rates, and analyzed trends and changes using joinpoint-regression models. Rates decrease in both sexes at the ages of 65 and older. In women, they increase in the ages of 1-29 years and 45-59 years. In men, they decrease in the ages of 15-39 years. Among women, age-adjusted rates remained stable between 1998 and 2021, with a non-significant annual decrease of 0.4 %. Among men, there was a significant annual decrease of 0.7 %. The years 2020 and 2021 had 8 % higher mortality compared to the two years prior to the COVID-19 pandemic. Suicide mortality in Spain slightly decreased among men and remained stable among women between 1998 and 2021, but there seems to be an increase following the COVID-19 pandemic.

Trends in stroke mortality in La Rioja (Spain) from 1999 to 2022.

INTRODUCTION: Stroke mortality has declined in recent decades, but there appears to be a slowdown in the decline in recent years. We analyze the trends in stroke mortality in La Rioja (Spain) for the period 1999-2022. METHODS: We evaluated stroke mortality using statistical data from the mortality registry of La Rioja (Spain). We adjusted the rates by age and sex and analyzed both overall strokes and subtypes: hemorrhagic and ischemic. To analyze the trend in mortality rates we constructed joinpoint regression models, with associated annual percentage change (APC) RESULTS: Age-standardized stroke mortality declined between 1999 and 2022: females from 98.0 to 29.2 per 100 000; males, from 131.6 to 44.8 per 100 000. We found a decrease in overall stroke mortality in all age groups, except those under 65 years old. Ischemic stroke mortality showed declines in the first decade (APC: 7.3%, CI95%: 4.1-19.1%) and increases in the second decade (APC: 1.6%, CI95%: -1.6-11.7%) among men. In women, the rates declined between 2018 and 2022(APC: -6.6%, CI95%: -5.1-30.6%) after an increase between 2015 and 2017 (APC: 23.5%, CI95%: -20.2-38.3%). For hemorrhagic stroke, we found a consistent rate of decline throughout the entire time period in men (APC: 2.4%, CI95%: 0.9 a 4.0%). In women, rates increased during the period 1999-2009(APC: 1.9%, CI95%: -2.1-22.8%) and decreased 2010-2022 (APC: 6.5%, CI95%: 4.0-25.6%). CONCLUSIONS: Stroke mortality rates have decreased, more so for haemorrhagic than ischaemic strokes.

Melatonin as a Coadjuvant in the Treatment of Patients with Fibromyalgia.

Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is accompanied by fatigue, sleep disturbances, anxiety, depression, lack of concentration, and neurocognitive impairment. As the currently available drugs are not completely successful against these symptoms and frequently have several side effects, many scientists have taken on the task of looking for nonpharmacological remedies. Many of the FMS-related symptoms have been suggested to be associated with an altered pattern of endogenous melatonin. Melatonin is involved in the regulation of several physiological processes, including circadian rhythms, pain, mood, and oxidative as well as immunomodulatory balance. Preliminary clinical studies have propounded that the administration of different doses of melatonin to patients with FMS can reduce pain levels and ameliorate mood and sleep disturbances. Moreover, the total antioxidant capacity, 6-sulfatoxymelatonin and urinary cortisol levels, and other biological parameters improve after the ingestion of melatonin. Recent investigations have proposed a pathophysiological relationship between mitochondrial dysfunction, oxidative stress, and FMS by looking at certain proteins involved in mitochondrial homeostasis according to the etiopathogenesis of this syndrome. These improvements exert positive effects on the quality of life of FMS patients, suggesting that the use of melatonin as a coadjuvant may be a successful strategy for the management of this syndrome.

Bladder cancer patients have increased NETosis and impaired DNaseI-mediated NET degradation that can be therapeutically restored in vitro.

Background: Neutrophils, key players of the immune system, also promote tumor development through the formation of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are extracellular networks of DNA, histones and cytoplasmic and granular proteins (calprotectin, myeloperoxidase, elastase, etc.) released by neutrophils upon activation. NETs regulate tumor growth while promoting angiogenesis and invasiveness, and tumor cells also stimulate NETosis. Although NETosis seems to be increased in cancer patients, an increase of NETs in plasma may also be mediated by an impaired degradation by plasma DNaseI, as evidenced in several immunological disorders like lupus nephritis. However, this has never been evidenced in bladder cancer (BC) patients. Herein, we aimed to evaluate the occurrence of increased NETosis in plasma and tumor tissue of BC patients, to ascertain whether it is mediated by a reduced DNaseI activity and degradation, and to in vitro explore novel therapeutic interventions. Methods: We recruited 71 BC patients from whom we obtained a plasma sample before surgery and a formalin-fixed paraffin embedded tumor tissue sample, and 64 age- and sex-matched healthy controls from whom we obtained a plasma sample. We measured NETs markers (cell-free fDNA, calprotectin, nucleosomes and neutrophil elastase) and the DNaseI activity in plasma with specific assays. We also measured NETs markers in BC tissue by immunofluorescence. Finally, we evaluated the ability of BC and control plasma to degrade in vitro-generated NETs, and evaluated the performance of the approved recombinant human DNaseI (rhDNaseI, Dornase alfa, Pulmozyme®, Roche) to restore the NET-degradation ability of plasma. In vitro experiments were performed in triplicate. Statistical analysis was conducted with Graphpad (v.8.0.1). Results: NETosis occurs in BC tissue, more profusely in the muscle-invasive subtype (P<0.01), that with the worst prognosis. Compared to controls, BC patients had increased NETosis and a reduced DNaseI activity in plasma (P<0.0001), which leads to an impairment to degrade NETs (P<0.0001). Remarkably, this can be therapeutically restored with rhDNaseI to the level of healthy controls. Conclusion: To the best of our knowledge, this is the first report demonstrating that BC patients have an increased NETosis systemically and in the tumor microenvironment, in part caused by an impaired DNaseI-mediated NET degradation. Remarkably, this defect can be therapeutically restored in vitro with the approved Dornase alfa, thus Pulmozyme® could become a potential therapeutic tool to locally reduce BC progression.

New Roles for Old Friends: Involvement of the Innate Immune System in Tumor Progression.

The association between the immune system and tumor progression has attracted much interest in the research community in recent years [...].

Neutrophil Extracellular Traps and Cancer: Trapping Our Attention with Their Involvement in Ovarian Cancer.

Neutrophils, the most abundant circulating leukocytes, play a well-known role in defense against pathogens through phagocytosis and degranulation. However, a new mechanism involving the release of neutrophil extracellular traps (NETs) composed of DNA, histones, calprotectin, myeloperoxidase, and elastase, among others, has been described. The so-called NETosis process can occur through three different mechanisms: suicidal, vital, and mitochondrial NETosis. Apart from their role in immune defense, neutrophils and NETs have been involved in physiopathological conditions, highlighting immunothrombosis and cancer. Notably, neutrophils can either promote or inhibit tumor growth in the tumor microenvironment depending on cytokine signaling and epigenetic modifications. Several neutrophils' pro-tumor strategies involving NETs have been documented, including pre-metastatic niche formation, increased survival, inhibition of the immune response, and resistance to oncologic therapies. In this review, we focus on ovarian cancer (OC), which remains the second most incidental but the most lethal gynecologic malignancy, partly due to the presence of metastasis, often omental, at diagnosis and the resistance to treatment. We deepen the state-of-the-art on the participation of NETs in OC metastasis establishment and progression and their involvement in resistance to chemo-, immuno-, and radiotherapies. Finally, we review the current literature on NETs in OC as diagnostic and/or prognostic markers, and their contribution to disease progression at early and advanced stages. The panoramic view provided in this article might pave the way for enhanced diagnostic and therapeutic strategies to improve the prognosis of cancer patients and, specifically, OC patients.

Increased levels of NETosis biomarkers in high-grade serous ovarian cancer patients' biofluids: Potential role in disease diagnosis and management.

Introduction: High-grade serous ovarian cancer (HGSOC) is the second most frequent gynecological malignancy but the most lethal, partially due to the spread of the disease through the peritoneal cavity. Recent evidence has shown that, apart from their role in immune defense through phagocytosis and degranulation, neutrophils are able to participate in cancer progression through the release of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are composed of DNA, histones, calprotectin, myeloperoxidase (MPO) and elastase and the NETosis process has been proposed as a pre-requisite for the establishment of omental metastases in early stages of HGSOC. Nevertheless, its role in advanced stages remains to be elucidated. Therefore, our principal aim is to characterize a NETosis biomarker profile in biofluids from patients with advanced HGSOC and control women. Methods: Specifically, five biomarkers of NETosis (cell-free DNA (cfDNA), nucleosomes, citrullinated histone 3 (citH3), calprotectin and MPO) were quantified in plasma and peritoneal fluid (PF) samples from patients (n=45) and control women (n=40). Results: Our results showed that HGSOC patients presented a higher concentration of cfDNA, citH3 and calprotectin in plasma and of all five NETosis biomarkers in PF than control women. Moreover, these biomarkers showed a strong ability to differentiate the two clinical groups. Interestingly, neoadjuvant treatment (NT) seemed to reduce NETosis biomarkers mainly systemically (plasma) compared to the tumor environment (PF). Discussion: In conclusion, NETosis biomarkers are present in the tumor environment of patients with advanced HGSOC, which might contribute to the progression of the disease. Besides, plasma cfDNA and calprotectin could represent minimally invasive surrogate biomarkers for HGSOC. Finally, NT modifies NETosis biomarkers levels mainly at the systemic level.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical Gßγ-mediated stimulation of Ca2+ release from intracellular stores by activation of PLCß (phospholipase Cß). Alone, this [Ca2+]i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at Gq-coupled receptors also increase [Ca2+]i. We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCß that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca2+]i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca2+]i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

Molecular basis for pericyte-induced capillary tube network assembly and maturation.

Here we address the functional importance and role of pericytes in capillary tube network assembly, an essential process that is required for vascularized tissue development, maintenance, and health. Healthy capillaries may be directly capable of suppressing human disease. Considerable advances have occurred in our understanding of the molecular and signaling requirements controlling EC lumen and tube formation in 3D extracellular matrices. A combination of SCF, IL-3, SDF-1α, FGF-2 and insulin ("Factors") in conjunction with integrin- and MT1-MMP-induced signaling are required for EC sprouting behavior and tube formation under serum-free defined conditions. Pericyte recruitment to the abluminal EC tube surface results in elongated and narrow tube diameters and deposition of the vascular basement membrane. In contrast, EC tubes in the absence of pericytes continue to widen and shorten over time and fail to deposit basement membranes. Pericyte invasion, recruitment and proliferation in 3D matrices requires the presence of ECs. A detailed analysis identified that EC-derived PDGF-BB, PDGF-DD, ET-1, HB-EGF, and TGFß1 are necessary for pericyte recruitment, proliferation, and basement membrane deposition. Blockade of these individual factors causes significant pericyte inhibition, but combined blockade profoundly interferes with these events, resulting in markedly widened EC tubes without basement membranes, like when pericytes are absent.

Experiencia de grupo terapéutico durante el confinamiento por COVID-19 en una unidad de agudos de psiquiatría / Therapeutic group experience during confinement by COVID-19 in an acute psychiatry unit

El presente trabajo consiste en la descripciónde las sesiones grupales que se efectuarondurante el confinamiento por COVID-19en la Unidad de Agudos 1 de Psiquiatría generaldel Hospital Sagrat Cor de Martorell,en Barcelona.Se planteó un grupo abierto con aquellospacientes ingresados que voluntariamenteaccedieran a participar, como una propuestaa la alta respuesta emocional del momento.Se efectuó una sesión grupal semanal de unahora de duración a lo largo de seis semanas.El equipo terapéutico quedó constituidotanto por profesionales de la unidad comode los provenientes de recursos ambulatoriostomando un carácter interdisciplinar. Participaronun total de 41 pacientes con unaheterogeneidad diagnóstica; trastornos dela personalidad (26,83%), trastorno bipolar(19.51%), esquizofrenia y otros trastornospsicóticos (19,51%) y trastornos depresivos(14,61%). El porcentaje restante (19,54%)corresponde a otros diagnósticos. El 46,34%del total de los pacientes ha presentadoconsumo de sustancias en comorbilidad. Seaprecian como temas principales: La aceptacióndel ingreso, la compresión de lasnormativas por COVID-19, el manejo de laangustia por el ingreso bajo las condicionesde confinamiento y el desarrollo de capacidadesde diálogo, responsabilidad y cuidadode los participantes. Se describieron en las terapeutas intervenciones más directivas alinicio de las sesiones a intervenciones deacompañamiento y facilitación a medida quese desarrollaba el grupo.ConclusionesLa actividad grupal permitió un espacio decontención emocional, seguridad, información,reflexión, educación e integración paralos participantes. (AU)

The present work consists of the descriptionof the group sessions that were carriedout during the confinement becauseof COVID-19 in the Acute Unit 1 of GeneralPsychiatry of the Hospital Sagrat Cor de Martorell,in Barcelona.An open group was proposed with thoseadmitted patients who voluntarily agreed toparticipate, as a proposal to the high emotionalresponse of the moment. A weeklyone-hour group session was held over sixweeks. The therapeutic team was constitutedby both professionals from the unit andthose from outpatient resources, adoptingan interdisciplinary character. The outstandingthemes extracted from the summariesof each session were described. A total of 41patients with diagnostic heterogeneity participated;personality disorders (26.83%), bipolar disorder (19.51%), schizophreniaand other psychotic disorders (19.51%) anddepressive disorders (14.61%). The remainingpercentage (19.54%) corresponds toother diagnoses. 46.34% of the total of patientshave presented substance use in comorbidity.The main themes are the management ofanxiety due to admission under confinementconditions; compression of regulations becauseof COVID-19; and the development ofa dialogue capacity, responsibility and careof the participants. More directive interventionswere described in the therapists at thebeginning of the sessions towards accompanimentinterventions as the group develops.ConclusionsThe group activity allowed a space foremotional containment, security, information,reflection, education and integrationfor the participants. (AU)

Strengthening data collection for neglected tropical diseases: What data are needed for models to better inform tailored intervention programmes?

Locally tailored interventions for neglected tropical diseases (NTDs) are becoming increasingly important for ensuring that the World Health Organization (WHO) goals for control and elimination are reached. Mathematical models, such as those developed by the NTD Modelling Consortium, are able to offer recommendations on interventions but remain constrained by the data currently available. Data collection for NTDs needs to be strengthened as better data are required to indirectly inform transmission in an area. Addressing specific data needs will improve our modelling recommendations, enabling more accurate tailoring of interventions and assessment of their progress. In this collection, we discuss the data needs for several NTDs, specifically gambiense human African trypanosomiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths (STH), trachoma, and visceral leishmaniasis. Similarities in the data needs for these NTDs highlight the potential for integration across these diseases and where possible, a wider spectrum of diseases.

Modelling to Quantify the Likelihood that Local Elimination of Transmission has Occurred Using Routine Gambiense Human African Trypanosomiasis Surveillance Data.

BACKGROUND: The gambiense human African trypanosomiasis (gHAT) elimination programme in the Democratic Republic of Congo (DRC) routinely collects case data through passive surveillance and active screening, with several regions reporting no cases for several years, despite being endemic in the early 2000s. METHODS: We use mathematical models fitted to longitudinal data to estimate the probability that selected administrative regions have already achieved elimination of transmission (EOT) of gHAT. We examine the impact of active screening coverage on the certainty of model estimates for transmission and therefore the role of screening in the measurement of EOT. RESULTS: In 3 example health zones of Sud-Ubangi province, we find there is a moderate (>40%) probability that EOT has been achieved by 2018, based on 2000-2016 data. Budjala and Mbaya reported zero cases during 2017-18, and this further increases our respective estimates to 99.9% and 99.6% (model S) and to 87.3% and 92.1% (model W). Bominenge had recent case reporting, however, that if zero cases were found in 2021, it would substantially raise our certainty that EOT has been met there (99.0% for model S and 88.5% for model W); this could be higher with 50% coverage screening that year (99.1% for model S and 94.0% for model W). CONCLUSIONS: We demonstrate how routine surveillance data coupled with mechanistic modeling can estimate the likelihood that EOT has already been achieved. Such quantitative assessment will become increasingly important for measuring local achievement of EOT as 2030 approaches.

Acción colectiva juvenil rural: resistencia y re-existencia en tiempos de posacuerdo (Riosucio, Colombia) / Rural collective youth action: resistance and re-existance in the post peace agreement (Riosucio, Colombia) / Ação coletiva da juventude rural: Resistência e reexistência em Riosucio (Colômbia), em tempos de pós-acordo

Resumen (analítico) Este artículo recoge los hallazgos de una investigación sobre las prácticas de resistencia y re-existencia presentes en la acción colectiva juvenil desplegada en Riosucio (Caldas), zona rural afectada por el conflicto armado colombiano. Tuvo como objetivo analizar los modos en que la acción colectiva juvenil construye horizontes de paz en tiempos del posacuerdo. La investigación es cualitativa etnográfica e incorpora la etnografía visual; colaboraron cuatro colectivos juveniles con quienes además se elaboró una pieza fílmica documental. Como principales conclusiones se plantea: el surgimiento de los colectivos como apuesta a las violencias que reconocen en el territorio local y nacional, así como el potencial del arte como mecanismo de resistencia y re-existencia para la construcción de paz en lo rural, epicentro histórico de la guerra en la país.

Abstract (analytical) This article collects the findings of a research of the practices of resistance and re-existence present in the youth collective action deployed in Riosucio (Caldas), a rural area affected by the Colombian armed conflict. Its purpose was to analyze the ways in which collective action youth builds peaceful horizons in times of post-agreement. The research is qualitative ethnographic and incorporates visual ethnography; four youth collectives collaborated and also elaborated a documentary film material. The main conclusions are: the surge of these collectives as a wager to the multiple violences they recognize in their local and national territory, and the potential of art as means of resistance and re-existance for the construction of peace in the rural area, the historical epicenter of the war in the country.

Resumo (analítico) Este artigo reúne os resultados de uma investigação sobre as práticas de resistência e de reexistên-cia presentes na ação coletiva juvenil implantada em Riosucio (Caldas), área rural afetada pelo conflito armado colombiano. Com o objetivo de analisar os modos de ação coletiva a juventude constrói horizontes de paz em tempos de pós-acordo. A pesquisa é qualitativa etnográfica e incorpora etnografia visual; Colaboraram quatro grupos de jovens com os quais também foi produzido um documentário. As principais conclusões são: a emergência dos grupos como aposta na violência que reconhecem no território local e nacional; e a potencialidade da arte como mecanismo de resistência e de reexistência para a construção da paz no campo, epicentro histórico da guerra no país.

The short third intracellular loop and cytoplasmic tail of bitter taste receptors provide functionally relevant GRK phosphorylation sites in TAS2R14.

For most G protein-coupled receptors, the third intracellular loop (IL3) and carboxy-terminal tail (CT) are sites for G protein-coupled receptor kinase (GRK)-mediated phosphorylation, leading to ß-arrestin binding and agonist-specific desensitization. These regions of bitter taste receptors (TAS2Rs) are extremely short compared with the superfamily, and their function in desensitization is unknown. TAS2R14 expressed on human airway smooth muscle cells relax the cell, suggesting a novel target for bronchodilators. To assess IL3 and CT in agonist-promoted TAS2R14 desensitization (tachyphylaxis), we generated fusion proteins of both the WT sequence and Ala substituted for Ser/Thr in the IL3 and CT sequences. In vitro, activated GRK2 phosphorylated WT IL3 and WT CT proteins but not Ala-substituted forms. TAS2R14s with mutations in IL3 (IL-5A), CT (CT-5A), and in both regions (IL/CT-10A) were expressed in human embryonic kidney 293T cells. IL/CT-10A and CT-5A failed to undergo desensitization of the intracellular calcium response compared with WT, indicating that functional desensitization by GRK phosphorylation is at residues in the CT. Desensitization of TAS2R14 was blocked by GRK2 knockdown in human airway smooth muscle cells. Receptor:ß-arrestin binding was absent in IL/CT-10A and CT-5A and reduced in IL-5A, indicating a role for IL3 phosphorylation in the ß-arrestin interaction for this function. Agonist-promoted internalization of IL-5A and CT-5A receptors was impaired, and they failed to colocalize with early endosomes. Thus, agonist-promoted functional desensitization of TAS2R14 occurs by GRK phosphorylation of CT residues and ß-arrestin binding. However, ß-arrestin function in the internalization and trafficking of the receptor also requires GRK phosphorylation of IL3 residues.

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.