Cranial anatomy of Acynodon adriaticus and extreme durophagous adaptations in Eusuchia (Reptilia: Crocodylomorpha).

Acynodon adriaticus, a small eusuchian from the Late Cretaceous of Italy, is known for its well-preserved cranial and postcranial material. Despite its excellent preservation, many details remain hidden due to the physical overlap between the elements and matrix obliteration. We used Micro-CT scans to reveal previously overlooked anatomical features and describe in detail the cranial and dental anatomy of this taxon, shedding new light on its palaeoecology. The holotypic specimen, SC 57248, represents a mature individual exhibiting signs of hyperossification, developed ornamentation, and various pathologies, including jaw arthritis and a possible dental anomaly. Acynodon adriaticus exhibits significant durophagous adaptations, including a robust, brevirostrine skull optimized for powerful biting and stress-load capacity. Its specialized dentition, lacking caniniform teeth, features anterior chisel-like teeth and hypertrophic posterior molariforms with thick enamel, indicative of a diet specializing in hard-shelled prey. The dentition pattern, accelerated molariform replacement rate, and reduced orbit size suggest adaptations for durophagous foraging in turbid, densely vegetated aquatic environments. The paleoecological context during the Late Cretaceous, characterized by increased freshwater habitats and high invertebrate diversity, likely facilitated the evolution of such specialized traits in A. adriaticus. This small crocodylomorph likely foraged slowly in shallow, benthic environments, using its powerful bite to process mollusks and large arthropods. The study of A. adriaticus, along with comparisons with other crocodylomorphs and ecomorphologically similar taxa like Iharkutosuchus makadii and Gnatusuchus pebasensis, provides a valuable morphofunctional model for understanding the evolutionary pathways of extinct crocodylians to durophagy.

Protein Language Models and Machine Learning Facilitate the Identification of Antimicrobial Peptides.

Peptides are bioactive molecules whose functional versatility in living organisms has led to successful applications in diverse fields. In recent years, the amount of data describing peptide sequences and function collected in open repositories has substantially increased, allowing the application of more complex computational models to study the relations between the peptide composition and function. This work introduces AMP-Detector, a sequence-based classification model for the detection of peptides' functional biological activity, focusing on accelerating the discovery and de novo design of potential antimicrobial peptides (AMPs). AMP-Detector introduces a novel sequence-based pipeline to train binary classification models, integrating protein language models and machine learning algorithms. This pipeline produced 21 models targeting antimicrobial, antiviral, and antibacterial activity, achieving average precision exceeding 83%. Benchmark analyses revealed that our models outperformed existing methods for AMPs and delivered comparable results for other biological activity types. Utilizing the Peptide Atlas, we applied AMP-Detector to discover over 190,000 potential AMPs and demonstrated that it is an integrative approach with generative learning to aid in de novo design, resulting in over 500 novel AMPs. The combination of our methodology, robust models, and a generative design strategy offers a significant advancement in peptide-based drug discovery and represents a pivotal tool for therapeutic applications.

The impact of photovoltaic self-consumption on the daily electricity demand in Spain: Definition of a model to estimate it.

Introduction: A radical shift in energy production is underway worldwide, replacing fossil fuels with renewable sources and causing structural changes in power generation systems. Problem statement: Photovoltaic installations for self-consumption have experienced a steep increase in recent years. They have reached a significant installed capacity to cause a noticeable reduction in consumption from the national grid, which can cause serious management problems. Objectives: In this work, the evolution of the Spanish demand in the last years is analyzed to identify the influence of self-consumption in the overall demand. In addition, a mathematical model is defined to estimate this influence. Methodology: The demand curves of equivalent days in years with high and low installed self-consumption photovoltaic systems have been compared. Then, an estimation of the electricity generated with this source is proposed, with a mathematical model that takes into account data on solar radiation, installed photovoltaic power for self-consumption and other relevant factors. Results: The analysis of the demand has shown a significant reduction of the electricity demand in daylight hours when the number of self-consumption photovoltaic systems increases. Moreover, the proposed model has been able to provide an estimation of the electricity generated with this source. The addition of these estimates to the actual consumption curves of years with a high number of self-consumption installations gives profiles close to those obtained when self-consumption was low. Recommendation: New storage systems need to be implemented and grid management need to be improved to take advantage of the surpluses produced by photovoltaic systems.

Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

Adherens junction-associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1-/- and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants.

Satisfaction, Qol and adherence of patients allergic to dust mites and/or pollens undergoing sublingual immunotherapy.

Aim: Sublingual immunotherapy (SLIT) changes history of allergic respiratory disease (ARD). However, adherence is a barrier for optimal outcomes.Patients & methods: In the QUALI study, 859 patients with house-dust mite (HDM) and/or pollen induced ARD uncontrolled with symptomatic treatment and undergoing SLIT for at least 6 months or including one pre-coseason (pollen) were collected.Results & conclusion: SLIT significantly improved allergic rhinoconjunctivitis (ARC) and asthma symptom control, leading to reduced medication, meaningful health-related quality of life gain, improved nasal, ocular and bronchial symptoms and everyday life activities. Patients were highly satisfied and most of them adhered to SLIT, being forgetfulness the main non-adherence motive. SLIT is a quick effective treatment against persistent moderate-to-severe symptoms in ARC and asthma but it should been improve forgetfulness, as non-adherence reason.

Sublingual immunotherapy (SLIT) has really changed how we deal with allergic respiratory disease. But there's a catch: sticking to the treatment can be tough.In the QUALI study, we looked at 859 patients dealing with dust mite and/or pollen allergies who were not getting relief from the usual treatments. We put them on SLIT for at least 6 months or during pollen season.This treatment made a big difference. Symptoms got better, people needed less medication and they felt better in their day-to-day lives. Most patients were happy with the treatment and stuck to it well, but some forgot sometimes.In short, SLIT works fast and works well for moderate to severe allergies and asthma. But we need to help people remember to stick with it.

Locked Distal Ulna Volar Dislocation Associated with a Malunited Fracture of the Distal Radius.

Background The volar dislocation of the distal ulna is an uncommon injury and often missed due to its rarity. If diagnosed early, it can be managed with a simple closed reduction followed by immobilization. Open reduction is recommended in case of any interposition preventing reduction. Case Description In this case report, we present a rare case of neglected volar distal ulna dislocation associated with a distal radius fracture presenting with a fixed supination deformity that was managed successfully with a Sauvé- Kapandji procedure using a modified approach to restore forearm rotation. At 10 months, the patient had a good union at the distal radio ulnar joint (DRUJ) with improved forearm rotations. Literature Review To our knowledge no previous cases of neglected volar distal ulna dislocation with distal radius fracture has been reported in the literature. Clinical Relevance If DRUJ stability cannot be restored after closed reduction of distal radius fracture, open reduction and internal fixation of the fracture should always be performed to avoid subsequent DRUJ subluxation/dislocations.

Synaptotagmin-11 facilitates assembly of a presynaptic signaling complex in post-Golgi cargo vesicles.

GABAB receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic function of GBRs is the gating of Cav2.2-type Ca2+ channels. However, the cellular compartment where stable GBR/Cav2.2 signaling complexes form remains unknown. In this study, we demonstrate that the vesicular protein synaptotagmin-11 (Syt11) binds to both the auxiliary GBR subunit KCTD16 and Cav2.2 channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, thus facilitating assembly of GBR/Cav2.2 signaling complexes. In addition, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Neurons of Syt11 knockout mice exhibit deficits in presynaptic GBRs and Cav2.2 channels, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition, highlighting the critical role of Syt11 in the assembly and stable expression of GBR/Cav2.2 complexes. These findings support that Syt11 acts as a vesicular scaffold protein, aiding in the assembly of signaling complexes from low-abundance components within transport vesicles. This mechanism enables insertion of pre-assembled functional signaling units into the synaptic membrane.

Limited herbivore migration during the Last Glacial Period of Kenya.

Eastern Africa is home to the largest terrestrial migrations on Earth. Though these migratory systems have been well studied for decades, little is known of their antiquity and evolutionary history. Serially sampled strontium stable isotopes (87Sr/86Sr) from tooth enamel can be used to track migration in mammals. Here we analyse 87Sr/86Sr for 79 bovid and equid individuals representing 18 species from four localities in Kenya to characterize prehistoric migratory systems during the Last Glacial Period (115-11.7 ka). Of the species analysed, 16 lack definitive evidence for migration, including blue wildebeest (Connochaetes taurinus), Thomson's gazelle (Eudorcas thomsonii) and plains zebra (Equus quagga), which are long-distance migrants today in the Greater Serengeti Ecosystem and historically in the Athi-Kapiti Plains. Only two species, the extinct wildebeests Rusingoryx atopocranion and Megalotragus sp., were migratory. These findings suggest a possible alternative narrative about ecosystem dynamics during the Last Glacial Period and shed light on the behaviour of both extant and extinct species at this time. In particular, these results indicate that migratory behaviour in extant species either emerged during the Holocene or was more spatiotemporally constrained in the past. Our results contribute to a growing body of evidence suggesting that the structure and function of geologically recent large mammal communities in eastern Africa differed considerably from those observed in the present day.

Preassembly of specific Gßγ subunits at GABAB receptors through auxiliary KCTD proteins accelerates channel gating.

GABAB receptors (GBRs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GBRs regulate fast synaptic transmission by gating Ca2+ and K+ channels via the Gßγ subunits of the activated G protein. It has been demonstrated that auxiliary GBR subunits, the KCTD proteins, shorten onset and rise time and increase desensitization of receptor-induced K+ currents. KCTD proteins increase desensitization of K+ currents by scavenging Gßγ from the channel, yet the mechanism responsible for the rapid activation of K+ currents has remained elusive. In this study, we demonstrate that KCTD proteins preassemble Gßγ at GBRs. The preassembly obviates the need for diffusion-limited G protein recruitment to the receptor, thereby accelerating G protein activation and, as a result, K+ channel activation. Preassembly of Gßγ at the receptor relies on the interaction of KCTD proteins with a loop protruding from the seven-bladed propeller of Gß subunits. The binding site is shared between Gß1 and Gß2, limiting the interaction of KCTD proteins to these particular Gß isoforms. Substituting residues in the KCTD binding site of Gß1 with those from Gß3 hinders the preassembly of Gßγ with GBRs, delays onset and prolongs rise time of receptor-activated K+ currents. The KCTD-Gß interface, therefore, represents a target for pharmacological modulation of channel gating by GBRs.

Radially Displaced Perilunate Injuries: A Report of Two Cases.

We present two unusual cases of radially displaced perilunate dislocations, one of which involved acute ulnar nerve compression requiring Guyon's canal release. The first case underwent closed reduction and cast immobilization but developed scapholunate instability, necessitating secondary ligament reconstruction. The second case, treated with open reduction and fixation, resulted in persistent volar intercalated segment instability of the proximal row and ulnar nerve paresthesia 1 year after surgery.

The interaction of the ribotoxin α-sarcin with complex model lipid vesicles.

Fungal ribotoxins are extracellular RNases that inactivate ribosomes by cleaving a single phosphodiester bond at the universally conserved sarcin-ricin loop of the large rRNA. However, to reach the ribosomes, they need to cross the plasma membrane. It is there where these toxins show their cellular specificity, being especially active against tumoral or virus-infected cells. Previous studies have shown that fungal ribotoxins interact with negatively charged membranes, typically containing phosphatidylserine or phosphatidylglycerol. This ability is rooted on their long, non-structured, positively charged loops, and its N-terminal ß-hairpin. However, its effect on complex lipid mixtures, including sphingophospholipids or cholesterol, remains poorly studied. Here, wild-type α-sarcin was used to evaluate its interaction with a variety of membranes not assayed before, which resemble much more closely mammalian cell membranes. The results confirm that α-sarcin is particularly sensitive to charge density on the vesicle surface. Its ability to induce vesicle aggregation is strongly influenced by both the lipid headgroup and the degree of saturation of the fatty acid chains. Acyl chain length is indeed particularly important for lipid mixing. Finally, cholesterol plays an important role in diluting the concentration of available negative charges and modulates the ability of α-sarcin to cross the membrane.

Efficacy of myofascial induction compared with its simulation on joint amplitude in people with axial spondylarthritis: Protocol of a randomized controlled clinical trial.

BACKGROUND: Axial spondyloarthritis (AxSpA) produces structural changes that cause alterations in body functions. One tissue that seems to have a predictive role in the etiology and progression of the disease is the soft tissue, particularly the fascia. However, little is known about the use of myofascial induction in people with AxSpA, and clinical evidence from physiotherapy regarding potential strategies is limited. OBJECTIVE: To evaluate the efficacy of myofascial induction compared with its simulation on joint amplitude in people with AxSpA. METHODS: In this randomized controlled parallel superiority clinical trial, 84 people with an AxSpA diagnosis confirmed by a rheumatologist will be randomly assigned to groups: the experimental group or the control group. The experimental group will receive myofascial induction, and the control group will undergo a simulation of the technique. Both groups will receive an examination session and six intervention sessions twice per week for three weeks. A baseline follow-up will be performed immediately after the intervention and four weeks after treatment. CONCLUSION: The results of this study may contribute to a better understanding of the efficacy of myofascial induction for joint mobility in people with AxSpA. The implications of these results have a potential transformative effect on the understanding, analysis, evaluation, and physiotherapeutic treatment of this health condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT04424589. Registered 11 June 2020.

In Silico Pipeline to Identify Tumor-Specific Antigens for Cancer Immunotherapy Using Exome Sequencing Data.

Tumor-specific antigens or neoantigens are peptides that are expressed only in cancer cells and not in healthy cells. Some of these molecules can induce an immune response, and therefore, their use in immunotherapeutic strategies based on cancer vaccines has been extensively explored. Studies based on these approaches have been triggered by the current high-throughput DNA sequencing technologies. However, there is no universal nor straightforward bioinformatic protocol to discover neoantigens using DNA sequencing data. Thus, we propose a bioinformatic protocol to detect tumor-specific antigens associated with single nucleotide variants (SNVs) or "mutations" in tumoral tissues. For this purpose, we used publicly available data to build our model, including exome sequencing data from colorectal cancer and healthy cells obtained from a single case, as well as frequent human leukocyte antigen (HLA) class I alleles in a specific population. HLA data from Costa Rican Central Valley population was selected as an example. The strategy included three main steps: (1) pre-processing of sequencing data; (2) variant calling analysis to detect tumor-specific SNVs in comparison with healthy tissue; and (3) prediction and characterization of peptides (protein fragments, the tumor-specific antigens) derived from the variants, in the context of their affinity with frequent alleles of the selected population. In our model data, we found 28 non-silent SNVs, present in 17 genes in chromosome one. The protocol yielded 23 strong binders peptides derived from the SNVs for frequent HLA class I alleles for the Costa Rican population. Although the analyses were performed as an example to implement the pipeline, to our knowledge, this is the first study of an in silico cancer vaccine using DNA sequencing data in the context of the HLA alleles. It is concluded that the standardized protocol was not only able to identify neoantigens in a specific but also provides a complete pipeline for the eventual design of cancer vaccines using the best bioinformatic practices. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00084-9.

Curative embolization of ruptured pediatric cerebral arteriovenous malformations.

INTRODUCTION: Embolization with the intention to cure has not been well studied in ruptured arteriovenous malformations (AVMs). Furthermore, the role of primary curative embolization of pediatric AVMs is uncertain. Hence, we aimed to characterize the safety and efficacy of curative embolization of ruptured pediatric AVMs and assess predictors of obliteration and complications. METHODS: A retrospective analysis of all pediatric (≤18 years) patients who underwent curative embolization of ruptured AVMs was conducted in two institutions between 2010 and 2022. The efficacy (complete angiographic obliteration after the last embolization session), recurrence (radiological recurrence of the lesion after confirmed obliteration in follow-up imaging), and safety (procedure-related complications and mortality) of the procedure were evaluated. RESULTS: Sixty-eight patients (38 females; mean age 12.4 ± 3.4 years) underwent a total of 109 embolization sessions. Median follow-up time was 18 months after embolization (ranged from 2 to 47 months). Complete angiographic obliteration was achieved in 42 patients (62%). In 30 patients (44%) the AVM was occluded with a single embolization session. Recurrence of a totally embolized lesion occurred in 9 patients (13%). Thirteen complications (11.9% of procedures) were observed, and no deaths were reported. A nidus size > 2 cm was the only independent predictor of complete obliteration (OR = 0.16; 95% CI 0.03 - 0.77; p = 0.030). CONCLUSION: Embolization of pediatric ruptured AVMs with curative intent can achieve acceptable obliteration rates. However, recurrence after complete obliteration and procedure-related complications of curative embolization of these lesions cannot be ignored. Ruptured AVMs ≤ 2 cm are adequate to achieve complete obliteration with curative endovascular management.

Randomized clinical trial comparing pericapsular nerve group (PENG) block and periarticular local anesthetic infiltration for total hip arthroplasty.

BACKGROUND: This randomized trial compared pericapsular nerve group block and periarticular local anesthetic infiltration in patients undergoing primary total hip arthroplasty. We hypothesized that, compared with pericapsular nerve group block, periarticular local anesthetic infiltration would decrease the postoperative incidence of quadriceps weakness at 3 hours fivefold (ie, from 45% to 9%). METHODS: Sixty patients undergoing primary total hip arthroplasty under spinal anesthesia were randomly allocated to receive a pericapsular nerve group block (n=30) using 20 mL of adrenalized bupivacaine 0.50%, or periarticular local anesthetic infiltration (n=30) using 60 mL of adrenalized bupivacaine 0.25%. Both groups also received 30 mg of ketorolac, either intravenously (pericapsular nerve group block) or periarticularly (periarticular local anesthetic infiltration), as well as 4 mg of intravenous dexamethasone.Postoperatively, a blinded evaluator carried out sensory assessment and motor assessment (knee extension and hip adduction) at 3, 6 and 24 hours. Furthermore, the blinded observer also recorded static and dynamic pain scores at 3, 6, 12, 18, 24, 36 and 48 hours; time to first opioid request; cumulative breakthrough morphine consumption at 24 hours and 48 hours; opioid-related side effects; ability to perform physiotherapy at 6, 24 and 48 hours; as well as length of stay. RESULTS: There were no differences in quadriceps weakness at 3 hours between pericapsular nerve group block and periarticular local anesthetic infiltration (20% vs 33%; p=0.469). Furthermore, no intergroup differences were found in terms of sensory block or motor block at other time intervals; time to first opioid request; cumulative breakthrough morphine consumption; opioid-related side effects; ability to perform physiotherapy; and length of stay. Compared with pericapsular nerve group block, periarticular local anesthetic infiltration resulted in lower static pain scores (at all measurement intervals) and dynamic pain scores (at 3 and 6 hours). CONCLUSION: For primary total hip arthroplasty, pericapsular nerve group block and periarticular local anesthetic infiltration result in comparable rates of quadriceps weakness. However, periarticular local anesthetic infiltration is associated with lower static pain scores (especially during the first 24 hours) and dynamic pain scores (first 6 hours). Further investigation is required to determine the optimal technique and local anesthetic admixture for periarticular local anesthetic infiltration. TRIAL REGISTRATION NUMBER: NCT05087862.

Soluble amyloid-ß precursor peptide does not regulate GABAB receptor activity.

Amyloid-ß precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release, or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.