Indium(III)-Catalyzed Synthesis of Pyrroles and Benzo[g]indoles by Intramolecular Cyclization of Homopropargyl Azides.

Pyrroles, privileged structural motifs in drug and material science, have been synthesized by indium(III)-catalyzed intramolecular cyclization of homopropargyl azides. This methodology exhibits a broad substrate scope, providing substituted pyrroles and bispyrroles in good yields. Furthermore, an atom-economical sequential method for the synthesis of benzo[g]indoles has been discovered from azido-diynes using InCl3 as catalyst. The method involves two successive intramolecular indium-catalyzed 5-endo-dig alkyne hydroamination and a hydroarylation reactions with 6-endo-dig regioselectivity.

Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.

The genetics of ß-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3-7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10-14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing ß-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of ß-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in ß-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.

Real-World Evaluation of the Effectiveness and Safety of Dupilumab in Bullous Pemphigoid: An Ambispective Multicenter Case Series.

BACKGROUND: Bullous pemphigoid affects elderly individuals with multiple comorbidities, making conventional treatments unsuitable. OBJECTIVE: Evaluate the effectiveness and safety of dupilumab in the treatment of bullous pemphigoid. METHODS: A multicenter ambispective cohort study was conducted in 34 hospitals. Patients with bullous pemphigoid treated with Dupilumab were included. Most of patients (97.1%) received an initial 600 mg dose followed by 300 mg every two weeks. OUTCOMES AND MEASURES: The primary outcome was the proportion of patients achieving complete remission within 4 weeks, defined as Investigator Global Assessment score of 0 or 1. Complete remission at weeks 16, 24, and 52, adverse events, reductions in peak pruritus numerical rating scale, and systemic glucocorticoid use were also assessed. RESULTS: The study included 103 patients with a median age of 77.3 years, 58.0% male. Complete remission was achieved by 53.4% within 4 weeks and 95.7% by week 52. Peak pruritus scale reduced by 70.0% by week 4 and was completely controlled by week 24. Thirteen patients presented adverse events, most of which were mild. Systemic glucocorticoid use reduced by 82.1% by week 52. Shorter disease duration and exclusive cutaneous involvement predicted better response at 16 weeks. No differences in response rates to dupilumab were observed between drug-associated bullous pemphigoid and idiopathic cases. No significant difference in response rates was observed between patients treated with dupilumab in monotherapy and those receiving dupilumab with concomitant treatments. CONCLUSIONS: Dupilumab is effective, rapid, and safe in managing bullous pemphigoid, reducing the need for corticosteroids and other treatments. Early initiation and exclusive skin involvement predict better outcomes.

Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance.

AIMS/HYPOTHESIS: Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications. METHODS: Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells. RESULTS: Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes. CONCLUSIONS/INTERPRETATION: These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.

Cost-effective allergy screening: a retrospective observational study.

Summary: Background. Allergies represent a substantial health concern affecting individuals across all age groups. Diagnostic screenings, such as phadiatop and phadiatop infant, are employed to identify specific IgE antibodies associated with allergic reactions. This study delves into the relationship between total IgE levels and screening test outcomes, with the objective of establishing a total IgE threshold capable of predicting the likelihood of negative results in these screenings. Methods. This retrospective observational study included adults and children under 15 years old who underwent total IgE tests in addition to phadiatop and phadiatop infant screenings from January 2018 to December 2022. Exclusion criteria were applied to patients with insufficient serum samples or those whose IgE determinations or screening tests had been invalidated according to standard laboratory protocols. Results. Data analysis uncovered a robust correlation between total IgE levels and screening test outcomes. Additionally, thresholds of 20 UI/mL and 28 UI/mL were pinpointed for total IgE levels, below which the likelihood of obtaining a positive result in phadiatop or phadiatop infant, respectively, significantly decreased. Conclusions. These findings present cost-effective strategies for healthcare practitioners by recommending the initial use of total IgE testing. Subsequently, reflex testing with phadiatop or phadiatop infant, depending on the IgE value, could be considered.

[What we know today about solitary rectal ulcer syndrome]. / Lo que sabemos hoy de síndrome úlcera rectal solitaria.

Solitary Rectal Ulcer Syndrome (SRUS) is a rare defecation disorder with varied clinical manifestations and often presents challenges in diagnosis. To date, there is no definitive treatment for SRUS. However, there is consensus that treatment should be individualized, multimodal, and focused on addressing potential causes of the disease. Surgery is reserved for correcting anatomical problems. This review provides an update on available data regarding the pathophysiology, presentation, clinical evaluation, and various treatment alternatives.

Cerium doped yttrium aluminum perovskite scintillator as an absolute ultracold neutron detector.

The upcoming UCNProBe experiment at Los Alamos National Laboratory will measure the beta decay rate of free neutrons with different systematic uncertainties than previous beam-based neutron lifetime experiments. We have tested a new 10B-coated Yttrium Aluminum Perovskite (YAP:Ce) scintillator and present its properties. The advantages of the YAP:Ce scintillator include its high Fermi potential, which reduces the probability for upscattering of ultracold neutrons (UCN), and its short decay time, which increases sensitivity at high counting rates. Birks' coefficient of YAP:Ce was measured to be (5.56-0.30+0.05)×10-4 cm/MeV. The loss of light due to the 120 nm 10B-coating was measured to be about 60%, and the loss of light from YAP:Ce due to transmission through a deuterated polystyrene scintillator was about 50%. The efficiency for neutron capture on the 10B coating was (86.8 ± 2.6)%, and a measurement using UCN showed that the YAP:Ce crystal counted 8%-28% more UCN compared to a ZnS:Ag screen. The difference may be due to the uneven coating of 10B on the rough surface of ZnS:Ag.

[Epilepsy in Angelman syndrome and the most common electroencephalographic findings]. / Epilepsia en el síndrome de Angelman y hallazgos electroencefalográficos más frecuentes.

INTRODUCTION: Angelman syndrome is a genetic disorder characterised by severe mental retardation, subtle dysmorphic facial features, a characteristic behavioural phenotype, seizures and abnormalities in video electroencephalograms (video EEG). Angelman syndrome may be associated with genetic mechanisms involving the region of chromosome 15q11-13. Up to 90% of cases have epileptic seizures, usually in the early years of life. Videoelectroencephalography patterns with some typical characteristics associated with Angelman syndrome have been reported, although these are not specific to it, and as such it is also useful for early diagnosis, especially in the first months or years of life. OBJECTIVE: To characterise the videoelectroencephalography findings of 17 patients diagnosed with Angelman syndrome, and compare them with previously published studies. PATIENTS AND METHODS: We conducted a retrospective observational study of 34 video EEGs performed on 17 patients diagnosed with Angelman syndrome at the clinical neurophysiology service of the Puerta de Hierro University Hospital in Madrid between 2019 and 2022. The primary objective was to characterise the videoelectroencephalographic findings and compare them with previously published studies. As secondary objectives, we analysed the patterns proposed by Dan and Boyd, and other demographic, genetic and clinical data. RESULTS: Video EEG supported the clinical suspicion in our study, as baseline brain activity was altered in all the patients. We identified a pattern similar to those defined by Dan and Boyd in 88% of the cases, and the type III pattern was the most common in our series. CONCLUSIONS: These findings confirm that video EEG is highly sensitive for the diagnosis of Angelman syndrome, and very useful as a diagnostic biomarker in the early stages of life.

TITLE: Epilepsia en el síndrome de Angelman y hallazgos electroencefalográficos más frecuentes.Introducción. El síndrome de Angelman es un trastorno genético caracterizado por retraso mental grave, rasgos faciales dismórficos sutiles, fenotipo conductual característico, crisis epilépticas y anomalías en el videoelectroencefalograma (video-EEG). El síndrome de Angelman puede estar asociado a mecanismos genéticos que involucran a la región del cromosoma 15q11-13. Hasta el 90% de los casos tiene crisis epilépticas, más frecuentemente en los primeros años de vida. Se han descrito patrones videoelectroencefalográficos con algunas características típicas asociadas a síndrome de Angelman, aunque no específicas, por lo que también es útil para el diagnóstico temprano, sobre todo en los primeros meses o años de vida. Objetivo. Caracterizar los hallazgos videoelectroencefalográficos de 17 pacientes diagnosticados de síndrome de Angelman y compararlos con estudios publicados previamente. Pacientes y métodos. Hemos realizado un estudio observacional retrospectivo de 34 video-EEG, realizados entre 2019 y 2022, de 17 pacientes con diagnóstico de síndrome de Angelman, llevados a cabo en el servicio de neurofisiología clínica del Hospital Universitario Puerta de Hierro. El objetivo principal fue caracterizar los hallazgos videoelectroencefalográficos y compararlos con estudios publicados previamente. Como objetivos secundarios, hemos analizado los patrones propuestos por Dan y Boyd, y otros datos demográficos, genéticos y clínicos. Resultados. El video-EEG apoyó la sospecha clínica en nuestro estudio, dado que la actividad cerebral de base se encontraba alterada en todos los pacientes. En el 88% de los casos fue posible identificar un patrón semejante a los definidos por Dan y Boyd, y, en nuestra serie, el patrón de tipo III fue el más frecuente. Conclusiones. Estos hallazgos confirman la alta sensibilidad del video-EEG para el diagnóstico de síndrome de Angelman y su gran utilidad como biomarcador diagnóstico en la primera etapa de la vida.

Investigating mechanoreceptor variability and morphometric proxies in Rhesus Macaques: Implications for primate precision touch studies.

The origin of primates has long been associated with an increased emphasis on manual grasping and touch. Precision touch, facilitated by specialized mechanoreceptors in glabrous skin, provides critical sensory feedback for grasping-related tasks and perception of ecologically-relevant stimuli. Despite its importance, studies of mechanoreceptors in primate hands are limited, in part due to challenges of sample availability and histological methods. Dermatoglyphs have been proposed as alternative proxies of mechanoreceptor density. We investigated the relationships between mechanoreceptors (Meissner and Pacinian corpuscles), dermatoglyphs, and demography in the apical finger pads of 15 juvenile to adult rhesus macaques (Macaca mulatta) from a free-ranging population at Cayo Santiago Primate Field Station (Puerto Rico). Our results indicate substantial interindividual variation in mechanoreceptor density (Meissner corpuscles: 11.9-43.3 corpuscles/mm2; Pacinian corpuscles: 0-4.5 corpuscles/mm2). While sex and digit were generally not associated with variation, there was strong evidence of a developmental effect. Specifically, apical pad length, Meissner corpuscle size, and Pacinian corpuscle depth increased while mechanoreceptor densities decreased throughout juvenescence, suggesting that primate mechanoreceptors change as fingers grow during adolescence and then stabilize at physical maturity. We also found Meissner corpuscle density was significantly associated with dermatoglyph ridge width and spacing, such that density predicted by a dermatoglyph model was strongly correlated with observed values. Dermatoglyphs thus offer a useful proxy of relative Meissner corpuscle density in primates, which opens exciting avenues of noninvasive research. Finally, our results underscore the importance of considering demographic factors and methodology in comparative studies of primate touch.

Laparoscopic Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy, an Update From the International PSOGI Registry.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are established treatments for peritoneal surface malignancies, traditionally performed via laparotomy. Recent advancements in laparoscopic approaches (L-CRS + HIPEC) have shown promising results in selected patients. METHODS: The PSOGI registry, established in November 2019, collects data from specialized centers performing L-CRS + HIPEC. Data were collected prospectively and analyzed retrospectively, excluding risk-reducing procedures without peritoneal disease. The learning curve was assessed using a 14-cases cutoff. RESULTS: Today, 323 patients have been registered, 193 were included finally. Perioperative outcomes improved after 14 cases: Length of hospital stay was 7.78 ± 3.64 days (consolidation) versus 8.8 ± 8.79 days (learning) and major morbidity was 0% (consolidation) versus 5% (learning), (p = n.s.). Estimated blood loss was lower in the consolidation phase. Oncological outcomes also improved: Recurrence rate was 8.7% (consolidation) versus 17.8% (learning). Disease-free survival 5 years, 65% (learning) versus 88% (consolidation) (p = 0.012). CONCLUSION: The L-CRS + HIPEC is a safe procedure with non-inferior oncologic outcomes which it is evaluating in an IDEAL setting by an international group. The validation of the learning curve, gives us the knowledge that a mentoring program must be setup to reduce the learning curve impact in oncologic failure.

Retrospective case-control non-inferiority analysis of ultrasound-guided erector spinae plane block in dogs undergoing mini-hemilaminectomy for intervertebral disc disease.

BACKGROUND: Veterinary medicine has seen significant advancements in locoregional anaesthesia and pain management, including the emergence of the erector spinae plane (ESP) block. However, limited clinical evidence exists on its efficacy and safety. OBJECTIVES: This study compares ultrasound-guided ESP block (ESP group) with an intraoperative intravenous ketamine infusion analgesic protocol (CRI group) in dogs undergoing thoracolumbar mini-hemilaminectomy, focusing on intraoperative opioid consumption, cardiovascular response to surgical stimulation (CR), postoperative pain scores (PS), and postoperative opioid consumption. METHODS: Retrospective, case-control, non-inferiority study conducted in a single centre. Data collected included demographics, bupivacaine dose, ESP block operator, intraoperative recorded variables (haemodynamic variables, CR, complications, rescue analgesia), pre- and postoperative analgesia, 24-hour PS and opioid administration, first food intake post-extubation and postoperative complications. Univariate and multiple regression analyses were applied. RESULTS: One-hundred dogs were included, 75 in the ESP group and 25 in the CRI group. Univariate analysis revealed no significant differences between treatment groups in terms of CR, PS, postoperative rescue analgesia, intraoperative and postoperative opioid consumption, or time to first meal intake. However, the multivariate regression analysis indicated that dogs receiving ketamine infusion had higher CR suspected to be nociception-related (p = 0.036), and higher postoperative opioid consumption (p = 0.013). CONCLUSION: Our study suggests that ultrasound-guided ESP block is as effective as intraoperative ketamine infusion providing perioperative analgesia in dogs undergoing thoracolumbar mini-hemilaminectomy for intervertebral disc disease. ESP group showed significantly lower CR suspected to be nociception-related intraoperatively and lower postoperative opioid consumption within the initial 24 hours.

Frontoparietal network topology as a neural marker of musical perceptual abilities.

Why are some individuals more musical than others? Neither cognitive testing nor classical localizationist neuroscience alone can provide a complete answer. Here, we test how the interplay of brain network organization and cognitive function delivers graded perceptual abilities in a distinctively human capacity. We analyze multimodal magnetic resonance imaging, cognitive, and behavioral data from 200+ participants, focusing on a canonical working memory network encompassing prefrontal and posterior parietal regions. Using graph theory, we examine structural and functional frontoparietal network organization in relation to assessments of musical aptitude and experience. Results reveal a positive correlation between perceptual abilities and the integration efficiency of key frontoparietal regions. The linkage between functional networks and musical abilities is mediated by working memory processes, whereas structural networks influence these abilities through sensory integration. Our work lays the foundation for future investigations into the neurobiological roots of individual differences in musicality.

Effects on growth, weight and body composition after CFTR modulators in children with cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is associated with compromised nutrition status, which is responsible for morbidity and mortality along with lung function decline. This study was designed to examine changes in anthropometric markers and body composition parameters by bioelectrical impedance analysis after CFTR modulator (CFTRm) treatment. METHODS: We compared anthropometric parameters and body composition before and after 6 and 12 months of CFTRm treatment. Results are stratified into subgroups according to the modulator used with dual therapy with lumacaftor + ivacaftor or tezacaftor + ivacaftor (LUMA/TEZ + IVA) or triple therapy with elexacaftor + tezacaftor + ivacaftor (ELE + TEZ + IVA). Body composition data are available in patients treated with ELE + TEZ + IVA. RESULTS: Two hundred and thirty-four children (55.1% male) were recruited. The median age was 13.6 years (inter-quartile range [IQR] 10.7-16.1). We can observe a statistically significant increase in the weight Z score and BMI Z score after CFTRm. In terms of changes in body composition, we observe a significant increase in fat mass (FM) expressed both in kilograms and as a percentage at 6 months (p < .05; Wilcoxon-test), with no such differences found at 12 months. We also observe a statistically significant increase in fat-free-mass (FFM), expressed in kilograms at 6 and 12 months (p < .05; Wilcoxon-test). CONCLUSION: Weight status improved and changes in body composition occurred in children after CFTRm therapy, including an increase of fat mass. Further studies are needed to confirm these changes in body composition and their impact on disease progression.

Does the diversity of vegetation and diatoms correlate with soil and water factors in a tropical cloud forest's complex land use/land cover scenario?

Soil and water characteristics in micro basins with different land uses/land cover (LULC) can influence riparian vegetation diversity, stream water quality, and benthic diatom diversity. We analyzed 18 streams in the upper part of the La Antigua River basin, México, surrounded by cloud forests, livestock pastures, and coffee plantations. Concentrations of P, C, and N were elevated in the humus of forested streams compared to other land uses. In contrast, cations, ammonium, and total suspended solids (TSS) of water streams were higher in pastures and coffee plantations. These results indicate that LULC affects stream chemistry differently across land uses. Vegetation richness was highest (86-133 spp.) in forest streams and lowest in pastures (46-102), whereas pasture streams had the greatest richness of diatoms (9-24), likely due to higher light and temperatures. Some soil and water characteristics correlated with both true diversity and taxonomic diversity; soil carbon exchange capacity (CEC) correlated with vegetation diversity (r = 0.60), while water temperature correlated negatively (r = - 0.68). Diatom diversity was related to soil aluminum (r = - 0.59), magnesium (r = 0.57), water phosphorus (r = 0.88), and chlorophyll (r = 0.75). These findings suggest that land use affects riparian vegetation, while physical and chemical changes influence diatom diversity in stream water and soil. The lack of correlation between vegetation and diatom diversity indicates that one cannot predict the other. This research is an essential first step in understanding how land use changes impact vegetation and diatom diversity in mountain landscapes, providing valuable insights for environmental monitoring and conservation efforts in tropical cloud forests.

Prepartum anti-inflammatory therapies in Holstein dairy cows blocked by parity and body condition score group: Effects on metabolic stress, systemic inflammation, performance, and health.

The objective of this study was to assess the effects of prepartum administration of anti-inflammatory therapies on body condition score (BCS), ß-hydroxybutyrate (BHB) concentration, haptoglobin (HP) concentration, milk yield, milk components, rumination time, clinical health events and reproductive performance in Holstein dairy cows. At 14 d before the expected calving date, cows (PAR; n = 170) and heifers (nulliparous [NUL]; n = 63) were blocked by BCS group (optimal = 3-3.5 [OPT]; over-conditioned cows [OVERC; BCS ≥ 3.75 pts.]) and parity (NUL; PAR) and randomly allocated to one of 3 treatment groups: 1) ASA (n = 78): receive one oral administration of acetylsalicylic acid (4 boluses; 480 grain/bolus); 2) MEL (n = 76): receive one oral administration with meloxicam (1mg/kg of BW), or 3) PLC (n = 77): receive one oral treatment with gelatin capsules filled with water. Body condition score was assessed, and blood samples were collected, weekly starting one week before treatment until 3 weeks after calving. Daily milk yields and daily rumination times were collected from on-farm computer records. Dairy Herd Improvement Association (DHIA) monthly test data were collected to assess milk yield, somatic cell counts, and milk components. Furthermore, health events, culling rate, and reproductive performance data were collected from on-farm computer records. The data were analyzed using MIXED, GLIMMIX, and LIFETEST procedures of SAS as a randomized complete block design. On average, MEL-NUL cows produced 4.77 ± 0.93 kg/d and 4.81 ± 0.92 kg/d more milk from wk 6 to wk 21 of lactation compared with ASA-NUL and PLC-NUL cows, respectively. Similarly, there was a week by treatment by body condition group interaction (P = 0.01), where OVERC cows treated with MEL produced more milk from wk 10 to wk 15 of lactation compared with ASA- OVERC and PLC-OVERC cows. Parous cows treated with ASA had lower BCS compared with PAR cows treated with MEL or PLC. A lower percentage of OVERC cows treated with ASA became sick in the first 60 DIM compared with MEL- OVERC and PLC- OVERC cows (ASA = 23.88 ± 7.26%, MEL = 46.36 ± 8.57%; PLC = 46.74 ± 8.53%; P = 0.04). Parous cows treated with ASA had (P = 0.03) a higher hazard ratio to become pregnant by 300 DIM compared with PAR MEL cows. Although the study was not sized for finding treatment differences in blocking criteria groups, these results suggest that treatment with prepartum anti-inflammatory therapies may have positive effects on milk yield and postpartum health in specific groups of cows, such as NUL and OVERC cows, while it may not be recommended for other animal categories, such as parous cows and cows with optimal BCS. Larger studies are needed to strengthen the associations observed in this study.