Neural representations of beat and rhythm in motor and association regions.

Humans perceive a pulse, or beat, underlying musical rhythm. Beat strength correlates with activity in the basal ganglia and supplementary motor area, suggesting these regions support beat perception. However, the basal ganglia and supplementary motor area are part of a general rhythm and timing network (regardless of the beat) and may also represent basic rhythmic features (e.g. tempo, number of onsets). To characterize the encoding of beat-related and other basic rhythmic features, we used representational similarity analysis. During functional magnetic resonance imaging, participants heard 12 rhythms-4 strong-beat, 4 weak-beat, and 4 nonbeat. Multi-voxel activity patterns for each rhythm were tested to determine which brain areas were beat-sensitive: those in which activity patterns showed greater dissimilarities between rhythms of different beat strength than between rhythms of similar beat strength. Indeed, putamen and supplementary motor area activity patterns were significantly dissimilar for strong-beat and nonbeat conditions. Next, we tested whether basic rhythmic features or models of beat strength (counterevidence scores) predicted activity patterns. We found again that activity pattern dissimilarity in supplementary motor area and putamen correlated with beat strength models, not basic features. Beat strength models also correlated with activity pattern dissimilarities in the inferior frontal gyrus and inferior parietal lobe, though these regions encoded beat and rhythm simultaneously and were not driven by beat alone.

Spinal muscular atrophy carrier screening program: awareness and attitude of healthcare professionals in Turkey.

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease caused by variants in the SMN1 gene, leading to progressive muscle weakness. The carrier frequency of SMN1 gene variants, including variant and copy number variations, is estimated to be around 1 in 50 people, while the global prevalence of SMA is 1-3 per 10,000 live births. In response to the increasing carrier proportion, especially due to consanguineous marriages, Turkey launched the SMA Carrier Screening Program in 2021. Notably, recent SMA cases have been observed in the children of healthcare workers who did not undergo carrier screening, prompting us to evaluate their awareness of this program. After receiving ethics approval, 1,322 healthcare professionals completed a 15-item survey based on the SMA Carrier Screening Guidelines. Of these, 5.8% were unaware of SMA, and 26% lacked information about the national screening program. Awareness of the screening program was significantly lower among secondary and tertiary healthcare professionals compared to primary healthcare professionals (p < 0.0001) and among non-physician healthcare professionals compared to physicians (p < 0.0001). Additionally, a serious lack of knowledge was observed concerning the parts of the screening covering the pregnancy period. Although there is generally high awareness of the SMA Carrier Screening Program among healthcare professionals, significant knowledge gaps exist. These findings highlight the need for increased efforts to more effectively deliver screening programs and continue the education of healthcare professionals. Education and awareness campaigns can enhance program awareness and effectiveness, reach wider audiences, and contribute to preventive measures for the health of future generations.

A newly discovered anatomical abdominal aorta anomaly; "Arax anomaly".

BACKGROUND: Abdominal aorta (AA) is part of descending aorta. It faces with variety of malformations during embryogenic period. CASE PRESENTATION: A 35 years old woman with previous history of long term diabetes mellitus had experiment of one non-complicated successful pregnancy under surgical delivery. She referred to achieve health services due to de-novo postprandial abdominal pain and bilateral lower limbs exertional claudication. RESULTS: Following normal findings in upper esophago-gastro-duodenal study, angiographic evaluation of AA showed novel aortic variation in which celiac trunk, superior mesenteric artery, and bilateral renal arteries originated from one common arterial root. This anomaly has not been seen whether in alive or cadaveric explorations until this presentation. CONCLUSION: Precise arterial mapping is highly recommended when any attributed procedure is indicated.

Spinal presentations in children with spinal muscular atrophy type 1 following gene therapy treatment with onasemnogene abeparvovec - The SMA REACH UK network experience.

Spinal muscular atrophy (SMA) is a neuromuscular disorder of mainly early onset and variable severity. Prior to the introduction of disease modifying therapies (DMTs), children with SMA type 1 typically died before 2 years of age and management was primarily palliative. Onasemnogene abeparvovec (OA), nusinersen, and risdiplam are novel DMTs which ameliorate the effects of the underlying genetic defect at least partially making SMA a treatable condition. Survival and achievement of previously unmet developmental milestones result in treated SMA type 1 children spending more time upright than expected based on the natural history of the treatment-naïve condition. Consequently, spinal asymmetry and kyphosis, features not typically seen in untreated SMA type 1 children due to early mortality, are increasingly common complications. Precise data regarding their prevalence, severity, and management are currently limited. This study describes the spinal features and management in 75 children with SMA type 1 who received OA between March 2021 and December 2022. Retrospective analysis from SMA REACH UK data showed that 44/75 (59 %) clinically had spinal asymmetry and 37 (49 %) had kyphosis. This study aims to raise awareness of this important feature as part of the changed natural history of SMA type 1 post OA treatment.

Profiling neuroinflammatory markers and response to nusinersen in paediatric spinal muscular atrophy.

Neuroinflammation is an emerging clinical feature in spinal muscular atrophy (SMA). Characterizing neuroinflammatory cytokines in cerebrospinal fluid (CSF) in SMA and their response to nusinersen is important for identifying new biomarkers and understanding the pathophysiology of SMA. We measured twenty-seven neuroinflammatory markers in CSF from twenty SMA children at different time points, and correlated the findings with motor function improvement. At baseline, MCP-1, IL-7 and IL-8 were significantly increased in SMA1 patients compared to SMA2, and were significantly correlated with disease severity. After six months of nusinersen treatment, CSF levels of eotaxin and MIP-1ß were markedly reduced, while IL-2, IL-4 and VEGF-A were increased. The decreases in eotaxin and MIP-1ß were associated with changes in motor scores in SMA1. We also detected a transient increase in MCP-1, MDC, MIP-1α, IL-12/IL-23p40 and IL-8 after the first or second injection of nusinersen, followed by a steady return to baseline levels within six months. Our study provides a detailed profile of neuroinflammatory markers in SMA CSF. Our data confirms the potential of MCP-1, eotaxin and MIP-1ß as new neuroinflammatory biomarkers in SMA1 and indicates the presence of a subtle inflammatory response to nusinersen during the early phase of treatment.

Real-World Data in Children with Spinal Muscular Atrophy Type 1 on Long-Term Ventilation Receiving Gene Therapy: A Prospective Cohort Study.

Patients with spinal muscular atrophy type 1 (SMA-1) requiring invasive ventilation can be eligible for gene therapy if they tolerate at least 8 h off ventilation per day. We aimed to assess the short-term safety and efficacy of gene therapy (onasemnogene abeparvovec; Zolgensma) on respiratory function in SMA-1 patients ventilated via tracheostomy pre-gene therapy. A prospective cohort study included 22 patients. Patients were weaned off ventilation for at least 8 h daily by optimizing ventilator settings and duration, using cough augmentation, managing excessive airway secretions, enhancing nutrition, screening for respiratory bacterial colonization, and treating infections. Gene therapy was administered at a median age of 26 (Q1: 18, Q3: 43) months with a mean follow-up period of 7.64 (SD: 6.50) months. Gene therapy was safe and effective in resolving paradoxical breathing, improving cough ability, reducing airway secretions, and enhancing CHOP-INTEND scores. The clinical assessment and management implemented pre-gene therapy were effective in safely weaning patients for at least 8 h off ventilation daily. Gene therapy at a late age was safe and effective over the short-term period; however, long-term follow-up is recommended. In conjunction with gene therapy, high-quality clinical care is beneficial and should be paired with gene therapy.

A Delayed Presentation of Superior Mesenteric Artery Syndrome Treated With Robotic-Assisted Strong Procedure.

Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is a rare condition resulting from compression of the third portion of the duodenum between the aorta and the superior mesenteric artery. When symptomatic, this compression may result in nausea, vomiting, epigastric discomfort, and weight loss, requiring clinical attention and imaging to make the diagnosis. Typically, SMA syndrome presents in young females and is associated with an underlying condition such as anorexia nervosa, cachexia, postoperative development after scoliosis surgery, etc. In this report, we present the case of an atypical delayed presentation of SMA syndrome in an 84-year-old male who had epigastric pain, nausea, intermittent vomiting, and a 30-pound weight loss over two years. SMA syndrome was diagnosed on a computed tomography (CT) scan by a decreased angle between the superior mesenteric artery and abdominal aorta, and treatment with a robotic-assisted strong procedure was performed. The patient was followed postoperatively in the clinic and tolerated the procedure well.

Aberrant connectivity of the lateralized readiness system in non-syndromic congenital mirror movements.

OBJECTIVES: Non-syndromic CMM has a complex phenotype. Abnormal corpus callosum and corticospinal tract processes are suggested mechanisms of the mirror movements. To further explore behavioural and neural phenotype(s) the present study tests the hypothesis that the response readiness network comprising supplementary motor area (SMA) and connections with motor cortex (M1) functions abnormally in CMM. METHODS: Twelve participants with (non-syndromic) CMM and a control group (n = 28) were tested on a probabilistic Go-NoGo task while electroencephalography (EEG) was recorded to assess possible group differences in lateralized readiness of voluntary hand movements together with measures of SMA-M1 functional connectivity. RESULTS: The CMM group demonstrated delayed lateralized readiness and stronger functional connectivity between left-brain SMA-M1 regions. Connectivity strength was correlated with measures of behavioural performance but not with extent of mirroring. CONCLUSIONS: Abnormalities in brain processes upstream of movement output likely reflect neurocompensation as a result of lifelong experience with mirroring in CMM. SIGNIFICANCE: These findings extend the known neural abnormalities in CMM to include brain networks upstream from those involved in motor output and raise the question of whether neurocompensatory plasticity might be involved.

Morphology of True Lumen and Surgical Outcomes of Acute Type A Aortic Dissection Repair with Superior Mesenteric Artery Malperfusion.

BACKGROUND: Acute type A aortic dissection (ATAD) can cause visceral malperfusion. Central aortic repair may resolve malperfusion but some require further intervention. This study aimed to review outcomes after ATAD presenting with visceral malperfusion and to evaluate the predictive value of true lumen (TL) morphologies in preoperative computed tomography (CT) for persistent superior mesenteric artery (SMA) ischemia after central repair. METHODS: Open surgical repair of ATAD performed between 2008-2023 at our institution was retrospectively reviewed. Patients with central repair first approach were included for analysis. Patients with inadequate CT scan data to assess luminal morphology were excluded. TL morphology was reviewed at the diaphragm level and categorized as concave or convex. The malperfusion pattern, static vs. dynamic, was assessed at SMA orifices. Data were analyzed using a contingency table and parametric and nonparametric methods. RESULTS: A total of 543 open ATAD repairs were performed. Of these, 263 patients were eligible under the inclusion criteria and, subsequently, analyzed. The mean age was 57±14, and 83 (31%) patients were female. SMA malperfusion developed in 42 (16%) of the 263 patients, including 26 patients with dynamic obstruction, 6 patients with static obstruction, and 10 patients with dynamic and static obstruction. Regarding dissection flap morphology, 78 patients (30%) exhibited concave morphology, while 185 patients (70%) had convex morphology. TL diameter was significantly larger in convex than concave (concave: 6 mm vs. convex: 16 mm, p<0.0001). The prevalence of clinically significant SMA malperfusion was higher in concave-shaped TL (concave 41% vs. convex 5%, p<0.0001). Dynamic SMA obstruction was more frequently observed in the concave group (concave 72% vs. convex 30%, P <0.001). However, significantly more patients with convex-shaped TL required bowel resection than concave (concave 13% vs. convex 70%, p<0.001). The operative mortality was higher in the convex group, although statistically insignificant (concave 19% vs. convex 50%, p=0.0059). CONCLUSION: Central repair first strategy could resolve more than 80% of SMA malperfusion in ATAD when the TL is concave-shaped at the level of the diaphragm. Convex-shaped TL morphology was associated with less incidence of SMA malperfusion but was more frequently associated with static obstruction and higher incidence of bowel resection. The morphology evaluation of the TL at the diaphragm level may be simple and beneficial for surgical planning for ATAD presenting with SMA malperfusion.

Postnatal management of preterm infants with spinal muscular atrophy: experience from German newborn screening.

BACKGROUND: The introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 (SMN2) copies. RESULTS: Twelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1-36.8) and birth weight of 2022 g (range: 645-3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 (SMN1) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity (n = 2), sepsis (n = 2), and jaundice (n = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term. CONCLUSIONS: Premature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn.

Proof of Concept of a New Revision Procedure for Ceramic Inlays of Acetabular Cups Using a Shape-Memory Alloy Actuator System.

The revision of ceramic inlays of acetabular cups is a challenging surgical procedure. The mechanical impact during the inlay extraction process can damage the ceramic or metal cup rim. To avoid these risks, a concept for a new revision procedure was developed. It is based on an actuator system, which allows a non-destructive release of the ceramic inlay. To integrate the actuator system, different design concepts of acetabular cup components were investigated, and an actuator based on shape-memory alloy (SMA) wires was developed. The process chain for the actuator, starting from nickel-titanium wires manufactured into the actuator geometry by laser welding and thermo-mechanical treatment for the shape setting process up to the functionality evaluation of the actuator system, was implemented on a laboratory scale. The new revision procedure is based on a phase transformation of the SMA wire actuator, which was obtained through two methods-applying an electrical current by an instrument and rinsing the wire with heated water. The phase transformation of the actuator resulted in a contraction between 3.2% and 4.3% compared to its length after pre-stretching and was able to release the ceramic inlay from the cup. Therefore, the developed actuator design and process chain is a proof of concept towards a new revision procedure for modular acetabular cups.

The spinal muscular atrophy gene product regulates actin dynamics.

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by low levels of the Survival of Motoneuron (SMN) protein. SMN interacts with and regulates the actin-binding protein profilin2a, thereby influencing actin dynamics. Dysfunctional actin dynamics caused by SMN loss disrupts neurite outgrowth, axonal pathfinding, and formation of functional synapses in neurons. Whether the SMN protein directly interacts with and regulates filamentous (F-) and monomeric globular (G-) actin is still elusive. In a quantitative single cell approach, we show that SMN loss leads to dysregulated F-/G-actin fractions. Furthermore, quantitative assessment of cell morphology suggests an F-actin organizational defect. Interestingly, this is mediated by an interaction of SMN with G- and F-actin. In co-immunoprecipitation, in-vitro pulldown and co-localization assays, we elucidated that this interaction is independent of the SMN-profilin2a interaction. Therefore, we suggest two populations being relevant for functional actin dynamics in healthy neurons: SMN-profilin2a-actin and SMN-actin. Additionally, those two populations may influence each other and therefore regulate binding of SMN to actin. In SMA, we showed a dysregulated co-localization pattern of SMN-actin which could only partially rescued by SMN restoration. However, dysregulation of F-/G-actin fractions was reduced by SMN restoration. Taken together, our results suggest a novel molecular function of SMN in binding to actin independent from SMN-profilin2a interaction.

Functional connectivity of sensorimotor network before and after surgery in the supplementary motor area.

After resective glioma surgery in the Supplementary Motor Area (SMA), patients often experience a transient disturbance of the ability to initiate speech and voluntary motor actions, known as the SMA syndrome (SMAS). It has been proposed that enhanced interhemispheric functional connectivity (FC) within the sensorimotor system may serve as a potential mechanism for recovery, enabling the non-resected SMA to assume the function of the resected region. The purpose of the present study was to investigate the extent to which changes in FC can be observed in patients after resolution of the SMAS. Eight patients underwent resection of left SMA due to suspected gliomas, resulting in various levels of the SMA syndrome. Resting-state functional MR images were acquired prior to the surgery and after resolution of the syndrome. At the group level we found an increased connectivity between the unaffected (right) SMA and the primary motor cortex on the same side following surgery. However, no significant increase in interhemispheric connectivity was observed. These findings challenge the prevailing notion that increased interhemispheric FC serves as the only mechanism underlying recovery from SMA syndrome and suggest the presence of one or more alternative mechanisms.

circ_SMA4 promotes gastrointestinal stromal tumors malignant progression by sponging miR-494-3p/KIT axis and activating JAK/STAT pathway.

Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are implicated in the development and progression of various tumors. The aim of this study was to investigate the effects of circ_SMA4 in Gastrointestinal Stromal Tumors (GISTs) malignant progression. Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in GISTs. The effect of circ_SMA4 on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo settings. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_SMA4/miR-494-3p/ KIT axis. The results revealed that circ_SMA4 was significantly upregulated in GISTs, and exhibited high diagnostic efficiency with an AUC of 0.9824 (P < 0.01). circ_SMA4 promoted cell proliferation, invasion, migration, while inhibiting apoptosis in GISTs cells, both in vitro and in vivo. Silencing circ_SMA4 partially inhibited GISTs malignant progression. Additionally, circ_SMA4 acted as a competing endogenous RNA (ceRNA) by targeting miR-494-3p, and KIT was identified as a functional gene for miR-494-3p in GISTs. Furthermore, the results confirmed that circ_SMA4/miR-494-3p/ KIT axis plays a role in activating the JAK/STAT signaling pathway in GISTs. Therefore, for the first time, we have identified and emphasized that circ_SMA4 is significantly upregulated and plays an oncogenic role in GISTs by sponging miR-494-3p to activate the KIT/JAK/STAT pathway. These findings underscore circ_SMA4 may serve as a novel diagnostic biomarker and therapeutic target for GISTs.

An early Transcriptomic Investigation in Adult Patients with Spinal Muscular Atrophy Under Treatment with Nusinersen.

Spinal muscular atrophy (SMA) is a rare degenerative disorder with loss of motor neurons caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, was approved for SMA treatment to compensate the deficit of the encoded protein SMN by modulating the pre-mRNA splicing of SMN2, the centromeric homologous of SMN1, thus inducing the production of a greater amount of biologically active protein. Here, we reported a 10-month transcriptomics investigation in 10 adult SMA who received nusinersen to search for early genetic markers for clinical monitoring. By comparing their profiles with age-matched healthy controls (HC), we also analyzed the changes in miRNA/mRNAs expression and miRNA-target gene interactions possibly associated with SMA. A multidisciplinary approach of HT-NGS followed by bioinformatics/biostatistics analysis was applied. Within the study interval, those SMA patients who showed some clinical improvements were characterized by having the SMN2/SMN1 ratio slightly increased over the time, while in the stable ones the ratio decreased, suggesting that the estimation of SMN2/SMN1 expression may be an early indicator of nusinersen efficacy. On the other hand, the expression of 38/147 genes/genetic regions DE at T0 between SMA and HC like TRADD and JUND resulted "restored" at T10. We also confirmed the dysregulation of miR-146a(-5p), miR-324-5p and miR-423-5p in SMA subjects. Of interest, miR-146a-5p targeted SMN1, in line with experimental evidence showing the key role of astrocyte-produced miR-146a in SMA motor neuron loss. Molecular pathways such as NOTCH, NF-kappa B, and Toll-like receptor signalings seem to be involved in the SMA pathogenesis.

Evaluating the clinical efficacy of a long-read sequencing-based approach for carrier screening of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1, which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the "2 + 0" carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA.

Conformations of membrane human immunodeficiency virus (HIV-1) envelope glycoproteins solubilized in Amphipol A18 lipid-nanodiscs.

Upon binding to the host cell receptor, CD4, the pretriggered (State-1) conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer undergoes transitions to downstream conformations important for virus entry. State 1 is targeted by most broadly neutralizing antibodies (bNAbs), whereas downstream conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. Extraction of Env from the membranes of viruses or Env-expressing cells disrupts the metastable State-1 Env conformation, even when detergent-free approaches like styrene-maleic acid lipid nanoparticles (SMALPs) are used. Here, we combine three strategies to solubilize and purify mature membrane Envs that are antigenically native (i.e., recognized by bNAbs and not pNAbs): (1) solubilization of Env with a novel amphipathic copolymer, Amphipol A18; (2) use of stabilized pretriggered Env mutants; and (3) addition of the State-1-stabilizing entry inhibitor, BMS-806. Amphipol A18 was superior to the other amphipathic copolymers tested (SMA and AASTY 11-50) for preserving a native Env conformation. A native antigenic profile of A18 Env-lipid-nanodiscs was maintained for at least 7 days at 4°C and 2 days at 37°C in the presence of BMS-806 and was also maintained for at least 1 h at 37°C in a variety of adjuvants. The damaging effects of a single cycle of freeze-thawing on the antigenic profile of the A18 Env-lipid-nanodiscs could be prevented by the addition of 10% sucrose or 10% glycerol. These results underscore the importance of the membrane environment to the maintenance of a pretriggered (State-1) Env conformation and provide strategies for the preparation of lipid-nanodiscs containing native membrane Envs.IMPORTANCEThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) mediate virus entry into the host cell and are targeted by neutralizing antibodies elicited by natural infection or vaccines. Detailed studies of membrane proteins like Env rely on purification procedures that maintain their natural conformation. In this study, we show that an amphipathic copolymer A18 can directly extract HIV-1 Env from a membrane without the use of detergents. A18 promotes the formation of nanodiscs that contain Env and membrane lipids. Env in A18-lipid nanodiscs largely preserves features recognized by broadly neutralizing antibodies (bNAbs) and conceals features potentially recognized by poorly neutralizing antibodies (pNAbs). Our results underscore the importance of the membrane environment to the native conformation of HIV-1 Env. Purification methods that bypass the need for detergents could be useful for future studies of HIV-1 Env structure, interaction with receptors and antibodies, and immunogenicity.

Fiberoptic endoscopic evaluation of swallowing (FEES) in children with spinal muscular atrophy type 1: feasibility, swallowing safety and efficacy, and dysphagia phenotype.

PURPOSE: Although dysphagia is a common symptom among patients with Spinal Muscular Atrophy Type 1 (SMA1), scant data exist on the application of Fiberoptic Endoscopic Evaluation of Swallowing (FEES) in this population. The aim was to analyze FEES feasibility, swallow safety and efficacy, dysphagia phenotype, and agreement with VideoFluoroscopic Swallow Study (VFSS) in children with symptomatic, medication-treated SMA1 and oral feeding. METHODS: 10 children with SMA1 underwent FEES. Six patients had also a VFSS. Two clinicians independently rated FEES and VFSS videos. Swallowing safety was assessed using the Penetration-Aspiration scale (PAS). Dysphagia phenotypes were defined according to the classification defined by Warnecke et al. Swallowing efficacy was evaluated with the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS) in FEES, whereas pharyngeal residue was rated as present or absent in VFSS. RESULTS: FEES was performed in all children without complications. Four children tolerated bolus trials during FEES, in 4 children swallowing characteristics were inferred based on post-swallow residues, while 2 children refused to eat and only saliva management was assessed. The dysphagia phenotype of predominance of residue in the piriform sinuses was documented in 7/8 children. The PAS score was < 3 in 3 children and > 5 in one child. Swallowing efficacy was impaired in 8/8 children. VFSS showed complete agreement with FEES. CONCLUSIONS: FEES is a feasible examination in children with SMA1. Swallowing safety and efficacy are impaired in nearly all patients with strong agreement between FEES and VFSS. Dysphagia is characterized by the predominance of residue in the piriform sinus.

The Potential Diagnostic Utility of SMAD4 and ACCS in the Context of Inflammation in Type 2 Diabetes Mellitus Patients.

The search for new parameters for the prediction of type 2 diabetes mellitus (T2DM) or its harmful consequences remains an important field of study. Depending on the low-grade inflammatory nature of diabetes, we investigated three proteins in T2DM patients: 1-aminocyclopropane-1-carboxylate synthase (ACCS), granulocyte-colony-stimulating factor (G-CSF), and Sma Mothers Against Decapentaplegic homolog-4 (SMAD4). In brief, sixty T2DM and thirty healthy controls had their serum levels of ACCS, G-CSF, SMAD4, and insulin tested using the ELISA method. The insulin resistance (IR) parameter (HOMA2IR), beta-cell function percentage (HOMA2%B), and insulin sensitivity (HOMA2%S) were all determined by the Homeostasis Model Assessment-2 (HOMA2) calculator. The predictability of these protein levels was investigated by neural network (NN) analysis and was associated with measures of IR. Based on the results, ACCS, G-CSF, and SMAD4 increased significantly in the T2DM group compared with the controls. Their levels depend on IR status and inflammation. The multivariate GLM indicated the independence of the levels of these proteins on the covariates or drugs taken. The receiver operating characteristic area under the curve (AUC) for the prediction of T2DM using NN analysis is 0.902, with a sensitivity of 71.4% and a specificity of 93.8%. The network predicts T2DM well with predicted pseudoprobabilities over 0.5. The model's predictive capability (normalized importance) revealed that ACCS is the best model (100%) for the prediction of T2DM, followed by G-CSF (75.5%) and SMAD4 (69.6%). It can be concluded that ACCS, G-CSF, and SMAD4 are important proteins in T2DM prediction, and their increase is associated with the presence of inflammation.

Specific peptides targeting the myocardiocyte are prognostic markers for heart attack: Function of α-SMA protein.

Myocardial infarction (MI) is a serious cardiovascular disease that often results in a significant decline in heart function and associated complications. α-SMA (α-smooth muscle cell actin) is an important biomarker in the process of cardiac remodeling and repair, and its expression level is closely related to myocardial remodeling and prognosis. Therefore, the purpose of this study was to investigate the potential of nanoparticles containing cardiomyocyte targeting peptides in predicting prognosis and α-SMA protein expression after myocardial infarction, with a view to providing new therapeutic strategies and clinical guidelines. In this study, a novel targeting nanoparticle was constructed, using cardiomyocyte specific peptides as targeting ligands, and characterized by loading different drugs. Subsequently, a mouse model of myocardial infarction was used to systematically evaluate the effect of nanoparticles on α-SMA protein expression and prognosis prediction ability after MI. The expression level of α-SMA was analyzed by Western blot and immunohistochemistry, and the prognosis was evaluated by cardiac function assessment. The study found that nanoparticles containing cardiomyocyte targeting peptides significantly increased α-SMA expression levels and improved heart function in animal models of myocardial infarction. Compared with the control group, the application of targeted nanoparticles was closely related to the level of myocardial cell repair and fibrosis, and could effectively predict the prognosis after myocardial infarction. Therefore, nanoparticles containing cardiomyocyte targeting peptides can not only effectively improve the expression of α-SMA, but also serve as an important prognostic tool after myocardial infarction.