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Water desolvation is one of the key components of the free energy of binding of small molecules to their receptors. Thus, understanding the energetic balance of solvation and desolvation resulting from individual water molecules can be crucial when estimating ligand binding, especially when evaluating different molecules and poses as done in High-Throughput Virtual Screening (HTVS). Over the last decades, several methods were developed to tackle this problem, ranging from fast approximate methods (usually empirical functions using either discrete atom-atom pairwise interactions or continuum solvent models), to more computationally expensive and accurate ones mostly based on Molecular Dynamics (MD) simulations, such as Grid Inhomogeneous Solvation Theory (GIST) or Double Decoupling. On one hand, MD-based methods are prohibitive to use in HTVS to estimate the role of waters on the fly for each ligand. On the other hand, fast and approximate methods show unsatisfactory level of accuracy, with low agreement with results obtained with the more expensive methods. Here we introduce WaterKit, a new grid-based sampling method with explicit water molecules to calculate thermodynamic properties using the GIST method. Our results show that the discrete placement of water molecules is successful in reproducing the position of crystallographic waters with very high accuracy, as well as providing thermodynamic estimates with accuracy comparable to more expensive MD simulations. Unlike these methods, WaterKit can be used to analyze specific regions on the protein surface, (such as the binding site of a receptor), without having to hydrate and simulate the whole receptor structure. The results show the feasibility of a general and fast method to compute thermodynamic properties of water molecules, making it well suited to be integrated in high-throughput pipelines such as molecular docking.

A new species of the genus Aspella Mörch, 1877 (Gastropoda: Muricidae), Aspella tusciae n. sp., is here described from the Pliocene of Tuscany, Italy, to indicate a species with paucispiral protoconch often reported as A. anceps (Lamarck, 1822) or A. emmae (Boettger, 1902) by authors dealing with Mediterranean Pliocene assemblages. The European Neogene congeners A. emmae (Boettger, 1902), A. subanceps (d’Orbigny, 1852) and A. pacaudi Goret, Ledon & Pons, 2013 are separated by their multispiral protoconch. The protoconch of A. sanfrae Novelli & Gambarino, 1984 is unknown, but it is separated from A. tusciae n. sp. based on teleoconch characters. We report for the first time A. pacaudi Goret, Ledon & Pons, 2013 for the Tuscan and Italian Pliocene. Separation of A. pacaudi from A. tusciae in the absence of their protoconch can be problematic. In the Tuscan Pliocene A. pacaudi is limited to the Zanclean and A. tusciae to the Piacenzian.

Glycine is a major neurotransmitter involved in several fundamental neuronal processes. The identity of the metabotropic receptor mediating slow neuromodulatory effects of glycine is unknown. We identified an orphan G protein–coupled receptor, GPR158, as a metabotropic glycine receptor (mGlyR). Glycine and a related modulator, taurine, directly bind to a Cache domain of GPR158, and this event inhibits the activity of the intracellular signaling complex regulator of G protein signaling 7–G protein β5 (RGS7-Gβ5), which is associated with the receptor. Glycine signals through mGlyR to inhibit production of the second messenger adenosine 3′,5′-monophosphate. We further show that glycine, but not taurine, acts through mGlyR to regulate neuronal excitability in cortical neurons. These results identify a major neuromodulatory system involved in mediating metabotropic effects of glycine, with implications for understanding cognition and affective states.

O presente trabalho tem por finalidade analisar o contexto e o processo racional de tomada de decisão entrelaçados ao método pragmático em um paradigma do constitucionalismo de efetividade. O ponto de partida é a certeza de que o direito não se resume ao plano dos conceitos. Realiza-se na experiência concreta e real, o que implica a necessária compreensão do racional processo de tomada de decisão; tanto em seu contexto de descoberta como em seu contexto de justificação, é fundamental para cultivarmos uma cultura de efetividade. O constitucionalismo da efetividade se concretiza no contexto do modelo cooperativo. Seus institutos e normas fundamentais se entrelaçam em influência recíproca ao método pragmático, permitindo a percepção de seus efeitos práticos na experiência jurídica em direção à efetivação dos direitos. Isso tudo faz com que o papel do judiciário se desloque de coadjuvante para partícipe fundamental no processo de construção normativa. A jurisdição ostenta uma função imprescindível de promoção da tutela dos direitos por meio de técnicas adequadas. Nesse contexto, é imprescindível investigar e refletir sobre o processo dinâmico de tomada de decisão de certificação do direito e de satisfação da tutela certificada. Essa dinâmica de decidir e efetivar a tutela não se realiza de forma aleatória, mas sim em um contexto real, dotado de regras, características e propósitos. Esse contexto de realização opera-se no modelo democrático e cooperativo que se legitima pela participação dialógica, porém sem ignorar seus elementos finalístico (efetividade), de estabilidade (previsibilidade) e de comprometimento (responsabilidade). A pretensão é analisar os efeitos práticos e dinâmicos desse modelo processual e sua correlação com a tomada de decisão racional, a partir de um método que seja capaz de interagir de forma real com o sujeito, o problema e o sistema. Assim, o método prestigia uma racionalidade real, que leva em conta os efeitos práticos da postura do sujeito e sua relação com o sistema a partir de um contexto problemático. Nesse cenário, o método funciona, em correlação com o contexto e regras do modelo cooperativo, como verdadeira parametrização das etapas decisórias, destacando e desvelando, sem ignorar a etapa de justificação, o contexto de descoberta, que, embora tenha um necessário momento perceptivo, também se desenvolve em um momento reflexivo.

Objective. To establish the safety and effectiveness of subtotal petrosectomy with cochlear implantation in patients affected by chronic middle ear disorders to refractory to previous surgical treatments. Methods. A multicentre, retrospective study was conducted on patients affected by recalcitrant chronic middle ear disorders who underwent cochlear implantation in combi-nation with subtotal petrosectomy. Patients’ details were collected from databases of 11 Italian tertiary referral centres. Additionally, a review of the most updated literature was carried out. Results. 55 patients were included with a mean follow-up time of 44 months. Cholestea-toma was the most common middle ear recurrent pathology and 50.9% of patients had an open cavity. 80% of patients underwent a single stage surgery. One case of explantation for device failure was reported among the 7 patients with post-operative complications. Conclusions. Subtotal petrosectomy with cochlear implantation is a benchmark for management of patients with recalcitrant chronic middle ear disorders. A single stage procedure is the most recommended strategy. Optimal follow-up is still debated. Further studies are required to investigate the role of this surgery in paediatric patients. © Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale.

Congenital syndactylies account for 1 to 2 out of 2000 birth defects. Although several types of syndactylies exist, we only studied embryonic syndactylies. The goal of our study was to compare 2 types of coverage flap for the reconstruction of the finger web spaces: a volar flap described by Blauth and a dorsal flap described by Gilbert. Between 1993 and 2015, children affected by simple and complex syndactylies (partial or complete) were treated in 2 french pediatric hospitals and were selected for our analytic, comparative, retrospective review. The 2 hospitals used different surgical techniques: one used a volar flap described by Blauth and the other a dorsal flap described by Gilbert. The children were followed up to look for signs according to the stages of the Classification of Withey and to evaluate a global result according to the score of Withey. Our secondary criteria of judgement were the aspect of the surgical scar according to the VSS (Vancouver Scar Scale) and the satisfaction of the parents and children. The age of the children, need for a surgical revision and time of last follow- up were also studied. We found statistically significant differences between group I (volar flap) and group II (dorsal flap) in favor of the volar flap: higher scores of Withey (even when the number of commissures was increasing) and better VSS (regardless of the number of web spaces treated). There was no statistically significant difference between the 2 groups in terms of age, follow-up, or rate of surgical revision. All in all, the volar flap presented less sequelae in terms of scar retraction. Regardless of the flap used, the cosmetic results of the full-thickness skin graft used impacted the result both on the receiving site (dyschromia, hairiness) and the donor site.

Background: Congenital cytomegalovirus (cCMV) infection is the leading cause of non-hereditary sensorineural hearing loss in children. While about 10% of children reportedly display symptoms at birth, 85–90% of cCMV infection cases are asymptomatic. However, 10–15% of these asymptomatic infants may later develop hearing, visual, or neurodevelopmental impairments. This study aimed to evaluate the impact of cCMV infection on newborns’ hearing function with a particular emphasis on progressive and late-onset cases. Methods: This study is a retrospective chart analysis with longitudinal character and was conducted in two Italian centers: Center 1 (from 1 November 2007 to 31 December 2021) and Center 2 (from 1 January 2012 to 31 December 2021). Data collected included newborn hearing screening results, characterization of hearing loss (unilateral/bilateral, degree of impairment), and audiological follow-up. Results: The cohort consisted of 103 children (42% males, 58% females). In total, 28 children presented with hearing impairment; 71.4% (20 out of 28) of the cases of hearing loss were severe/profound, with 35.7% of the cases due to unilateral hearing loss. Out of twenty-eight, six experienced progression of hearing loss and four had late-onset hearing loss. Conclusions: In the absence of universal cCMV screening, hearing screening at birth for cCMV remains a critical factor for early diagnosis. A significant percentage of children affected by cCMV with normal audiological evaluations at birth is easily lost to follow-up. Close collaboration between neonatologists, pediatricians, and audiological services is fundamental to ensure timely diagnosis and treatment of cCMV-related hearing loss.

Purpose The study aims to assess the benefit of sequential bilateral cochlear implantation in children with congenital bilateral profound hearing loss, submitted to the first implant at an early age. Methods We enrolled all the bilateral sequential cochlear implanted children who received the first implant within 48 months and the second within 12 years of age at our Institution. The children were submitted to disyllabic word recognition tests and Speech Reception Threshold (SRT) assessment using the OLSA matrix sentence test with the first implanted device (CI1), with the second implanted device (CI2), and with both devices (CIbil). Furthermore, we measured the datalogging of both devices. Then we calculated the binaural SRT gain (b-SRTgain) and checked the correlations between speech perception results and the b-SRTgain with the child’s age at CI1 and CI2, DELTA and the datalogging reports. Results With the bilateral electric stimulation, we found a significant improvement in disyllabic word recognition scores and in SRT. Moreover, the datalogging showed no significant differences in the time of use of CI1 and CI2. We found significant negative correlations between speech perception abilities with CI2 and age at CI2 and DELTA, and between the SRT with CI1 and the b-SRTgain. Conclusions From this study we can conclude that in a sequential CI procedure, even if a short inter-implant delay and lower ages at the second surgery can lead to better speech perception with CI2, children can benefit from bilateral stimulation independently of age at the second surgery and the DELTA.

We describe the formalization of the reactive docking protocol, a method developed to model and predict reactions between small molecules and biological macromolecules. The method has been successfully used in a number of applications already, including recapitulating large proteomics datasets, performing structure-reactivity target optimizations and prospective virtual screenings. By modeling a near-attack conformation-like state, no QM calculations are required to model ligand and receptor geometries. Here, we present its generalization using a large dataset containing more than 400 ligand-target complexes, 8 nucleophilic modifiable residue types, and more than 30 warheads. The method correctly predicts the modified residue in ~85% of complexes and shows enrichments comparable to standard focused virtual screenings in ranking ligands. This performance supports this approach for the docking and screening of reactive ligands in virtual chemoproteomics and drug design campaigns.

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core “SuFExable” hubs—exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)—enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1 H -1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function – a key objective of click chemistry – of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Irregular applications can be found in different scientific fields. In computer-aided drug design, molecular docking simulations play an important role in finding promising drug candidates. AutoDock is a software application widely used for predicting molecular interactions at close distances. It is characterized by irregular computations and long execution runtimes. In recent years, a hardware-accelerated version of AutoDock , called AutoDock-GPU , has been under active development. This work benchmarks the recent code and algorithmic enhancements incorporated into AutoDock-GPU . Particularly, we analyze the impact on execution runtime of techniques based on early termination. These enable AutoDock-GPU to explore the molecular space as necessary, while safely avoiding redundant computations. Our results indicate that it is possible to achieve average runtime reductions of 50% by using these techniques. Furthermore, a comprehensive literature review is also provided, where our work is compared to relevant approaches leveraging hardware acceleration for molecular docking.

ObjectivesThis study presents the results obtained in a group of patients with asymmetric hearing loss undergoing cochlear implantation at our institution. Prognostic factors are discussed in relation to different rehabilitative approaches for asymmetric hearing loss remediation. The current literature is also discussed.MethodsNineteen adult patients with post-verbal asymmetric hearing loss were enrolled. The results were assessed by means of a speech perception test, completed in silence and with background noise, and a speech reception threshold test (Oldenburg Sentence Test). The subjectively perceived benefits were assessed using the Speech, Spatial and Qualities of Hearing Scale.ResultsStatistically significant improvements were achieved by all patients in terms of speech perception and speech reception threshold, and in subjective benefits.ConclusionThe results confirm the literature findings which suggest that patients with asymmetric hearing loss generally gain substantial benefit from cochlear implantation because of the binaural input, with significant improvement in speech perception abilities in noise, speech reception threshold, and squelch abilities.

The goal of this study was to describe the long-term functional outcomes of the procedure described by Dubert (stabilized arthroplasty with intermetacarpal arthrodesis) for painful carpometacarpal impingement of the little finger. Between 2005 and 2017, 8 patients (1 woman and 7 men) were operated on who had a mean age of 38 years (24–53 years). Seven cases were post-traumatic (malunion) and one was due to septic arthritis. A total of 5 patients were available for a retrospective clinical, functional, and radiological follow-up at a mean of 73 months (23–108 months). Clinical parameters included pain on VAS, grip strength, Quick Disability of Arm, Shoulder and Hand questionnaire, Patient-Rated Wrist Evaluation, and a subjective hand value (0–100%). Fusion was achieved in all cases. Of the 8 patients, one developed complex regional pain syndrome and one had persistent pain that required secondary proximal metacarpal resection. At the last follow-up, all patients were satisfied and reported a significant reduction in pain and improvement in strength. Mean Quick Disability of Arm, Shoulder, and Hand questionnaire, Patient-Rated Wrist Evaluation and subjective hand value were 19/100 points, 21/100 points and 75%, respectively. Our study suggests that the stabilized arthroplasty of the fifth finger, as describe by Dubert, is an efficient and reliable method to reduce pain and improve hand function in patients suffering from carpometacarpal impingement of the little finger. Level of evidence retrospective series, IV

AlphaFold2 is a promising new tool for researchers to predict protein structures and generate high-quality models, with low backbone and global root-mean-square deviation (RMSD) when compared with experimental structures. However, it is unclear if the structures predicted by AlphaFold2 will be valuable targets of docking. To address this question, we redocked ligands in the PDBbind datasets against the experimental co-crystallized receptor structures and against the AlphaFold2 structures using AutoDock-GPU. We find that the quality measure provided during structure prediction is not a good predictor of docking performance, despite accurately reflecting the quality of the alpha carbon alignment with experimental structures. Removing low-confidence regions of the predicted structure and making side chains flexible improves the docking outcomes. Overall, despite high-quality prediction of backbone conformation, fine structural details limit the naive application of AlphaFold2 models as docking targets.

Purpose When referring to enlarged vestibular aqueduct (EVA) we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA) and Pendred Syndrome (PDS), a disease continuum associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases. The study was aimed to analyse the clinical and audiological features of a monocentric cohort of Caucasian patients with NSEVA/PDS, their genetic assessment and morphological inner ear features. Methods We retrospectively reviewed the audiologic, genetic and anamnestic data of 66 patients with NSEVA/PDS followed by our audiology service. Results SLC26A4 mutations was significantly correlated with the presence of PDS rather than NSEVA (p p p = 0.001). Furthermore, patients with PDS showed significantly worse pure tone audiometry (PTA) than patients with NSEVA (p = 0.001). Anatomically normal ears presented significantly better PTA than ears associated with Mondini Malformation or isolated EVA (p Conclusion NSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology. Our findings can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association with thyroid dysfunction.

Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by PRLTS3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in PRLTS3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In PRLTS3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in PRLTS3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided.

Resume L’entorse de l’articulation metacarpo-phalangienne du pouce est une lesion frequente en traumatologie de la main, interessant principalement le ligament lateral ulnaire. Son diagnostic essentiellement clinique necessite imperativement un bilan radiologique et dans certains cas le recours a l’echographie ou l’IRM. Les lesions instables ou avec deplacement d’un fragment osseux sont une indication chirurgicale dans les 4 semaines post traumatiques. Au-dela, il faut privilegier une reconstruction ligamentaire. Le but de cette etude est d’apporter des arguments parfois anciens et des elements plus recents quant au choix therapeutique le mieux adapte en pratique. Dans ce but, nous nous efforcerons de repondre a plusieurs questions : (1) Qu’est-ce qu’une lesion de Stener, en donnant l’historique et sa physiopathologie ; (2) Au-dela de l’examen clinique, quels examens paracliniques proposer en cas de doutes en expliquant notamment la place de l’echographie et de l’IRM ; (3) Quand et qui operer en cas de lesion aigue, sur quels arguments radio cliniques ; (4) Quelles reparations proposer en cas de lesion aigue, en cas de lesion chronique.

Virtual screening using molecular docking is now routinely used for the rapid evaluation of very large ligand libraries. As such, it has become an increasingly common approach in early-stage drug discovery. These screenings generate large amounts of data proportional to the size of the compound library used, which must be stored and filtered before visual analysis. As the size of compound libraries which can feasibly be screened grows, so do the challenges in result management and storage. Here we introduce Ringtail, a new Python tool in the AutoDock Suite for efficient storage and analysis of virtual screening data based on portable SQLite databases. Although Ring- tail is designed to work with AutoDock-GPU and AutoDock Vina out-of-the-box, its modular design allows for easy extension to support input file types from other dock- ing software, different storage solutions, and its incorporation into other applications. Ringtail’s SQLite database output can dramatically reduce the required storage by selecting individual poses to store and by taking advantage of the relational database format. We observed disk usage reductions of between 36-46 fold compared to raw AutoDock-GPU DLG output for a 50-pose docking and, and more than 3 times more efficient than achievable by only the reduction of stored poses. Filtering times are also dramatically reduced, requiring minutes to filter millions of ligands. Thus, Ring- tail a tool that can immediately integrate into existing virtual screening pipelines using AutoDock-GPU and Vina, and both scriptable and modifiable to fit specific user needs.

Background: The Carina system (Cochlear Ltd., Sydney, Australia) is a totally implantable device providing acoustic amplification in adult patients with moderate-to-severe sensorineural or mixed hearing loss. One of the main concerns about such a totally implantable device has been represented by the subcutaneous battery lifespan. The aim of this article is to report the analysis of battery performances in a series of Carina-implanted patients after a long follow up. Methods: In this retrospective study, the technical data of a series of patients implanted with the Carina middle ear implant in our clinic have been analysed, extracting the data from the log of telemetric measures. Results: The mean lifespan cutback was 0.43 h/years (from 0 to 0.71 h/year), with a strong negative significant correlation between the follow-up period and the percentage of battery residual lifespan. Conclusion: The lifespan of the Carina’s battery seems consistent with the manufacturer statement of a pluri-decennial lifespan, avoiding the need of an early surgical substitution and providing a full day of use of the system even after up to 12 years from the implantation.

In the barrel field of the rodent primary somatosensory cortex (S1bf), excitatory cells in layer 2/3 (L2/3) display sparse firing but reliable subthreshold response during whisker stimulation. Subthreshold responses encode specific features of the sensory stimulus, for example, the direction of whisker deflection. According to the canonical model for the flow of sensory information across cortical layers, activity in L2/3 is driven by layer 4 (L4). However, L2/3 cells receive excitatory inputs from other regions, raising the possibility that L4 partially drives L2/3 during whisker stimulation. To test this hypothesis, we combined patch-clamp recordings from L2/3 pyramidal neurons in S1bf with selective optogenetic inhibition of L4 during passive whisker stimulation in both anesthetized and awake head-restrained mice. We found that L4 optogenetic inhibition did not abolish the subthreshold whisker-evoked response nor it affected spontaneous membrane potential fluctuations of L2/3 neurons. However, L4 optogenetic inhibition decreased L2/3 subthreshold responses to whisker deflections in the preferred direction, and it increased L2/3 responses to stimuli in the nonpreferred direction, leading to a change in the direction tuning. Our results contribute to reveal the circuit mechanisms underlying the processing of sensory information in the rodent S1bf.

In recent years, therapeutic peptides (TPs) have gained a lot interest as demonstrated by the 60 peptides approved as drugs in major markets and 150+ peptides currently in clinical trials. However, while small molecule docking is routinely used in rational drug design efforts, docking peptides has proven challenging partly because docking scoring functions, developed and calibrated for small molecules, perform poorly for these molecules. Here, we present Random Forest classifiers trained to discriminate correctly docked peptides. We show that, for a testing set of 47 protein-peptide complexes, structurally dissimilar from the training set and previously used to benchmark AutoDock Vina’s ability to dock short peptides, these Random Forest classifiers improve docking power from ~25% for AutoDock scoring functions to an average of ~70%. These results pave the way for peptide-docking success rates comparable to those of small molecule docking. To develop these classifiers, we compiled the ProptPep37_2021 dataset, a curated, high-quality set of 322 crystallographic protein-peptides complexes annotated with structural similarity information. The dataset also provides a collection of high-quality putative poses with a range of deviations from the crystallographic pose, providing correct and incorrect poses (i.e., decoys) of the peptide for each entry. The ProptPep37_2021 dataset as well as the classifiers presented here are freely available.

In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-π stacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.

The occurrence of compartment syndrome after a viper bite is a rare phenomenon and its treatment remains controversial. We report the case of an 11-year-old boy who developed compartment syndrome of the right upper limb following a viper bite. Decompression by fasciotomy was performed urgently with a good outcome. Surgical decompression for compartment syndrome following a viper bite is not a common treatment according to the literature. Fast access to care and antivenom administration seem to be effective at treating the compartment syndrome without recourse to fasciotomy.

Neuroendocrine adenomas of the middle ear are rare tumors that represent less than 2% of primary tumors of the ear. In this paper, we describe a case of a 40-year-old woman who developed neuroendocrine adenoma of the middle ear. The specific management strategy for this rare tumor is unclear; information in the available literature on the management of this tumor is varied. However, an extensive demolition seems to be the gold standard treatment for this tumor to avoid recurrence and regional metastases in the lymph node or distant metastases. For the present case, we performed an incisional biopsy to confirm the diagnosis, and thereafter, we performed a canal-wall-down tympanoplasty. For cases like the present one, careful long-term clinical and instrumental follow-up is required to monitor progress and facilitate patient recovery.

De novo formation of the double-membrane compartment autophagosome is seeded by small vesicles carrying membrane protein autophagy-related 9 (ATG9), the function of which remains unknown. Here we find that ATG9A scrambles phospholipids of membranes in vitro. Cryo-EM structures of human ATG9A reveal a trimer with a solvated central pore, which is connected laterally to the cytosol through the cavity within each protomer. Similarities to ABC exporters suggest that ATG9A could be a transporter that uses the central pore to function. Moreover, molecular dynamics simulation suggests that the central pore opens laterally to accommodate lipid headgroups, thereby enabling lipids to flip. Mutations in the pore reduce scrambling activity and yield markedly smaller autophagosomes, indicating that lipid scrambling by ATG9A is essential for membrane expansion. We propose ATG9A acts as a membrane-embedded funnel to facilitate lipid flipping and to redistribute lipids added to the outer leaflet of ATG9 vesicles, thereby enabling growth into autophagosomes.

The AutoDock suite provides a comprehensive toolset for computational ligand docking and drug design and development. The suite builds on 30 years of methods development, including empirical free energy force fields, docking engines, methods for site prediction, and interactive tools for visualization and analysis. Specialized tools are available for challenging systems, including covalent inhibitors, peptides, compounds with macrocycles, systems where ordered hydration plays a key role, and systems with substantial receptor flexibility. All methods in the AutoDock suite are freely available for use and reuse, which has engendered the continued growth of a diverse community of primary users and third-party developers. This article is protected by copyright. All rights reserved.

Introduction Large cutaneous defects exposing the whole tibial crest are difficult to cover and are conventionally best treated with free flaps. This article describes a technical modification of the adipofascial flap in this indication. Methods The “flip-flap” is vascularized by the posterior tibial artery perforators harvested on the medial aspect of the leg. The hypodermal and fascial tissue is de-epidermized and elevated from the posterior midline up to the medial edge of the soleus muscle, then folded over the exposed tibial crest like a page of a book. Results A 27 × 6 cm effect was successfully covered on a 72 year-old patient with vascular status precluding free flap. The flap healed by day 21. Discussion/conclusion This technical modification is simple and allows coverage of large tibial crest skin defect when a free flap is not possible.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse – small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1 – a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical, and biophysical analyses indicate that this compound increases LYPLAL1’s catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

Diversity Oriented Clicking (DOC) is a discovery method geared towards the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core “SuFExable” hubs – exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) – enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented beta-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the biological function – another key objective of click chemistry – of this new scaffold as covalent inhibitors of human neutrophil elastase (hNE). The ease of diversification of SASFs through click pathways, enabling rapid access to biologically important molecules, further validates Diversity Oriented Clicking as an effective and robust method for lead discovery.

The study aims to assess the benefit of sequential bilateral cochlear implantation in children with congenital bilateral profound hearing loss, submitted to the first implant at an early age.We enrolled all the bilateral sequential cochlear implanted children who received the first implant within 48 months and the second within 12 years of age at our Institution. The children were submitted to disyllabic word recognition tests and Speech Reception Threshold (SRT) assessment using the OLSA matrix sentence test with the first implanted device (CI1), with the second implanted device (CI2), and with both devices (CIbil). Furthermore, we measured the datalogging of both devices. Then we calculated the binaural SRT gain (b-SRTgain) and checked the correlations between speech perception results and the b-SRTgain with the child's age at CI1 and CI2, DELTA and the datalogging reports.With the bilateral electric stimulation, we found a significant improvement in disyllabic word recognition scores and in SRT. Moreover, the datalogging showed no significant differences in the time of use of CI1 and CI2. We found significant negative correlations between speech perception abilities with CI2 and age at CI2 and DELTA, and between the SRT with CI1 and the b-SRTgain.From this study we can conclude that in a sequential CI procedure, even if a short inter-implant delay and lower ages at the second surgery can lead to better speech perception with CI2, children can benefit from bilateral stimulation independently of age at the second surgery and the DELTA.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub ( https://covid19forecasthub.org/ ) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Neural activity in the hippocampus is known to reflect how animals move through an environment(1,2). Although navigational behaviour may show considerable stability(3–6), the tuning stability of individual hippocampal neurons remains unclear(7–12). Here we used wireless calcium imaging to longitudinally monitor the activity of dorsal CA1 hippocampal neurons in freely flying bats performing highly reproducible flights in a familiar environment. We find that both the participation and the spatial selectivity of most neurons remain stable over days and weeks. We also find that apparent changes in tuning can be largely attributed to variations in the flight behaviour of the bats. Finally, we show that bats navigating in the same environment under different room lighting conditions (lights on versus lights off) exhibit substantial changes in flight behaviour that can give the illusion of neuronal instability. However, when similar flight paths are compared across conditions, the stability of the hippocampal code persists. Taken together, we show that the underlying hippocampal code is highly stable over days and across contexts if behaviour is taken into account.

Tendo em vista a preponderância da utilização de memórias da infância e da adolescência na literatura contemporânea e a problematização da experiência do colonialismo português na África, este artigo tem como enfoque a análise dessas memórias em relação ao espaço do continente africano. Para tanto, optou-se por utilizar como corpus os seguintes romances: Caderno de memórias coloniais (2009), de Isabela Figueiredo, A árvore das palavras (1997), de Teolinda Gersão, e O retorno (2012), de Dulce Maria Cardoso. Essas narrativas enfatizam o processo de formação desses sujeitos, que ocorre em concomitância a um momento histórico extremamente violento como é o colonialismo. Compreende-se essas memórias como subterrâneas (POLLAK, 1989) devido ao fato de assumirem a via da contramão do discurso histórico oficial. Dessa forma, o despertar para si e para o mundo acontece pelos olhos de quem vê com estranhamento muitas das ações tidas como naturais por adultos devido ao fato de estarem menos condicionados a um sistema disciplinar (FOUCAULT, 2004). Compõem o aporte teórico deste estudo autores como Maurice Halbwachs, Michael Pollak, Michel Foucault, entre outros.

Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at cortical synapses between pyramidal cells (PCs) and fast-spiking interneurons (FS INs) in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory (E/I) balance in specific circuits is a key pathogenic mechanism. Here, we investigated the cortical layer 2/3 (L2/3) feedback inhibition microcircuit involving somatostatin-expressing (SOM) INs in FHM1 mice of both sexes carrying a gain-of-function mutation in Ca

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages.