The role of brain perfusion SPECT in the diagnosis of frontotemporal dementia: A systematic review.

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is the second most common cause of presenile dementia. The clinical distinction between FTD, Alzheimer's disease (AD), and other dementias is a clinical challenge. Brain perfusion SPECT may contribute to the diagnosis of FTD, but its value is unclear. METHODS: We performed a systematic review to investigate the diagnostic accuracy of the brain SPECT in (1) distinguishing FTD from AD and other dementias and (2) differentiating FTD variants. RESULTS: Overall, 391 studies were retrieved on the initial search and 35 studies composed the final selection, comprising a total number of 3142 participants of which 1029 had FTD. The sensitivity and the specificity for the differential diagnosis of FTD versus AD ranged from 56% to 88% and from 51% to 93%, respectively. SPECT is not superior to the clinical method of diagnosis, but the combination of SPECT with clinical data seems to improve the diagnostic accuracy. CONCLUSION: Brain perfusion SPECT has a limited value in the diagnostic framework of FTD. SPECT can be performed when FDG-PET is not available. SPECT is recommended only for selected cases when the diagnosis is challenging using conventional methods.

Urinary Symptoms Change and Quality of Life After Robotic Radical Prostatectomy: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: To present the patient-reported quality of life (QoL) outcomes from a prospective, randomized controlled trial comparing the use of pelvic floor muscle training (PFMT) and duloxetine after robot-assisted radical prostatectomy (RARP). METHODS: We identified 213 men with organ-confined disease having post-RARP urinary incontinence who were randomly assigned to received PFMT, duloxetine, combined PFMT-duloxetine and pelvic floor muscle home exercises. Urinary symptoms burden was measured by marked clinical important difference improvement (MCID) defined by using the International Prostate Symptom Score (IPSS) difference of - 8 points (ΔIPSS ≤-8). QoL was assessed according to Visual Analog Scale (VAS), King's Health Questionnaire (KQH), and International Index of Erectile Function (IIEF-5). Multivariable regression analyses aimed to predict MCID, burden of urinary symptoms (IPSS ≥8), and patients reporting to be satisfied (IPSS QoL ≤2) or comfortable (VAS ≤1) post-RARP. RESULTS: Moderate to severe urinary symptoms decreased from 48% preoperatively to 40%, 34%, and 23% at 3, 6, and 12months post-RARP. After surgery, MCID improvement was observed in 19% of patients, and deterioration in 3.3%. Large prostate was the only factor associated to MCID (OR 1.03 [95%CI 1.01-1.05], P = .005). At 6months, patients reached the same degree of preoperative satisfaction. Neurovascular bundle preservation was the only predictor of being comfortable regarding urinary symptoms postoperatively (OR 12.8 [CI95% 1.47-111.7], P = .02 at 3months) and was also associated to higher median postoperative IIEF-5. CONCLUSION: Despite urinary incontinence following RARP, patients with larger prostates experience a reduction of lower urinary tract symptoms within a year, which subsequently elevates QoL. Furthermore, nerve-sparing surgery augments erectile function and urinary outcomes, shaping postoperative QoL.

Assessing the efficacy of pelvic floor muscle training and duloxetine on urinary continence recovery following radical prostatectomy: A randomized clinical trial.

BACKGROUND: Urinary incontinence (UI) can negatively impact quality of life (QoL) after robot-assisted radical prostatectomy (RARP). Pelvic floor muscle training (PFMT) and duloxetine are used to manage post-RARP UI, but their efficacy remains uncertain. We aimed to investigate the efficacy of PFMT and duloxetine in promoting urinary continence recovery (UCR) after RARP. METHODS: A randomized controlled trial involving patients with urine leakage after RARP from May 2015 to February 2018. Patients were randomized into 1 of 4 arms: (1) PFMT-biofeedback, (2) duloxetine, (3) combined PFMT-biofeedback and duloxetine, (4) control arm. PFMT consisted of pelvic muscle exercises conducted with electromyographic feedback weekly, for 3 months. Oral duloxetine was administered at bedtime for 3 months. The primary outcome was prevalence of continence at 6 months, defined as using ≤1 security pad. Urinary symptoms and QoL were assessed by using a visual analogue scale, and validated questionnaires. RESULTS: From the 240 patients included in the trial, 89% of patients completed 1 year of follow-up. Treatment compliance was observed in 88% (92/105) of patients receiving duloxetine, and in 97% (104/107) of patients scheduled to PFMT-biofeedback sessions. In the control group 96% of patients had achieved continence at 6 months, compared with 90% (p = 0.3) in the PMFT-biofeedback, 73% (p = 0.008) in the duloxetine, and 69% (p = 0.003) in the combined treatment arm. At 6 months, QoL was classified as uncomfortable or worse in 17% of patients in the control group, compared with 44% (p = 0.01), 45% (p = 0.008), and 34% (p = 0.07), respectively. Complete preservation of neurovascular bundles (NVB) (OR: 2.95; p = 0.048) was the only perioperative intervention found to improve early UCR. CONCLUSIONS: PFMT-biofeedback and duloxetine demonstrated limited impact in improving UCR after RP. Diligent NVB preservation, along with preoperative patient and disease characteristics, are the primary determinants for early UCR.

Structural studies with crotoxin B from Crotalus durissus collilineatus venom suggest a heterodimeric assembly formed by two new isoforms.

In accidents involving Crotalus snakes, the crotoxin complex (CTX) plays lethal action due to its neurotoxic activity. On the other hand, CTX have potential biotechnological application due to its anti-tumoral, anti-inflammatory, antimicrobial, analgesic and immunomodulatory properties. CTX is a heterodimer composed of Crotoxin A (CA or crotapotin), the acidic nontoxic and non-enzymatic component and; Crotoxin B (CB), a basic, toxic and catalytic PLA2. Currently, there are two classes of CTX isoforms, whose differences in their biological activities have been attributed to features presented in CB isoforms. Here, we present the crystal structure of CB isolated from the Crotalus durissus collilineatus venom. It amino acid sequence was assigned using the SEQUENCE SLIDER software, which revealed that the crystal structure is a heterodimer composed of two new CB isoforms (colCB-A and colCB-B). Bioinformatic and biophysical analyses showed that the toxin forms a tetrameric assembly in solution similar to CB from Crotalus durissus terrificus venom, despite some differences observed at the dimeric interface. By the previously proposed classification, the colCB-B presents features of the class I isoforms while colCB-A cannot be classified into classes I and II based on its amino acid sequence. Due to similar features observed for other CB isoforms found in the NCBI database and the results obtained for colCB-A, we suggest that there are more than two classes of CTX and CB isoforms in crotalic venoms.

Safety and efficacy of sotagliflozin in patients with type II diabetes mellitus and chronic kidney disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Sotagliflozin is a dual sodium-glucose co-transporter 1 and 2 inhibitor that increases glucosuria and natriuresis in patients with type 2 diabetes mellitus (T2DM). However, the safety and efficacy in patients with concomitant chronic kidney disease (CKD) remains unclear. Therefore, we aimed to conduct a meta-analysis to evaluate the current evidence in this regard. METHODS: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the safety and efficacy of Sotagliflozin in patients with T2DM and CKD compared with placebo. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. The study was recorded in PROSPERO registry (CRD42023449631). RESULTS : We included three studies totaling 11,648 patients followed for 15.7 ± 5.9 months. Reduction in HbA1C (mean difference - 0.33%; 95% CI [- 0.54, - 0.11]; p = 0.003; I2 = 100%) and weight (mean difference - 1.01 kg; 95% CI [- 1.17, - 0.86]; p < 0.00001; I2 = 96%) were significantly higher in the Sotagliflozin group compared with placebo. All-cause mortality (RR 0.98; 95% CI [0.81, 1.20]; p = 0.87; I2 = 0%) and major adverse cardiovascular events (RR 0.70; 95% CI [0.40, 1.21]; p = 0.20; I2 = 39%) were not significantly different between groups. However, estimated glomerular filtration rate reduction (mean difference - 0.95; 95% CI [- 1.32, - 0.58]; p < 0.00001; I2 = 98%), genital mycotic infections (RR 2.73; 95% CI [1.96, 3.79]; p < 0.00001; I2 = 0%), diarrhea (RR 1.42; 95% CI [1.24. 1.63]; p < 0.00001; I2 = 0%) and volume depletion (RR 1.31; 95% CI [1.11, 1.56]; p = 0.002; I2 = 0%) were more common with Sotagliflozin. CONCLUSIONS: In patients with T2DM and CKD, Sotagliflozin appears to be effective for glycemic control and weight loss. Although the medication seemed safe concerning mortality and cardiovascular events, it induced estimated glomerular filtration rate reduction, and was associated with a higher risk of genital mycotic infections, diarrhea, and volume depletion.

Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands.

Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds.

The CCP4 suite: integrative software for macromolecular crystallography.

The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces. The CCP4 suite has experienced several considerable changes since its last reference article, involving new infrastructure, original programs and graphical interfaces. This article, which is intended as a general literature citation for the use of the CCP4 software suite in structure determination, will guide the reader through such transformations, offering a general overview of the new features and outlining future developments. As such, it aims to highlight the individual programs that comprise the suite and to provide the latest references to them for perusal by crystallographers around the world.

In silico evaluation of pharmacokinetics properties of withanolides and simulation of their biological activities against Alzheimer's disease.

The withanolides are naturally occurring steroidal lactones found mainly in plants of the Solanaceae family. The subtribe Withaninae includes species like Withania sominifera, which are a source of many bioactive withanolides. In this work, we selected and evaluate the ADMET-related properties of 91 withanolides found in species of the subtribe Withaninae computationally, to predict the relationship between their structures and their pharmacokinetic profiles. We also evaluated the interaction of these withanolides with known targets of Alzheimer's disease (AD) through molecular docking and molecular dynamics. Withanolides presented favorable pharmacokinetic properties, like high gastrointestinal absorption, lipophilicity (logP ≤ 5), good distribution and excretion parameters, and a favorable toxicity profile. The specie Withania aristata stood out as an interesting source of the promising withanolides classified as 5-ene with 16-ene or 17-ene. These withanolides presented a favourable pharmacokinetic profile and were also highlighted as the best candidates for inhibition of AD-related targets. Our results also suggest that withanolides are likely to act as cholinesterase inhibitors by interacting with the catalytic pocket in an energy favorable and stable way.Communicated by Ramaswamy H. Sarma.

Characterization and subchronic oral toxicity of Pentaclethra macroloba (pracaxi) oil in Rattus norvegicus (lin. Wistar).

The trend of replacing antimicrobials as growth promoters in animal nutrition is growing. Functional oils emerge as an alternative because of their richness in bioactive compounds and bioavailability. The present study aims to evaluate the fatty acid profile, antioxidant capacity, composition of phenolic compounds, and toxic capacity in Wistar rats of pracaxi oil (Pentaclethra macroloba). DDPH (2,2-diphenyl-1-picrylhydrazyl), FRAP (Ferric Reducing Antioxidant Power), and ABTS (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) were performed to assess antioxidant capacity. The composition of phenolic compounds was determined by specific reagents. For the evaluation of subchronic oral toxicity, 40 Wistar albino rats (20 males and 20 females) were randomized into 10 groups with different levels of pracaxi oil administered orally. The doses administered were 0, 300, 600, 1200 and 2400 mg/kg (Group 1 to 5 females and Group 6 to 10 males). The animals were submitted to evaluations described in the OECD manual (Guide 407). The analytical results showed that pracaxi oil has different fatty acids in its chemical composition: oleic, linoleic, arachidic, and behenic acids, which account for more than 90% of its composition. In a smaller percentage, lauric acid (0.17%), myristic (0.09%), palmitic (1.49%), stearic (3.45%), and linolenic acid (1.39%) were also found. According to the results of the antioxidant tests, pracaxi oil has a high antioxidant capacity and is a product with a high presence of phenolic compounds. Regarding the toxicity assessment, there were no alterations in the clinical signs and weight of organs. However, in histology, there were mild alterations of a possible toxic process with the increase in the oil dose. This research is extremely valuable since pracaxi oil is a product with little information about its potential use in animal nutrition.

Fragment-Based Ab Initio Phasing of Peptidic Nanocrystals by MicroED.

Electron diffraction (MicroED/3DED) can render the three-dimensional atomic structures of molecules from previously unamenable samples. The approach has been particularly transformative for peptidic structures, where MicroED has revealed novel structures of naturally occurring peptides, synthetic protein fragments, and peptide-based natural products. Despite its transformative potential, MicroED is beholden to the crystallographic phase problem, which challenges its de novo determination of structures. ARCIMBOLDO, an automated, fragment-based approach to structure determination, eliminates the need for atomic resolution, instead enforcing stereochemical constraints through libraries of small model fragments, and discerning congruent motifs in solution space to ensure validation. This approach expands the reach of MicroED to presently inaccessible peptide structures including fragments of human amyloids, and yeast and mammalian prions. For electron diffraction, fragment-based phasing portends a more general phasing solution with limited model bias for a wider set of chemical structures.

Inherited Fanconi syndrome.

BACKGROUND: Fanconi-Debré-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities. DATA SOURCES: We searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment. RESULTS: FRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe's syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson's disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease. CONCLUSION: The early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life.

Revisão clínica: introdução de antipsicóticos na atenção primária à saúde / Clinical review: introduction of antipsychotics into primary health care / Revisión clínica: introducción de antipsicóticos en la atención primaria de salud

Os antipsicóticos são a primeira linha de tratamento para os sintomas psicóticos e suas síndromes. A psicose pode se apresentar como: delírios, alucinações, desorganização do pensamento e alteração do comportamento. Estima-se que 13 a 23% da população os apresente em algum momento ao longo da vida. Esta revisão clínica pretende auxiliar na tomada de decisão sobre quando e como introduzir antipsicóticos na atenção primária à saúde, levando em conta sua eficácia, o perfil de efeitos colaterais e os principais cuidados com as comorbidades relevantes. Realizou-se revisão da literatura nas bases de dados eletrônicos United States National Library of Medicine (PubMed), BMJ Best Practice e UpToDate ­ sumarizadores de evidência ­ no período de outubro a novembro de 2020. Foram incluídos artigos que abordassem a introdução de antipsicóticos na atenção primária, em maiores de 18 anos, com publicação após 2010, em português, inglês, espanhol ou francês. Foram obtidos 76 artigos considerados elegíveis. Destes, 27 foram selecionados para leitura integral. O antipsicótico deve ser recomendado para qualquer pessoa que apresente um primeiro episódio de psicose. Preferencialmente, a escolha terapêutica deve fazer parte do plano conjunto, centrado na pessoa, levando em conta os efeitos colaterais. Não há superioridade na eficácia entre um antipsicótico ou outro, nem mesmo entre grupos. Analisou-se o perfil de eficácia, efeitos adversos, segurança e tolerabilidade dos principais fármacos disponíveis, facilitando a tomada de decisão perante a introdução dos antipsicóticos. Pela escassa literatura nacional, não foi possível analisar o perfil específico para a população brasileira.

Antipsychotics are the first line of treatment for psychotic symptoms and syndromes. Psychosis can present itself as: delusions, hallucinations, disorganized thinking, and altered behavior. It is estimated that 13 to 23% of the population will experience these symptoms at some point in their lifetime. This clinical review aims to assist in the decision-making about when and how to introduce antipsychotics into primary health care, considering their effectiveness, side effect profile, and the main care practices for relevant comorbidities. A literature review was carried out in the electronic databases PubMed, BMJ Best Practice, and UpToDate ­ electronic databases summarizing evidence ­ from October to November 2020. Articles that addressed the introduction of antipsychotics into primary health care, in patients over 18 years of age, published after 2010, in Portuguese, English, Spanish or French, were included. A total of 76 articles were considered eligible. Of these, 27 were selected for full reading. The antipsychotic should be recommended for anyone who experiences a first episode of psychosis. Preferably, the therapeutic choice should be part of a person-centered shared decision-making, considering the side effects. There is no superiority in effectiveness between one antipsychotic or another, not even between groups. The profile of efficacy, adverse effects, safety, and tolerability of the main drugs available were analyzed, facilitating decision-making regarding the introduction of antipsychotics. Due to the scarce national literature, it was not possible to analyze the specific profile for the Brazilian population.

Los antipsicóticos son la primera línea de tratamiento de los síntomas psicóticos y sus síndromes. La psicosis puede presentarse como: delirios, alucinaciones, pensamiento desorganizado y comportamiento alterado. Se estima que del 13 al 23% de la población los presenta en algún momento de su vida. Esta revisión clínica tiene como objetivo ayudar en la toma de decisiones sobre cuándo y cómo introducir los antipsicóticos en la atención primaria de salud, teniendo en cuenta su efectividad, el perfil de efectos secundarios y la atención principal de las comorbilidades relevantes. Se llevó a cabo una revisión de la literatura en las bases de datos electrónicas PubMed, BMJ Best Practice y Uptodate ­ bases de datos electrónicas que resumen la evidencia ­ de octubre a noviembre de 2020. Criterios de inclusión: artículos que hayan abordado la introducción de antipsicóticos en atención primaria, mayores de 18 años, publicados después de 2010, en portugués, inglés, español o francés. Se consideraron elegibles 76 artículos. De estos, 27 fueron seleccionados para lectura completa. El antipsicótico debe recomendarse a cualquier persona que tenga un primer episodio de psicosis. Preferiblemente, la elección terapéutica debe formar parte del plan conjunto, centrado en la persona, teniendo en cuenta los efectos secundarios. No hay superioridad en la efectividad entre un antipsicótico u otro, ni siquiera entre grupos. Sintetizar el perfil de eficacia, efectos adversos, seguridad y tolerabilidad de los principales fármacos disponibles, facilitando la toma de decisión sobre la introducción de antipsicóticos. Debido a la escasa literatura nacional, no ha sido posible analizar el perfil específico de la población brasileña.

Structural and functional studies of a snake venom phospholipase A2-like protein complexed to an inhibitor from Tabernaemontana catharinensis.

Snake envenomation is an ongoing global health problem and tropical neglected disease that afflicts millions of people each year. The only specific treatment, antivenom, has several limitations that affects its proper distribution to the victims and its efficacy against local effects, such as myonecrosis. The main responsible for this consequence are the phospholipases A2 (PLA2) and PLA2-like proteins, such as BthTX-I from Bothrops jararacussu. Folk medicine resorts to plants such as Tabernaemontana catharinensis to palliate these and other snakebite effects. Here, we evaluated the effect of its root bark extract and one of its isolated compounds, 12-methoxy-4-methyl-voachalotine (MMV), against the in vitro paralysis and muscle damage induced by BthTX-I. Secondary and quaternary structures of BthTX-I were not modified by the interaction with MMV. Instead, this compound interacted in an unprecedented way with the region inside the toxin hydrophobic channel and promoted a structural change in Val31, loop 58-71 and Membrane Disruption Site. Thus, we hypothesize that MMV inhibits PLA2-like proteins by preventing entrance of fatty acid into the hydrophobic channel. These data may explain the traditional use of T. catharinensis extract and confirm MMV as a promising candidate to complement antivenom or a structural guide to develop more effective inhibitors.

BR-EMS 2021 life table for the Brazilian insured population / Tábuas de mortalidade BR-EMS 2021 do mercado segurador brasileiro / Tabla de vida BR-EMS 2021 para la población asegurada brasileña

Abstract This article presents the Brazilian private insurance market's actuarial life tables, BR- EMS 2021. Using Bayesian inference on the parameters of the Heligman- Pollard law of mortality and data from 23 insurance groups over 15 years, totaling 3.5 billion registers, the data were corrected through a two hidden-layer neural network. The resulting tables show that the insured population exhibits lower mortality rates than the general Brazilian population, even lower than the national populations of well-developed countries such as the USA. Moreover, besides the expected gender gap in mortality rates, there is a clear distance between the death and survivorship insurance coverage groups. Likewise, the insured population characteristics mitigate well-known regional structural discrepancies in the Brazilian population, indicating that being part of the selected population of insured individuals is thus associated with a more effective protection against death than other outstanding factors such as geographic region of residence.

Resumo Este artigo apresenta as tábuas de vida do mercado de seguros privados brasileiro, BR-EMS 2021. Os dados obtidos de 23 grupos seguradores ao longo de 15 anos, totalizando 3,5 bilhões de registros, foram corrigidos por meio de rede neural com duas camadas ocultas. Usando a inferência bayesiana para estimar os parâmetros sob a lei de mortalidade Heligman-Pollard, as tábuas obtidas mostram que a população segurada apresenta probabilidades de morte mais baixas do que a população brasileira em geral e até mesmo em relação a populações nacionais de países desenvolvidos, como os EUA. Além da esperada diferença de gênero nas taxas de mortalidade, há uma clara distância entre as probabilidades de morte dos grupos de cobertura de risco e cobertura de sobrevivência. Da mesma forma, é demonstrado que as tábuas regionais da população segurada não apresentam as discrepâncias regionais conhecidas no Brasil, indicando que fazer parte da população selecionada de segurados está associado a um fator de proteção mais eficaz do que outros fatores, como a região geográfica de residência.

Resumen Este artículo presenta las tablas de vida del mercado de seguros privados brasileño, BR-EMS 2021. Los datos, obtenidos de 23 grupos de seguros a lo largo de 15 años, totalizando 3,5 mil millones de registros, fueron corregidos usando una red neuronal con dos capas ocultas. Mediante la inferencia bayesiana para estimar los parámetros bajo la ley de mortalidad de Heligman-Pollard, las tablas obtenidas muestran que la población asegurada tiene tasas de mortalidad más bajas que la población general brasileña e incluso más bajas que las poblaciones nacionales de países desarrollados, como los Estados Unidos de Norteamérica. Además de la diferencia de género esperada en las tasas de mortalidad, hay una clara distinción entre las tablas de grupos de cobertura de riesgo y cobertura de sobrevivientes. Asimismo, se demuestra que las tablas regionales de población asegurada no presentan las conocidas discrepancias estructurales regionales en Brasil, lo que indica que participar de la población de asegurados está asociado con una protección contra la muerte más efectiva que otros factores como la región geográfica de residencia.

Verification: model-free phasing with enhanced predicted models in ARCIMBOLDO_SHREDDER.

Structure predictions have matched the accuracy of experimental structures from close homologues, providing suitable models for molecular replacement phasing. Even in predictions that present large differences due to the relative movement of domains or poorly predicted areas, very accurate regions tend to be present. These are suitable for successful fragment-based phasing as implemented in ARCIMBOLDO. The particularities of predicted models are inherently addressed in the new predicted_model mode, rendering preliminary treatment superfluous but also harmless. B-value conversion from predicted LDDT or error estimates, the removal of unstructured polypeptide, hierarchical decomposition of structural units from domains to local folds and systematically probing the model against the experimental data will ensure the optimal use of the model in phasing. Concomitantly, the exhaustive use of models and stereochemistry in phasing, refinement and validation raises the concern of crystallographic model bias and the need to critically establish the information contributed by the experiment. Therefore, in its predicted_model mode ARCIMBOLDO_SHREDDER will first determine whether the input model already constitutes a solution or provides a straightforward solution with Phaser. If not, extracted fragments will be located. If the landscape of solutions reveals numerous, clearly discriminated and consistent probes or if the input model already constitutes a solution, model-free verification will be activated. Expansions with SHELXE will omit the partial solution seeding phases and all traces outside their respective masks will be combined in ALIXE, as far as consistent. This procedure completely eliminates the molecular replacement search model in favour of the inferences derived from this model. In the case of fragments, an incorrect starting hypothesis impedes expansion. The predicted_model mode has been tested in different scenarios.

Heparanase 1 Upregulation Promotes Tumor Progression and Is a Predictor of Low Survival for Oral Cancer.

Background: Oral cavity cancer is still an important public health problem throughout the world. Oral squamous cell carcinomas (OSCCs) can be quite aggressive and metastatic, with a low survival rate and poor prognosis. However, this is usually related to the clinical stage and histological grade, and molecular prognostic markers for clinical practice are yet to be defined. Heparanase (HPSE1) is an endoglycosidase associated with extracellular matrix remodeling, and although involved in several malignancies, the clinical implications of HPSE1 expression in OSCCs are still unknown. Methods: We sought to investigate HPSE1 expression in a series of primary OSCCs and further explore whether its overexpression plays a relevant role in OSCC tumorigenesis. mRNA and protein expression analyses were performed in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function strategy using an ORF vector targeting HPSE1 were employed to investigate the endogenous modulation of HPSE1 and its effects on proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), angiogenesis, migration, and invasion of oral cancer in vitro. Results: We demonstrated that HPSE1 is frequently upregulated in OSCC samples and cell lines and is an unfavorable prognostic indicator of disease-specific survival when combined with advanced pT stages. Moreover, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis and inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition by significantly decreasing the expression of N-cadherin and vimentin. Furthermore, a conditioned medium of HPSE1-downregulated cells resulted in reduced vascular endothelial growth. Conclusion: Our results confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression as it is associated with several important biological processes for oral tumorigenesis, and can be managed as a prognostic marker for patients with OSCC.

Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut.

Mucinases of human gut bacteria cleave peptide bonds in mucins strictly depending on the presence of neighboring O-glycans. The Akkermansia muciniphila AM0627 mucinase cleaves specifically in between contiguous (bis) O-glycans of defined truncated structures, suggesting that this enzyme may recognize clustered O-glycan patches. Here, we report the structure and molecular mechanism of AM0627 in complex with a glycopeptide containing a bis-T (Galß1-3GalNAcα1-O-Ser/Thr) O-glycan, revealing that AM0627 recognizes both the sugar moieties and the peptide sequence. AM0627 exhibits preference for bis-T over bis-Tn (GalNAcα1-O-Ser/Thr) O-glycopeptide substrates, with the first GalNAc residue being essential for cleavage. AM0627 follows a mechanism relying on a nucleophilic water molecule and a catalytic base Glu residue. Structural comparison among mucinases identifies a conserved Tyr engaged in sugar-π interactions in both AM0627 and the Bacteroides thetaiotaomicron BT4244 mucinase as responsible for the common activity of these two mucinases with bis-T/Tn substrates. Our work illustrates how mucinases through tremendous flexibility adapt to the diversity in distribution and patterns of O-glycans on mucins.

Tumour microenvironment and focal therapy for prostate cancer.

PURPOSE OF REVIEW: Although most studies focus on the tumour component of prostate cancer (PCa), increasing attention is being paid to the prostatic tumour microenvironment (TME) and its role in diagnosis, prognosis, and therapy development. Herein, we review the prognostic capability of tumour and nontumour derived biomarkers, the immunomodulatory effects of focal therapy (FT) on TME, and its potential as part of a multidisciplinary approach to PCa treatment. RECENT FINDINGS: Tumour cells have always been the natural candidates to explore new biomarkers, but recent evidence highlights the prognostic contribution of TME cell markers. TME plays a critical role in PCa progression and tumours may escape from the immune system by establishing a microenvironment that suppresses effective antitumour immunity. It has been demonstrated that FT has an immunomodulatory effect and may elicit an immune response that can either favour or inhibit tumorigenesis. TME shows to be an additional target to enhance oncological control. SUMMARY: A better understanding of TME has the potential to reliably elucidate PCa heterogeneity and assign a prognostic profile in accordance with prostate tumour foci. The joint contribution of biomarkers derived from both tumour and TME compartments may improve patient selection for FT by accurately stratifying disease aggressivity according to the characteristics of tumour foci. Preclinical studies have suggested that FT may act as a TME modulator, highlighting its promising role in multimodal therapeutic management.

Data standardization of plant-pollinator interactions.

BACKGROUND: Animal pollination is an important ecosystem function and service, ensuring both the integrity of natural systems and human well-being. Although many knowledge shortfalls remain, some high-quality data sets on biological interactions are now available. The development and adoption of standards for biodiversity data and metadata has promoted great advances in biological data sharing and aggregation, supporting large-scale studies and science-based public policies. However, these standards are currently not suitable to fully support interaction data sharing. RESULTS: Here we present a vocabulary of terms and a data model for sharing plant-pollinator interactions data based on the Darwin Core standard. The vocabulary introduces 48 new terms targeting several aspects of plant-pollinator interactions and can be used to capture information from different approaches and scales. Additionally, we provide solutions for data serialization using RDF, XML, and DwC-Archives and recommendations of existing controlled vocabularies for some of the terms. Our contribution supports open access to standardized data on plant-pollinator interactions. CONCLUSIONS: The adoption of the vocabulary would facilitate data sharing to support studies ranging from the spatial and temporal distribution of interactions to the taxonomic, phenological, functional, and phylogenetic aspects of plant-pollinator interactions. We expect to fill data and knowledge gaps, thus further enabling scientific research on the ecology and evolution of plant-pollinator communities, biodiversity conservation, ecosystem services, and the development of public policies. The proposed data model is flexible and can be adapted for sharing other types of interactions data by developing discipline-specific vocabularies of terms.

SEQUENCE SLIDER: integration of structural and genetic data to characterize isoforms from natural sources.

Proteins isolated from natural sources can be composed of a mixture of isoforms with similar physicochemical properties that coexist in the final steps of purification. Yet, even where unverified, the assumed sequence is enforced throughout the structural studies. Herein, we propose a novel perspective to address the usually neglected sequence heterogeneity of natural products by integrating biophysical, genetic and structural data in our program SEQUENCE SLIDER. The aim is to assess the evidence supporting chemical composition in structure determination. Locally, we interrogate the experimental map to establish which side chains are supported by the structural data, and the genetic information relating sequence conservation is integrated into this statistic. Hence, we build a constrained peptide database, containing most probable sequences to interpret mass spectrometry data (MS). In parallel, we perform MS de novo sequencing with genomic-based algorithms to detect point mutations. We calibrated SLIDER with Gallus gallus lysozyme, whose sequence is unequivocally established and numerous natural isoforms are reported. We used SLIDER to characterize a metalloproteinase and a phospholipase A2-like protein from the venom of Bothrops moojeni and a crotoxin from Crotalus durissus collilineatus. This integrated approach offers a more realistic structural descriptor to characterize macromolecules isolated from natural sources.