Type IIB Research Articles

Effects of chronic alcohol intoxication on aerobic exercise-induced adaptations in female mice.

Chronic alcohol intoxication decreases muscle strength/function and causes mitochondrial dysfunction. Aerobic exercise training improves mitochondrial oxidative capacity and increases muscle mass and strength. Presently, the impact of chronic alcohol on aerobic exercise-induced adaptations was investigated. Female C57BL/6Hsd mice were randomly assigned to one of four groups: control sedentary (CON SED; n = 26), alcohol sedentary (ETOH SED; n = 27), control exercise (CON EX; n = 28), and alcohol exercise (ETOH EX; n = 25). Exercise mice had running wheel access for 2 h a day, 7 days a week. All mice were fed either control or an alcohol-containing liquid diet. Grip strength testing and EchoMRI were performed before and after the interventions. After 6 wk, hindlimb muscles were collected for molecular analyses. A subset of mice performed a treadmill run to fatigue (RTF), then abstained from alcohol for 2 wk and repeated the RTF. Alcohol decreased lean mass and forelimb grip strength compared with control-fed mice. Alcohol blunted the exercise-induced increase in muscle mass (plantaris and soleus), type IIa fiber percentage in the plantaris, and run time to fatigue. Mitochondrial markers (Citrate synthase activity and Complex I-IV, COXIV and Cytochrome C protein expression) were increased with exercise regardless of ETOH in the gastrocnemius but not tibialis anterior muscle. Two weeks of alcohol abstinence improved RTF time in ETOH EX but not in ETOH SED. These data suggest that alcohol impairs some exercise-induced adaptations in skeletal muscle, but not all were negatively affected, indicating that exercise may be a beneficial behavior even while consuming alcohol.NEW & NOTEWORTHY Alcohol consumption during an aerobic exercise training period prevented training-induced increases in run to fatigue time and grip strength. Cessation of alcohol allowed for recovery of endurance performance within 2 wk. The worsened exercise performance after alcohol was unrelated to impairments in markers of mitochondrial health. Therefore, some adaptations to exercise training are impaired with alcohol use (endurance performance, muscle growth, and strength), while others remain mostly unaffected (mitochondrial health).

The planar limit of the N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\mathcal{N} $$\\end{document} = 2 E-theory: numerical calculations and the large λ expansion

We study correlation functions of local operators and Wilson loop expectation values in the planar limit of a 4d N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\mathcal{N} $$\\end{document} = 2 superconformal SU(N) YM theory with hypermultiplets in the symmetric and antisymmetric representations of the gauge group. This so called E theory is closely related to N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\mathcal{N} $$\\end{document} = 4 SYM and has a holographic description in terms of a ℤ2 orientifold of AdS5 × S5. Using recent matrix model results based on supersymmetric localization we develop efficient numerical methods to calculate two- and three-point functions of certain single trace operators as well as 1/2-BPS Wilson loop expectation values as a function of the ’t Hooft coupling λ. We use our numerical results to arrive at simple analytic expressions for these correlators valid up to sixth order in the λ−1/2 strong coupling expansion. These results provide explicit field theory predictions for the α′ corrections to the supergravity approximation of type IIB string theory on the AdS5 × S5/ℤ2 orientifold.

Factors associated with false lumen changes in patients with superior mesenteric artery dissection.

False lumen changes (FLCs) are the main reference for the prognosis judgment and treatment plan selection for type IIa superior mesenteric artery dissection (SMAD). For this retrospective study, 55 patients with symptomatic type IIa SMAD were included. Computational fluid dynamics (CFD) analysis was used to explore the hemodynamic basis of FLCs. Correlation and multiple linear regression analyses were performed to identify clinical, morphological and hemodynamic factors associated with FLCs. The FLCs of patients with successful conservative treatment (n = 29) are significantly higher than those with failed conservative treatment (n = 26) (58.5 ± 21.1% vs 10.9 ± 17.4%, p < 0.0001). Positive correlations were seen between FLCs and the morphological parameters false lumen length (FLL)/dissection entrance length (DEL) and FLL. In terms of hemodynamic parameters, negative correlations were seen between FLCs and time-averaged wall shear stress (TAWSS), vorticity, and high areas of TAWSS and vorticity, whereas positive correlations were seen between FLCs and oscillatory shear index (OSI), relative residence time (RRT), and high areas of OSI and RRT. Multiple linear regression analysis identified symptom duration (odds ratio [OR], 0.93; 95% CI, 0.91-0.96; p < 0.0001), FLL/DEL (OR, 1.30; 95% CI, 1.01-1.67; p = 0.044), and high RRT area (OR, 2.03; 95% CI, 1.48-2.78; p < 0.0001) as predictors of FLCs. The clinical predictor symptom duration, morphological factor FLL/DEL, and the hemodynamic factor high RRT area can serve as predictors of FLCs in patients with symptomatic type IIa SMAD.

R7-branes as charge conjugation operators

R7-branes are a class of recently discovered nonsupersymmetric real codimension-two duality defects in type IIB string theory predicted by the swampland cobordism conjecture. For type IIB realizations of 6D SCFTs with N=(2,0) supersymmetry, wrapping an R7-brane “at infinity” leads to a topological operator associated with a zero-form charge conjugation symmetry that squares to the identity. Similar considerations hold for those theories obtained from further toroidal compactification, but this can be obstructed by bundle curvature effects. Using some minimal data on the topological sector of the R7-branes, we extract the associated fusion rules for these charge conjugation operators. More broadly, we sketch a top down realization of various topological operators/interfaces associated with C, R, and T transformations. We also use holography to provide strong evidence for the existence of the R7-brane which is complementary to the cobordism conjecture. Similar considerations apply to other string-realized QFTs with symmetry operators constructed via nonsupersymmetric branes which carry a conserved charge. Published by the American Physical Society 2024

Gluon scattering in AdS at finite string coupling from localization

We consider gluons scattering in Type IIB string theory on AdS5 × S5/ℤ2 in the presence of D7 branes, which is dual to the flavor multiplet correlator in a certain 4d N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\mathcal{N} $$\\end{document} = 2 USp(2N) gauge theory with SO(8) flavor symmetry and complexified coupling τ. We compute this holographic correlator in the large N and finite τ expansion using constraints from derivatives of the mass deformed sphere free energy, which we compute to all orders in 1/N and finite τ using supersymmetric localization. In particular, we fix the F4 higher derivative correction to gluon scattering on AdS at finite string coupling τs = τ in terms of Jacobi theta functions, which feature the expected relations between the SL(2, ℤ) duality and the SO(8) triality of the CFT, and match it to the known flat space term. We also use the flat space limit to compute D2F4 corrections of the correlator at finite τ in terms of a non-holomorphic Eisenstein series. At weak string coupling, we find that the AdS correlator takes a form which is remarkably similar to that of the flat space Veneziano amplitude.

Differential effects of the venoms of Russell’s viper and Indian cobra on human myoblasts

Local tissue damage following snakebite envenoming remains a poorly researched area. To develop better strategies to treat snakebites, it is critical to understand the mechanisms through which venom toxins induce envenomation effects including local tissue damage. Here, we demonstrate how the venoms of two medically important Indian snakes (Russell's viper and cobra) affect human skeletal muscle using a cultured human myoblast cell line. The data suggest that both venoms affect the viability of myoblasts. Russell’s viper venom reduced the total number of cells, their migration, and the area of focal adhesions. It also suppressed myogenic differentiation and induced muscle atrophy. While cobra venom decreased the viability, it did not largely affect cell migration and focal adhesions. Cobra venom affected the formation of myotubes and induced atrophy. Cobra venom-induced atrophy could not be reversed by small molecule inhibitors such as varespladib (a phospholipase A2 inhibitor) and prinomastat (a metalloprotease inhibitor), and soluble activin type IIb receptor (a molecule used to promote regeneration of skeletal muscle), although the antivenom (raised against the Indian ‘Big Four’ snakes) has attenuated the effects. However, all these molecules rescued the myotubes from Russell’s viper venom-induced atrophy. This study demonstrates key steps in the muscle regeneration process that are affected by both Indian Russell’s viper and cobra venoms and offers insights into the potential causes of clinical features displayed in envenomed victims. Further research is required to investigate the molecular mechanisms of venom-induced myotoxicity under in vivo settings and develop better therapies for snakebite-induced muscle damage.

A rare case of type II tri-allelic inheritance at vWA, SE33, D8S1179, and D13S317 loci demonstrated by STR analysis in paternity testing.

Short tandem repeat (STR) typing has been regularly used in paternity disputes and forensic human identification linked caseworks. Occasionally, forensic scientists come across aberrant allele patterns during STR typing because of mutations, genetic variations, and other abnormalities. The tri-allelic pattern of STR is rare, particularly, the case where this pattern exists at 4 loci. Here, we report the type II tri-allelic patterns observed at vWA, SE33, D8S1179, and D13S317 loci in the product of conception (POC) sample during the course of our regular paternity case investigation. The DNA extracted from the blood samples and tissue of POC were subjected to STR typing for autosomal and sex STR loci using the commercial QIAGEN's Investigator® IDplex Plus Kit and QIAGEN's Investigator® 24plex QS Kit. Capillary electrophoresis was carried out in 3500 and 3500xL Genetic Analyzer Applied Biosystems and genotyped using GeneMapper ID-X Software v1.5 and v1.6. In this case of paternity inclusion, the POC sample displayed type II tri-allelic patterns at vWA (16, 19, 20), SE33 (19, 28.2, 29.2), D13S317 (16, 19, 20), and D8S1179 (10, 13, 17) loci. In addition, the POC displayed an abnormal genotype with a heterozygous peak imbalance (type II-B) of (1:2) pattern at D3S1358, D21S11, and D16S539 loci, of (2:1) pattern at D1S1656, D12S391, D10S1248, D2S1338, D2S441, D18S317, FGA, CSF1PO, and D5S818 loci, and type II-C allelic pattern (one single peak with triplicate height) at D19S433 and DS7820 loci. Understanding of such anomalous genotypes improves the knowledge about tri-allelic pattern of CODIS loci and helps in the appropriate interpretation of the results in STR typing.

Treatment of L5-S1 Floating Calcified Lumbar Disc Herniation with Percutaneous Endoscopic Interlaminar Discectomy.

The floating calcified tissue in floating calcified lumbar disc herniation (FCLDH) is hard and often adheres to the dura mater, which can easily cause nerve root damage during surgery, making the operation challenging. We proposed the classification of FCLDH and a new technique for removing floating calcified tissue and reported the clinical efficacy and safety of this new technique in clinical practice. From January 2019 to October 2021, 24 patients (13 males and 11 females, 46.4 ± 7.72 years) with L5-S1 floating calcified lumbar disc herniation were treated with percutaneous endoscopic interlaminar discectomy (PEID). According to FCLDH classification, a total of Type Ia: nine cases, Type Ib: five cases, Type IIa: four cases, and Type IIa: six cases were included. The visual analogue scale (VAS) and Oswestry disability index (ODI) were recorded pre-operatively and 3 days postoperatively, 6 months postoperatively, and at the last follow-up. The postoperative curative effect was evaluated according to the modified MacNab criteria. Computed tomography (CT) and magnetic resonance imaging (MRI) of the lumbar spine were performed 3 days after surgery to evaluate the efficacy of the surgery. All patients successfully underwent PEID. The VAS and ODI scores at 3 days postoperatively, 6 months postoperatively, and at the last follow-up were significantly improved and statistically significant compared to those of the preoperative period (p < 0.05). All the patients were followed up for 12-24 months (mean, 16.6 ± 4.6 months). At the last follow-up, according to the modified MacNab criteria, 15 cases were excellent, eight were good, and one was fair. The combined excellent and good rate was 95.83% (23/24). Postoperative review revealed that all floating calcified tissues were effectively removed and the nerve roots were adequately decompressed without complications such as cerebrospinal fluid leakage and lumbar spine infection. The classification of FCLDH we proposed can well guide the selection of surgical plans. PEID combined with floating calcified tissue removal technology has good efficacy in the treatment of L5-S1 FCLDH, ensuring accurate removal of calcified tissue, reducing complications and improving the quality of life of affected individuals.

Platelet-derived growth factor signaling in pericytes promotes hypothalamic inflammation and obesity.

Pericytes are a vital component of the blood-brain barrier, and their involvement in acute inflammation was recently suggested. However, it remains unclear whether pericytes contribute to hypothalamic chronic inflammation and energy metabolism in obesity. The present study investigated the impact of pericytes on the pathophysiology of obesity by focusing on platelet-derived growth factor (PDGF) signaling, which regulates pericyte functions. Tamoxifen-inducible systemic conditional PDGF receptor β knockout mice (Pdgfrb∆SYS-KO) and Calcium/calmodulin-dependent protein kinase type IIa (CaMKIIa)-positive neuron-specific PDGF receptor β knockout mice (Pdgfrb∆CaMKII-KO) were fed a high-fat diet, and metabolic phenotypes before and 3 to 4weeks after dietary loading were examined. Intracellular energy metabolism and relevant signal transduction in lipopolysaccharide- and/or platelet-derived growth factor-BB (PDGF-BB)-stimulated human brain pericytes (HBPCs) were assessed by the Seahorse XFe24 Analyzer and Western blotting. The pericyte secretome in conditioned medium from HBPCs was studied using cytokine array kit, and its impact on polarization was examined in bone marrow-derived macrophages (BMDMs), which are microglia-like cells. Energy consumption increased and body weight gain decreased after high-fat diet loading in Pdgfrb∆SYS-KO mice. Cellular oncogene fos (cFos) expression increased in proopiomelanocortin (POMC) neurons, whereas microglial numbers and inflammatory gene expression decreased in the hypothalamus of Pdgfrb∆SYS-KO mice. No significant changes were observed in Pdgfrb∆CaMKII-KO mice. In HBPCs, a co-stimulation with lipopolysaccharide and PDGF-BB shifted intracellular metabolism towards glycolysis, activated mitogen-activated protein kinase (MAPK), and modulated the secretome to the inflammatory phenotype. Consequently, the secretome showed an increase in various proinflammatory chemokines and growth factors including Epithelial-derived neutrophil-activating peptide 78 (C-X-C motif chemokine ligand (CXCL)5), Thymus and activation-regulated chemokine (C-C motif chemokine (CCL)17), Monocyte chemoattractant protein 1 (CCL2), and Growth-regulated oncogene α (CXCL1). Furthermore, conditioned medium from HBPCs stimulated the inflammatory priming of BMDMs, and this change was abolished by the C-X-C motif chemokine receptor (CXCR) inhibitor. Consistently, mRNA expression of CXCL5 was elevated by lipopolysaccharide and PDGF-BB treatment in HBPCs, and the expression was significantly lower in the hypothalamus of Pdgfrb∆SYS-KO mice than in control Pdgfrbflox/flox mice (FL) following 4 weeks of HFD feeding. PDGF receptor β signaling in hypothalamic pericytes promotes polarization of macrophages by changing their secretome and contributes to the progression of obesity.

Is identification and dissection of the external laryngeal nerve necessary during thyroidectomy? A prospective study

BackgroundCompared to the recurrent laryngeal nerve, the EBSLN (or external laryngeal nerve) is less studied in terms of its course and relationship with the thyroid gland. This is a prospective intraoperative study designed to identify the anatomical variations of the EBSLN in relation to the IPC, the superior thyroid pedicle, and the point where the nerve crosses the STA. Additionally, the study aims to propose a technical procedure for its preservation.MethodsWe conducted a prospective study of 50 patients (total of 100 nerves) undergoing total thyroidectomy at the Department of Surgery ‘B’ in Ibn Sina Hospital, Rabat. Intraoperatively, the EBSLN was visually identified and preserved before ligating the superior thyroid vessels. Each nerve was categorized using established classification systems.ResultsThe overall pooled EBSLN identification rate was 82%. Cernea type IIa (nerves crossing the STA less than 1 cm above the upper edge of the superior thyroid pole) and Friedman type II (nerves piercing the lower fibers of the IPC) were the most prevalent (64% and 44%, respectively). Kierner type IV (nerves crossing the branches of the STA immediately above the upper pole of the thyroid gland) was represented in 27% of cases.ConclusionA better understanding of surgical anatomy of the neck allows for better results of thyroidectomy by preserving the external and recurrent laryngeal nerves.

The effect of screw orientation on internal fixation of Letenneur type II Hoffa fractures: a biomechanics study

BackgroundTo investigate the biomechanical effects of screw orientation and fracture block size on the internal fixation system for Letenneur type II Hoffa fractures.MethodsThe fracture models were randomly divided into six groups according to the fracture subtypes and the direction of nail placement, and a plumb line of the posterior condylar tangent was made across the base of the posterior femoral condyle. The fracture blocks of the three types of fracture were calculated and recorded in the sagittal position, and the biomechanical performance of the six groups was evaluated by biomechanical tests. The axial load on the fracture block at a displacement of 2 mm was set as the failure load, a gradually increasing axial load was applied to each fracture model using a customized indenter at a load of 250-750 N, and the displacements and failure loads of the six groups were recorded at different axial loads.ResultsBiomechanical test results showed that the larger the fracture block, the greater was the stability when nailing from front to back, and the smaller the fracture block, the greater was the strength when nailing from back to front (p < 0.001). As the fracture block became larger, the biomechanical advantage of nailing from posterior to anterior decreased.The displacement under 250 N load were 1.351 ± 0.113 mm, 1.465 ± 0.073 mm for Group IIa AP and Group IIa PA. The displacement under 500 N load were 2.596 ± 0.125 mm, 2.344 ± 0.099 mm for Group IIa AP and Group IIa PA. The displacement under 750 N load were 3.997 ± 0.164, 3.386 ± 0.125 mm for Group IIa AP and Group IIa PA. The failure loads were 384 ± 14 N, 415 ± 19 N for Group IIa AP and Group IIa PA. In the type IIa fracture group, the difference was no longer significant (p > 0.001). Therefore, there is a mechanical threshold that ranges from 38.36 to 52.33% between type IIa and type IIb fractures.ConclusionsThe effect of the nailing direction on the strength of fixation has a fracture-block critical point, which is consistent overall with the trend that the larger the fracture block is, the greater the stability when nailing from anterior to posterior, and the smaller the fracture block is, the greater the strength when nailing from posterior to anterior.

Metagenome-assembled genomes of three Hepatoplasmataceae provide insights into isopod-mollicute symbiosis.

The digestive organs of terrestrial isopods harbour bacteria of the recently proposed mollicute family Hepatoplasmataceae. The only complete genome available so far for Hepatoplasmataceae is that of 'Candidatus Hepatoplasma crinochetorum'. The scarcity of genome sequences has hampered our understanding of the symbiotic relationship between isopods and mollicutes. Here, we present four complete metagenome-assembled genomes (MAGs) of uncultured Hepatoplasmataceae members identified from shotgun sequencing data of isopods. We propose genomospecies names for three MAGs that show substantial sequence divergence from any previously known Hepatoplamsataceae members: 'Candidatus Tyloplasma litorale' identified from the semiterrestrial isopod Tylos granuliferus, 'Candidatus Hepatoplasma vulgare' identified from the common pill bug Armadillidium vulgare, and 'Candidatus Hepatoplasma scabrum' identified from the common rough woodlouse Porcellio scaber. Phylogenomic analysis of 155 mollicutes confirmed that Hepatoplasmataceae is a sister clade of Metamycoplasmataceae in the order Mycoplasmoidales. The 16S ribosomal RNA gene sequences and phylogenomic analysis showed that 'Candidatus Tyloplasma litorale' and other semiterrestrial isopod-associated mollicutes represent the placeholder genus 'g_Bg2' in the r214 release of the Genome Taxonomy Database, warranting their assignment to a novel genus. Our analysis also revealed that Hepatoplasmataceae lack major metabolic pathways but has a likely intact type IIA CRISPR-Cas9 machinery. Although the localization of the Hepatoplasmatacae members have not been verified microscopically in this study, these genomic characteristics are compatible with the idea that these mollicutes have an ectosymbiotic lifestyle with high nutritional dependence on their host, as has been demonstrated for other members of the family. We could not find evidence that Hepatoplasmataceae encode polysaccharide-degrading enzymes that aid host digestion. If they are to provide nutritional benefits, it may be through extra-copy nucleases, peptidases, and a patatin-like lipase. Exploration of potential host-symbiont interaction-associated genes revealed large, repetitive open reading frames harbouring beta-sandwich domains, possibly involved with host cell adhesion. Overall, genomic analyses suggest that isopod-mollicute symbiosis is not characterized by carbohydrate degradation, and we speculate on their potential role as defensive symbionts through spatial competition with pathogens to prevent infection.

Short-Term Effects of Botulinum Toxin-A Injection on the Medial Gastrocnemius Histological Features in Ambulant Children with Cerebral Palsy: A Longitudinal Pilot Study.

Botulinum toxin-A (BoNT-A) injection is known to exert beneficial effects on muscle tone, joint mobility and gait in children with cerebral palsy (CP). However, recent animal and human studies have raised the concern that BoNT-A might be harmful to muscle integrity. In CP-children, the impact of BoNT-A on muscle structure has been poorly studied, and inconsistent results have been reported. This study was aimed at determining the time course effect of a single BoNT-A administration on medial gastrocnemius (MG) morphology in CP-children. MG microbiopsies from 12 ambulant and BoNT-A-naïve CP-children (age, 3.4 (2.3) years, ranging from 2.5 to 7.8 years; seven boys and five girls; GMFCS I = 5, II = 4 and III = 3) were collected before and 3 and 6 months after BoNT-A treatment to analyze the fiber cross-sectional area (fCSA) and proportion; capillarization; and satellite cell (SC) content. Compared with the baseline, the fCSA decreased at 3 months (-14%, NS) and increased at 6 months (+13%, NS). Fiber size variability was significantly higher at 3 months (type I: +56%, p = 0.032; type IIa: +37%, p = 0.032) and 6 months (type I: +69%, p = 0.04; type IIa: +121%, p = 0.032) compared with the baseline. The higher type I proportion seen at 3 months was still present and more pronounced at 6 months (type I: +17%, p = 0.04; type IIx: -65%, p = 0.032). The capillary fiber density was reduced at 3 months (type I: -43%, NS; type II: -44%, p = 0.0320) but normalized at 6 months. There was a non-significant increase in SC/100 fibers at 3 months (+75%, NS) and 6 months (+40%, NS) compared with the baseline. These preliminary data suggest that BoNT-A induced alterations in the MG of children with CP, which were still present 6 months after BoNT-A injection but with signs of muscle recovery.

Flux vacua of the mirror octic

We determine all flux vacua with flux numbers Nflux ≤ 10 for a type IIB orientifold-compactification on the mirror-octic three-fold. To achieve this, we develop and apply techniques for performing a complete scan of flux vacua for the whole moduli space — we do not randomly sample fluxes nor do we consider only boundary regions of the moduli space. We compare our findings to results in the literature.

Unveiling the Potential of Nelumbo nucifera-Derived Liensinine to Target The Myostatin Protein and to Counteract Muscle Atrophy.

Muscle atrophy refers to a decline in muscle mass and function, which has become a global concern due to the aging population. Various clinical trials have investigated the inhibitors of myostatin (MSTN). They have shown promising improvements in muscle function and quality of life. However, there are no drugs specifically targeting MSTN that have been approved for clinical use. In this study, we virtually screened liensinine (LIE), a food (Nelumbo nucifera)-derived compound, with low toxicity, from over 1.1 million compounds. We subsequently identified it as a potential candidate that targets MSTN by a cellular thermal shift assay (CETSA) and drug affinity response target stability (DARTS) assay. Further validation through cellular and in vivo studies demonstrated its promising potential in combating muscle atrophy. The mechanism of action may involve hindering the interaction between MSTN and the activin receptor type IIB (ActRIIB) and downregulating the expression of downstream proteins, including the muscle RING-finger protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx)/Atrogin-1, ultimately promoting muscle regeneration. These results provide a strong foundation for future studies to explore the therapeutic potential of LIE in clinical settings.

Circulating basophils in patients with type IIb autoimmune chronic spontaneous urticaria have a lower histamine content

AbstractBackgroundPatients suffering from chronic spontaneous urticaria (CSU) are typically classified as type I or type IIb autoimmune CSU, but further patient stratification is hindered by the lack of biomarkers.ObjectivesWe investigated whether the histamine content of individual basophils differ between patient subtypes in CSU to evaluate its potential as a biomarker.MethodsA total of 101 patients diagnosed with CSU were included in the study. The histamine content per circulating basophil was derived from the basophil count in peripheral blood and levels of total cellular blood histamine. These measures, together with results from the serum‐induced basophil histamine release assay (s‐BHRA), were correlated to information on demographics, clinical characteristics, patient reported outcomes and laboratory analyses.ResultsThe histamine content per basophil was significantly different between s‐BHRA positive and ‐negative patients (0.175 vs. 1.40 pg/cell, p &lt; 0.001) and showed a significant negative correlation to the degree of basophil activation in s‐BHRA (ρ = −0.209, p = 0.036). Furthermore, the amount of histamine in individual basophils was found to be significantly correlated with levels of total cellular blood histamine (ρ = 0.376, p &lt; 0.001), eosinophil counts (ρ = 0.205, p = 0.040), levels of thyroid stimulating hormone (ρ = −0.246, p = 0.014) and titre of antibodies against thyroid peroxidase (ρ = −0.216, p = 0.031) and thyroglobulin (ρ = −0.203, p = 0.044).ConclusionsLow content of intracellular histamine in circulating basophils is associated with known markers of type IIb autoimmune CSU. Further studies are required to assess whether the amount of histamine in basophils can be used to monitor or predict response to treatment in patients.

Formation of misoriented blocks during single-crystal CVD diamond growth

This paper presents the results of a CVD diamond crystal growth experiment on an HPHT type IIa substrate (9 × 9 mm). Data acquired through cathodoluminescence and EBSD methods shed light on the aspects of the formation of a polycrystalline shell around a single crystal of CVD diamond. CVD diamond exhibits orientation features of the polycrystalline shell, microblocks, low-angle boundaries, and linear hexagonal macrostructures of dislocation origin. Crystal splitting occurs when the dislocation density increases from the geometric center to the periphery. Such CVD diamonds exhibit a continuous transition from single crystal to polycrystal through a block-type crystal.

A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice

AbstractIron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in β-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in β-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the β-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of β-thalassemia.

Functional profile of perilesional gray matter in focal cortical dysplasia: an fMRI study.

We aim to investigate the functional profiles of perilesional gray matter (GM) in epileptic patients with focal cortical dysplasia (FCD) and to correlate these profiles with FCD II subtypes, surgical outcomes, and different antiseizure medications (ASMs) treatment response patterns. Nine patients with drug-responsive epilepsy and 30 patients with drug-resistant epilepsy (11 were histologically confirmed FCD type IIa, 19 were FCD type IIb) were included. Individual-specific perilesional GM and contralateral homotopic GM layer masks were generated. These masks underwent a two-voxel (2 mm) dilation from the FCD lesion and contralateral homotopic region, resulting in 10 GM layers (20 mm). Layer 1, the innermost, progressed to Layer 10, the outermost. Amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) analyses were conducted to assess the functional characteristics of ipsilateral perilesional GM and contralateral homotopic GM. Compared to the contralateral homotopic GM, a significant reduction of ALFF was detected at ipsilateral perilesional GM layer 1 to 6 in FCD type IIa (after Bonferroni correction p < 0.005, paired t-test), whereas a significant decrease was observed at ipsilateral perilesional GM layer 1 to 2 in FCD type IIb (after Bonferroni correction p < 0.005, paired t-test). Additionally, a significant decrease of the ReHo was detected at ipsilateral perilesional GM layer 1 compared to the CHRs in FCD type IIb. Notably, complete resection of functional perilesional GM alterations did not correlate with surgical outcomes. Compared to the contralateral homotopic GM, a decreased ALFF in the ipsilateral perilesional GM layer was detected in drug-responsive patients, whereas decreased ALFF in the ipsilateral perilesional GM layer 1-6 and decreased ReHo at ipsilateral perilesional GM layer 1 were observed in drug-resistant patients (after Bonferroni correction p < 0.005, paired t-test). Our findings indicate distinct functional profiles of perilesional GM based on FCD histological subtypes and ASMs' response patterns. Importantly, our study illustrates that the identified functional alterations in perilesional GM may not provide sufficient evidence to determine the epileptogenic boundary required for surgical resection.

Emergent M-theory limit

It has been recently proposed that at each infinite distance limit in the moduli space of quantum gravity a perturbative description emerges with fundamental degrees of freedom given by those infinite towers of states whose typical mass scale is parametrically not larger than the ultraviolet cutoff, identified with the species scale. This proposal is applied to the familiar ten-dimensional type IIA and IIB superstring theories, when considering the limit of infinite string coupling. For type IIB, the light towers of states are given by excitations of the D1-brane, as expected from self-duality. Instead, for type IIA at strong coupling, which is dual to M-theory on S1, we make the observation that the emergent degrees of freedom are bound states of transversal M2- and M5-branes with Kaluza-Klein momentum along the circle. We speculate on the interpretation of the necessity of including all these states for a putative quantum formulation of M-theory. Published by the American Physical Society 2024