Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.

Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFß in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.

Knowledge Graphs for drug repurposing: a review of databases and methods.

Drug repurposing has emerged as a effective and efficient strategy to identify new treatments for a variety of diseases. One of the most effective approaches for discovering potential new drug candidates involves the utilization of Knowledge Graphs (KGs). This review comprehensively explores some of the most prominent KGs, detailing their structure, data sources, and how they facilitate the repurposing of drugs. In addition to KGs, this paper delves into various artificial intelligence techniques that enhance the process of drug repurposing. These methods not only accelerate the identification of viable drug candidates but also improve the precision of predictions by leveraging complex datasets and advanced algorithms. Furthermore, the importance of explainability in drug repurposing is emphasized. Explainability methods are crucial as they provide insights into the reasoning behind AI-generated predictions, thereby increasing the trustworthiness and transparency of the repurposing process. We will discuss several techniques that can be employed to validate these predictions, ensuring that they are both reliable and understandable.

CD94+ natural killer cells potentiate pulmonary ischaemia-reperfusion injury.

BACKGROUND: Pulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. We recently demonstrated a central role of airway-centred natural killer (NK) cells in mediating IRI; however, there are no existing effective therapies for directly targeting NK cells in humans. METHODS: We hypothesised that a depleting anti-CD94 monoclonal antibody (mAb) would provide therapeutic benefit in mouse and human models of IRI based on high levels of KLRD1 (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients. RESULTS: We found that CD94 is highly expressed on mouse and human NK cells, with increased expression during IRI. Anti-mouse and anti-human mAbs against CD94 showed effective NK cell depletion in mouse and human models and blunted lung damage and airway epithelial killing, respectively. In two different allogeneic orthotopic lung transplant mouse models, anti-CD94 treatment during induction reduced early lung injury and chronic inflammation relative to control therapies. Anti-CD94 did not increase donor antigen-presenting cells that could alter long-term graft acceptance. CONCLUSIONS: Lung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.

Nonlinear comparative analysis of Greenland and Antarctica ice cores data.

We analyze the temperature time series of the EPICA Dome C ice cores in Antarctica and of the Greenland project, Summit, with durations of 800 000 and 248 000 years, respectively, with a recent mathematical tool defined through the Fourier phases of the series, known as the J-index. This data driven index can differentiate between purely random dynamics and dynamics with a deterministic component. It is sensitive to nonlinear components and robust to the presence of noise. Our J-index data analysis shows that both Greenland and Antarctica climatic fluctuations possess deterministic traits and suggests the presence of an underlying nonlinear dynamics. Furthermore, in both regions, it reveals the simultaneous occurrence of an important global event known as the "Pelukian transgression." For Antarctica, it also detects the marine isotopic stage 11. Additionally, our calculation of the time series Hurst exponents and our detrended fluctuation analysis show the presence of long-range persistent correlations for Antarctica and anti-persistent correlations for Greenland. For the latter case, our fractal dimension determinations are indicative of a more complex climatic dynamics in Greenland with respect to Antarctica. Our results are encouraging for further development of climate variability deterministic models for these regions.

Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization.

The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited. Here we use multiple approaches to dissect the functional and structural effects of orthosteric versus allosteric ligands. We find, using electrophysiological and live cell imaging assays, that both agonists and positive allosteric modulators (PAMs) can drive activation and internalization of group II and III mGluRs. The effects of PAMs are pleiotropic, boosting the maximal response to orthosteric agonists and serving independently as internalization-biased agonists across mGluR subtypes. Motivated by this and intersubunit FRET analyses, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.

Antifungal capabilities of gut microbial communities of three dung beetle species (Scarabaeidae: Scarabaeinae).

Gut microbial communities are part of the regulatory array of various processes within their hosts, ranging from nutrition to pathogen control. Recent evidence shows that dung beetle's gut microbial communities release substances with antifungal activity. Because of the enormous diversity of gut microorganisms in dung beetles, there is a possibility of discovering novel compounds with antifungal properties. We tested the antifungal activity mediated by gut microbial communities of female dung beetles against nine phytopathogenic fungi strains (Colletotrichum asianum-339, C. asianum-340, C. asianum-1, C. kahawae-390, C. karstii-358, C. siamense-220, Fusarium oxysporum-ATCC338, Nectria pseudotrichia-232, Verticillium zaelandica-22). Our tests included the gut microbial communities of three species of dung beetles: Canthon cyanellus (roller beetle), Digitonthophagus gazella (burrower beetle), and Onthophagus batesi (burrower beetle), and we followed the dual confrontation protocol, i.e., we challenged each fungal strain with the microbial communities of each species of beetles in Petri dishes containing culture medium. Our results showed that gut microbial communities of the three dung beetle species exhibit antifungal activity against at least seven of the nine phytopathogenic fungal strains. The gut microbial communities of Onthophagus batesi significantly decreased the mycelial growth of the nine phytopathogenic fungi strains; the gut microbial communities of Canthon cyanellus and Digitonthophagus gazella significantly reduced the mycelial growth of seven strains. These results provide a basis for investigating novel antifungal substances within gut microbial communities of dung beetles.

Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains.

G protein-coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to intracellular transducers including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. In addition to their critical interactions with the transmembrane core of active GPCRs, all three classes of transducers have also been reported to interact with receptor C-terminal domains (CTDs). An underexplored aspect of GPCR CTDs is their possible role as lipid sensors given their proximity to the membrane. CTD-membrane interactions have the potential to control the accessibility of key regulatory CTD residues to downstream effectors and transducers. Here, we report that the CTDs of two closely related family C GPCRs, metabotropic glutamate receptor 2 (mGluR2) and mGluR3, bind to membranes and that this interaction can regulate receptor function. We first characterize CTD structure with NMR spectroscopy, revealing lipid composition-dependent modes of membrane binding. Using molecular dynamics simulations and structure-guided mutagenesis, we then identify key conserved residues and cancer-associated mutations that modulate CTD-membrane binding. Finally, we provide evidence that mGluR3 transducer coupling is controlled by CTD-membrane interactions in live cells, which may be subject to regulation by CTD phosphorylation and changes in membrane composition. This work reveals an additional mechanism of GPCR modulation, suggesting that CTD-membrane binding may be a general regulatory mode throughout the broad GPCR superfamily.

Early safety and efficiency outcomes of a novel interdisciplinary laparoscopic resection rectopexy combined with sacrocolpopexy for women with obstructive defecation syndrome and pelvic organ prolapse: a single center study.

BACKGROUND: Obstructive defecation syndrome (ODS) defines a disturbed defecation process frequently associated with pelvic organ prolapse (POP) in women that substantially compromises quality of life. Conservative management offers limited relief and a surgical intervention may be required. This is characterized by individual approaches. AIM OF THE STUDY: This retrospective single center study evaluated the surgical and clinical short-term outcome of a novel interdisciplinary laparoscopic resection rectopexy (L-RRP) with mesh- sacrocolpopexy (L-SCP) for women suffering from ODS and POP. METHODS: The study participants underwent surgery in an interdisciplinary laparoscopic approach. Safety was the primary endpoint, assessed via postoperative morbidity classified by Clavien-Dindo scale. Secondary outcomes included evaluation of bowel function, fecal and urinary incontinence and pelvic organ prolapse status at 12 months follow-up. Additionally, a biological mesh (BM) was offered to women, who asked for an alternative to synthetic mesh material (SM). RESULTS: Of the 44 consecutive patients requiring surgery for ODS and POP, 36 patients underwent the interdisciplinary surgical approach; 28 patients with SM and 8 patients with BM. In total 5 complications occurred, four of them were classified as minor. One minor complication was observed in the BM group. One anastomotic leakage occurred in the SM group. The two ODS scores, the bowel dysfunction score, and the incontinence score improved significantly (p = 0.006, p = 0.003, p < 0.001, and p = 0.0035, respectively). Pelvic floor anatomy was fully restored (POP-Q 0) for 29 (80%) patients after surgery. 17 patients (47%) suffered from urinary incontinence before surgery, which was restored in 13 patients (76.5%). CONCLUSIONS: The interdisciplinary approach with L-RRP and L-SCP and the use of a BM in a small subgroup were technically feasible, safe, and effective in this single center setting. The study's retrospective design, the small sample size and the lack of comparators limit the generalizability of the findings requiring future randomized trials. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov, trial number NCT05910021, date of registration 06/10/2023.

Deuteration as a General Strategy to Enhance Azobenzene-Based Photopharmacology.

Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds have been implemented to improve photoswitch characteristics, ranging from the nature of the photoswitch itself (e.g. azobenzenes, dithienylethenes, hemithioindigo) to fine-tuning of aromatic units and substituents. Herein, we present deuterated azobenzene photoswitches as a general means of enhancing the performance of photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity (higher molar extinction coefficient), photoswitch efficiency (higher photoisomerization quantum yield), and photoswitch kinetics (faster macroscopic rate of photoisomerization) with minimal alteration to the underlying structure of the photopharmacological ligand. We report synthesized deuterated azobenzene-based ligands for the optimized optical control of ion channel and G protein-coupled receptor (GPCR) function in live cells, setting the stage for the straightforward, widespread adoption of this approach.

Emerging modes of regulation of neuromodulatory G protein-coupled receptors.

In the nervous system, G protein-coupled receptors (GPCRs) control neuronal excitability, synaptic transmission, synaptic plasticity, and, ultimately, behavior through spatiotemporally precise initiation of a variety of signaling pathways. However, despite their critical importance, there is incomplete understanding of how these receptors are regulated to tune their signaling to specific neurophysiological contexts. A deeper mechanistic picture of neuromodulatory GPCR function is needed to fully decipher their biological roles and effectively harness them for the treatment of neurological and psychiatric disorders. In this review, we highlight recent progress in identifying novel modes of regulation of neuromodulatory GPCRs, including G protein- and receptor-targeting mechanisms, receptor-receptor crosstalk, and unique features that emerge in the context of chemical synapses. These emerging principles of neuromodulatory GPCR tuning raise critical questions to be tackled at the molecular, cellular, synaptic, and neural circuit levels in the future.

Seamless Fusion: Multi-Modal Localization for First Responders in Challenging Environments.

In dynamic and unpredictable environments, the precise localization of first responders and rescuers is crucial for effective incident response. This paper introduces a novel approach leveraging three complementary localization modalities: visual-based, Galileo-based, and inertial-based. Each modality contributes uniquely to the final Fusion tool, facilitating seamless indoor and outdoor localization, offering a robust and accurate localization solution without reliance on pre-existing infrastructure, essential for maintaining responder safety and optimizing operational effectiveness. The visual-based localization method utilizes an RGB camera coupled with a modified implementation of the ORB-SLAM2 method, enabling operation with or without prior area scanning. The Galileo-based localization method employs a lightweight prototype equipped with a high-accuracy GNSS receiver board, tailored to meet the specific needs of first responders. The inertial-based localization method utilizes sensor fusion, primarily leveraging smartphone inertial measurement units, to predict and adjust first responders' positions incrementally, compensating for the GPS signal attenuation indoors. A comprehensive validation test involving various environmental conditions was carried out to demonstrate the efficacy of the proposed fused localization tool. Our results show that our proposed solution always provides a location regardless of the conditions (indoors, outdoors, etc.), with an overall mean error of 1.73 m.

Enhancing Kidney Transplant Outcomes: The Impact of Living Donor Programs.

INTRODUCTION: The protocol for deceased donor kidney transplants has been standardised. The procedure for a living donor has peculiarities derived from the differences in the graft. When a living kidney donor program is implemented, changes occur in both the profile of the kidney transplant candidate and in the postoperative treatments. AIMS: To discover whether a living donor program influences the functional outcomes of kidney grafts in a longstanding classical deceased donor kidney transplant program and to identify the factors associated with transplant outcomes. METHODS: Retrospective observational multicentre study. SAMPLE: Kidney transplant patients in two urology referral centres for renal transplant in Spain between 1994 and 2019. Groups: TV (living transplant): patients given kidney transplants from living donors (n = 150); TCpre11 (deceased transplant previous to 2011): patients given kidney transplants from deceased donors before the living donor program was implemented (n = 650); and TCpost11 (deceased transplant after 2011): patients given kidney transplants from deceased donors after the living donor program was implemented (n = 500). RESULTS: Mean age was 55.75 years (18-80 years), higher in TCpre11. There were 493 female patients (37.92%) and 1007 male patients (62.08%). Mean body mass index (BMI) was 26.69 kg/m2 (17.50-42.78 kg/m2), higher in TCpre11. Mean ischemia time was 17.97 h (6-29 h), higher in TCpost11. Median duration of urethral catheter: 8 days (6-98 days), higher in TCpost11. Median duration of double-J ureteral stent: 58 days (24-180 days), higher in TCpost11. Pretransplant UTIs: 17.77%, higher in TCpre11 (25.69%) than in TV (12%), higher in TV (12%) than TCpost11 (9.2%), and higher in TCpre11 (25.69%) than TCpost11 (9.2%). Acute renal rejection in 9.33% of TV, 14.77% of TCpre11, and 9.8% of TCpost11. Multivariate analysis: TCpost11 featured higher BMI, more smoking, and chronic renal failure progression time. Lower use of nonantibiotic prophylaxis to prevent recurrent urinary tract infections, increased duration of urethral catheters due to obstructive problems, and favoured deterioration of kidney function was observed in the deceased donor program. The living donor (LD) program had a strong influence on deceased donor transplants in the prelysis phase. Implementation of a LD program was associated with a decrease in the likelihood of acute rejection in TCpost11 and an increase in the tendency towards normal kidney function. CONCLUSIONS: Implementing living donor transplant programs affects functional outcomes in deceased donor transplants, reducing the probability of acute rejection and increasing the tendency towards normal kidney function. Preventing recurrent urinary tract infections with measures other than antibiotics, smoking cessation, delaying the removal of the double-J stent from the graft, and pre-emptive transplant (transplant prior to dialysis) are associated with improved renal function of the graft.

Short- and long-term outcomes after distal pancreatectomy with radiologic infiltration of splenic vessels for pancreatic ductal adenocarcinoma.

BACKGROUND: The effect of radiologic splenic vessels involvement (RSVI) on the survival of patients with pancreatic adenocarcinoma (PAC) located in the body and tail of the pancreas is controversial, and its influence on postoperative morbidity after distal pancreatectomy (DP) is unknown. This study aimed to determine the influence of RSVI on postoperative complications, overall survival (OS), and disease-free survival (DFS) in patients undergoing DP for PAC. METHODS: A multicenter retrospective study of DP was conducted at 7 hepatopancreatobiliary units between January 2008 and December 2018. Patients were classified according to the presence of RSVI. A Clavien-Dindo grade of >II was considered to represent a major complication. RESULTS: A total of 95 patients were included in the analysis. Moreover, 47 patients had vascular infiltration: 4 had arterial involvement, 10 had venous involvement, and 33 had both arterial and venous involvements. The rates of major complications were 20.8% in patients without RSVI, 40.0% in those with venous RSVI, 25.0% in those with arterial RSVI, and 30.3% in those with both arterial and venous RSVIs (P = .024). The DFS rates at 3 years were 56% in the group without RSVI, 50% in the group with arterial RSVI, and 16% in the group with both arterial and venous RSVIs (P = .003). The OS rates at 3 years were 66% in the group without RSVI, 50% in the group with arterial RSVI, and 29% in the group with both arterial and venous RSVIs (P < .0001). CONCLUSION: RSVI increased the major complication rates after DP and reduced the OS and DFS. Therefore, it may be a useful prognostic marker in patients with PAC scheduled to undergo DP and may help to select patients likely to benefit from neoadjuvant treatment.

Hereditary Transthyretin Amyloidosis and the Impact of Classic and New Treatments on Kidney Function: A Review.

Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as abnormal amyloid fibrils and accumulate throughout the body. The kidney is one of the main organs affected in amyloid light chain (AL) amyloidosis and ATTRv amyloidosis. The most common clinical presentation is proteinuria, which consists mainly of albumin; this is the first step in the natural history of ATTRv nephropathy. Not all TTR mutations are equal in terms of ATTRv kidney involvement. Kidney involvement in ATTRv itself is difficult to define, given the numerous associated confounding factors. There are several treatments available to treat ATTRv, including orthotopic liver transplant (OLT), which is the classic treatment for ATTRv. However, we should be careful regarding the use of calcineurin inhibitors in the setting of OLT because these can be nephrotoxic. New treatments for amyloidosis may have an impact on kidney function, including drugs that target specific pathways involved in the disease. Tafamidis and diflunisal, which are TTR stabilizers, patisiran (RNA interference agent), and inotersen (antisense oligonucleotide inhibitor) have been shown to reduce TTR amyloid. Tafamidis and patisiran are medications that have reduced the progression of kidney disease in amyloidosis, but inotersen and diflunisal may damage kidney function.

Profiling the proximal proteome of the activated µ-opioid receptor.

The µ-opioid receptor (µOR) represents an important target of therapeutic and abused drugs. So far, most understanding of µOR activity has focused on a subset of known signal transducers and regulatory molecules. Yet µOR signaling is coordinated by additional proteins in the interaction network of the activated receptor, which have largely remained invisible given the lack of technologies to interrogate these networks systematically. Here we describe a proteomics and computational approach to map the proximal proteome of the activated µOR and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor (GPCR) activity. We demonstrate that distinct opioid agonists exert differences in the µOR proximal proteome mediated by endocytosis and endosomal sorting. Moreover, we identify two new µOR network components, EYA4 and KCTD12, which are recruited on the basis of receptor-triggered G-protein activation and might form a previously unrecognized buffering system for G-protein activity broadly modulating cellular GPCR signaling.

Fourier phase index for extracting signatures of determinism and nonlinear features in time series.

Detecting determinism and nonlinear properties from empirical time series is highly nontrivial. Traditionally, nonlinear time series analysis is based on an error-prone phase space reconstruction that is only applicable for stationary, largely noise-free data from a low-dimensional system and requires the nontrivial adjustment of various parameters. We present a data-driven index based on Fourier phases that detects determinism at a well-defined significance level, without using Fourier transform surrogate data. It extracts nonlinear features, is robust to noise, provides time-frequency resolution by a double running window approach, and potentially distinguishes regular and chaotic dynamics. We test this method on data derived from dynamical models as well as on real-world data, namely, intracranial recordings of an epileptic patient and a series of density related variations of sediments of a paleolake in Tlaxcala, Mexico.

An epigenetic barrier sets the timing of human neuronal maturation.

The pace of human brain development is highly protracted compared with most other species1-7. The maturation of cortical neurons is particularly slow, taking months to years to develop adult functions3-5. Remarkably, such protracted timing is retained in cortical neurons derived from human pluripotent stem cells (hPSCs) during in vitro differentiation or upon transplantation into the mouse brain4,8,9. Those findings suggest the presence of a cell-intrinsic clock setting the pace of neuronal maturation, although the molecular nature of this clock remains unknown. Here we identify an epigenetic developmental programme that sets the timing of human neuronal maturation. First, we developed a hPSC-based approach to synchronize the birth of cortical neurons in vitro which enabled us to define an atlas of morphological, functional and molecular maturation. We observed a slow unfolding of maturation programmes, limited by the retention of specific epigenetic factors. Loss of function of several of those factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1 and EHMT2 or DOT1L, at progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. Thus our findings reveal that the rate at which human neurons mature is set well before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. Mechanistically, this barrier holds transcriptional maturation programmes in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation.

An illness-death multistate model to implement delta adjustment and reference-based imputation with time-to-event endpoints.

With a treatment policy strategy, therapies are evaluated regardless of the disturbance caused by intercurrent events (ICEs). Implementing this estimand is challenging if subjects are not followed up after the ICE. This circumstance can be dealt with using delta adjustment (DA) or reference-based (RB) imputation. In the survival field, DA and RB imputation have been researched so far using multiple imputation (MI). Here, we present a fully analytical solution. We use the illness-death multistate model with the following transitions: (a) from the initial state to the event of interest, (b) from the initial state to the ICE, and (c) from the ICE to the event. We estimate the intensity function of transitions (a) and (b) using flexible parametric survival models. Transition (c) is assumed unobserved but identifiable using DA or RB imputation assumptions. Various rules have been considered: no ICE effect, DA under proportional hazards (PH) or additive hazards (AH), jump to reference (J2R), and (either PH or AH) copy increment from reference. We obtain the marginal survival curve of interest by calculating, via numerical integration, the probability of transitioning from the initial state to the event of interest regardless of having passed or not by the ICE state. We use the delta method to obtain standard errors (SEs). Finally, we quantify the performance of the proposed estimator through simulations and compare it against MI. Our analytical solution is more efficient than MI and avoids SE misestimation-a known phenomenon associated with Rubin's variance equation.

Dissecting the molecular basis for the modulation of neurotransmitter GPCR signaling by GINIP.

It is well established that G-protein-coupled receptors (GPCRs) stimulated by neurotransmitters are critical for neuromodulation. Much less is known about how heterotrimeric G-protein (Gαßγ) regulation after receptor-mediated activation contributes to neuromodulation. Recent evidence indicates that the neuronal protein GINIP shapes GPCR inhibitory neuromodulation via a unique mechanism of G-protein regulation that controls pain and seizure susceptibility. However, the molecular basis of this mechanism remains ill-defined because the structural determinants of GINIP responsible for binding and regulating G proteins are not known. Here, we combined hydrogen-deuterium exchange mass spectrometry, computational structure predictions, biochemistry, and cell-based biophysical assays to demonstrate an effector-like binding mode of GINIP to Gαi. Specific amino acids of GINIP's PHD domain first loop are essential for G-protein binding and subsequent regulation of Gαi-GTP and Gßγ signaling upon neurotransmitter GPCR stimulation. In summary, these findings shed light onto the molecular basis for a post-receptor mechanism of G-protein regulation that fine-tunes inhibitory neuromodulation.

Descontrol glucémico: desafío de salud pública en prepandemia y pandemia.

OBJETIVO: Comparar el control glucémico entre pacientes con diabetes mellitus tipo 2 prepandemia vs pandemia de Covid-19 que acudieron a unidades de salud de primer nivel de atención de la Ciudad de México. Material y métodos. Se analizaron los registros de 23 912 pacientes con diabetes; 78.7% fueron del grupo prepandemia (2016 a 2020) y 21.3% del grupo pandemia (marzo 2020 a julio 2021). Se calcularon medidas de tendencia central y de dispersión, pruebas t de Student y se ajustó un modelo de regresión logística múltiple. RESULTADOS: La mayoría de los pacientes con diabetes fueron mujeres (66.6 y 62.6%) con edad promedio de 59 y 58 años, respectivamente, y con hemoglobina glucosilada (HbA1) final de 7.7 vs el grupo pandemia (8.0). Las variables asociadas con el descontrol glucémico incluyeron periodo, nivel de HbA1, sobrepeso, obesidad, antecedente de padres con diabetes, número de medicamentos y tipo de insulina. CONCLUSIONES: La mayoría de los pacientes con diabetes en ambos grupos tuvieron descontrol glucémico. Los pacientes del grupo pandemia tuvieron mayor descontrol glucémico de HbA1 comparados con los del grupo prepandemia. Después de recibir atención médica en ambos grupos, los pacientes mejoraron su control glucémico.