A novel ATP13A2 variant causing complicated hereditary spastic paraplegia.

BACKGROUND: ATP13A2 is a monogenic causative gene of Parkinson's disease, whose biallelic mutations can result in Kufor-Rakeb syndrome. Biallelic mutations in ATP13A2 have also been reported in pure or complicated hereditary spastic paraplegia (HSP). Here, we report clinical, neuroimaging, and genetic findings from a patient with a novel homozygous mutation in ATP13A2 presenting with HSP plus parkinsonism. METHODS: Whole genome sequencing was performed on the patient, a 46-year-old Chinese woman from a consanguineous family, to identify the genetic cause. Furthermore, functional studies of the identified ATP13A2 mutation were conducted. RESULTS: The patient initially presented with abnormal gait because of lower-limb spasticity and recurrent seizures. Parkinsonism (presenting as bradykinesia and rigidity) and peripheral neuropathy in lower limbs further evolved and resulted in her eventual use of a wheelchair. Symmetrically decreased dopamine transporter density was detected within the bilateral putamen and caudate nucleus in dopamine transporter-positron emission tomography. Genetic analysis revealed a novel homozygous missense mutation in ATP13A2 (c.2780 T > C, p.Leu927Pro), which was heterozygous in the patient's parents and son. Functional studies suggested that this mutation results in the reduced expression and altered subcellular localization of ATP13A2. CONCLUSIONS: Our report broadens the genetic and phenotypic spectrum of ATP13A2-related HSP. Further research is needed to fully elucidate the mechanism linking ATP13A2 variants to HSP.

Full-resolution, full-field-of-view, and high-quality fast Fourier single-pixel imaging.

Fourier single-pixel imaging (FSI) uses Fourier basis patterns for spatial light modulation to acquire the Fourier spectrum of the object image. The object image can be reconstructed via an inverse Fourier transform. However, the Fourier basis patterns are inherently gray scale, which results in the difficulty that the patterns can hardly be generated at a high speed by using a commonly used spatial light modulator-digital micromirrors device. To tackle this problem, fast FSI, which uses upsampled and dithered Fourier basis patterns to approximate the gray scale patterns, has been reported, but the achievable spatial resolution has to be sacrificed in the pattern upsampling process. Here we propose a method that can achieve not only full-resolution but also full-field-of-view and high-quality FSI. The key to the proposed method is to use a new, to the best of our knowledge, error diffusion dithering algorithm combined with two different scanning strategies to generate two sets of binarized Fourier basis patterns for spatial light modulation. As a result, two images with a sub-pixel shift from each other are reconstructed. It results in the final high-quality reconstruction by synthesizing the two images. We experimentally demonstrate the method can produce a high-quality 1024 × 768-pixel and full resolution image with a digital micromirror device with 1024 × 768 micromirrors.

The key players of parthanatos: opportunities for targeting multiple levels in the therapy of parthanatos-based pathogenesis.

Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis.

Low intensity pulsed ultrasound reduces liver inflammation caused by fatigue exercise.

Low-intensity pulsed ultrasound (LIPUS) has been shown to have many benefits, such as inhibiting inflammation, stimulating cell proliferation and differentiation, promoting angiogenesis, and so on. So, can exercise fatigue induced liver inflammation be effectively relieved by LIPUS? If possible, what is the possible mechanism? This study first investigated the effect of different intensity exercise on liver inflammation. Rats were divided into three groups: normal control group, exercise fatigue group, and aerobic exercise group. The results showed that aerobic exercise increases both anti-inflammatory factors and pro-inflammatory factors, while fatigue exercise decreases anti-inflammatory factors and increases pro-inflammatory factors, leading to severe liver injury and fibrosis. Then, we investigated the therapeutic effect of LIPUS on liver inflammation caused by exercise fatigue. Starting from the 6th week, the liver was irradiated with LIPUS of 80 mW/cm2 for 20 min/d after daily exercise for 7 weeks. The results showed that LIPUS significantly decreased liver injury and fibrosis, significantly up-regulated the expression of STAT6, IL-13, and its receptors IL-13Rα1, and down regulated the expression of NF-κBp65 in exercise fatigue rats. These results indicate that LIPUS can reduce fatigue-induced liver inflammation, and the mechanism is related to the regulation of the IL-13/STAT6/NF-κBp65 pathway.

Low-intensity pulsed ultrasound mitigates cognitive impairment by inhibiting muscle atrophy in hindlimb unloaded mice.

Microgravity leads to muscle loss, usually accompanied by cognitive impairment. Muscle reduction was associated with the decline of cognitive ability. Our previous studies showed that low-intensity pulsed ultrasound (LIPUS) promoted muscle hypertrophy and prevented muscle atrophy. This study aims to verify whether LIPUS can improve cognitive impairment by preventing muscle atrophy in hindlimb unloaded mice. In this study, mice were randomly divided into normal control (NC), hindlimb unloading (HU), hindlimb unloading + LIPUS (HU+LIPUS) groups. The mice in the HU+LIPUS group received a 30 mW/cm2 LIPUS irradiation on gastrocnemius for 20 min/d. After 21 days, LIPUS significantly prevented the decrease in muscle mass and strength caused by tail suspension. The HU+LIPUS mice showed an enhanced desire to explore unfamiliar environments and their spatial learning and memory abilities, enabling them to quickly identify differences between different objects, as well as their social discrimination abilities. MSTN is a negative regulator of muscle growth and also plays a role in regulating cognition. LIPUS significantly inhibited MSTN expression in skeletal muscle and serum and its receptor ActRIIB expression in brain, upregulated AKT and BDNF expression in brain. Taken together, LIPUS may improve the cognitive dysfunction in hindlimb unloaded rats by inhibiting muscle atrophy through MSTN/AKT/BDNF pathway.

Facilitated dynamics of an active polymer in 2D crowded environments with obstacles.

Understanding the behaviors of a single active chain in complex environments is not only an interesting topic in non-equilibrium physics but also has applicative implications in biological/medical engineering. In this work, by using molecular simulations, we systematically study the dynamical and conformational behaviors of an active polymer in crowded environments, i.e., a single active chain confined in 2D space with randomly arranged obstacles. We found that the competition between the chain's activity and rigidity in the presence of obstacles leads to many interesting dynamical and conformational states, such as the diffusive expanded state, the diffusive collapsed state, and the localized collapsed state. Importantly, we found a counter-intuitive phenomenon, i.e., crowded environments facilitate the diffusion of the active polymer within a large parameter space. As the crowdedness (packing fraction of obstacles) increases, the parameter space in which crowding-enhanced diffusion occurs still remains. This abnormal dynamics is attributed to a structural reason that the obstacles prevent active chains from collapsing. Our findings capture some generic features of active polymers in complex environments and provide insights into the design of novel drug delivery systems.

Patterns of plant carbon, nitrogen, and phosphorus concentration in relation to productivity in China's terrestrial ecosystems.

Plant nitrogen (N) and phosphorus (P) content regulate productivity and carbon (C) sequestration in terrestrial ecosystems. Estimates of the allocation of N and P content in plant tissues and the relationship between nutrient content and photosynthetic capacity are critical to predicting future ecosystem C sequestration under global change. In this study, by investigating the nutrient concentrations of plant leaves, stems, and roots across China's terrestrial biomes, we document large-scale patterns of community-level concentrations of C, N, and P. We also examine the possible correlation between nutrient content and plant production as indicated by vegetation gross primary productivity (GPP). The nationally averaged community concentrations of C, N, and P were 436.8, 14.14, and 1.11 mg·g-1 for leaves; 448.3, 3.04 and 0.31 mg·g-1 for stems; and 418.2, 4.85, and 0.47 mg·g-1 for roots, respectively. The nationally averaged leaf N and P productivity was 249.5 g C GPP·g-1 N·y-1 and 3,157.9 g C GPP·g-1 P·y-1, respectively. The N and P concentrations in stems and roots were generally more sensitive to the abiotic environment than those in leaves. There were strong power-law relationships between N (or P) content in different tissues for all biomes, which were closely coupled with vegetation GPP. These findings not only provide key parameters to develop empirical models to scale the responses of plants to global change from a single tissue to the whole community but also offer large-scale evidence of biome-dependent regulation of C sequestration by nutrients.

Control of Chromatin Organization and Chromosome Behavior during the Cell Cycle through Phase Separation.

Phase-separated condensates participate in various biological activities. Liquid-liquid phase separation (LLPS) can be driven by collective interactions between multivalent and intrinsically disordered proteins. The manner in which chromatin-with various morphologies and activities-is organized in a complex and small nucleus still remains to be fully determined. Recent findings support the claim that phase separation is involved in the regulation of chromatin organization and chromosome behavior. Moreover, phase separation also influences key events during mitosis and meiosis. This review elaborately dissects how phase separation regulates chromatin and chromosome organization and controls mitotic and meiotic chromosome behavior.

Unusual self-diffusion behaviors of polymer adsorbed on rough surfaces.

We investigate the diffusion dynamics of a single polymer strongly adsorbed on surfaces in an extremely broad chain length and surface roughness by means of molecular dynamics simulations. Our simulations demonstrate that with the increase in chain length, the diffusion dynamics of polymer chains exhibits three regimes: the Rouse dynamics with D ∼ N-1 when the lateral size of polymer chains is smaller than a half of distance between obstacles on rough surfaces; the reptationlike dynamics with D ∼ N-1.5 and τr ∼ N3 when the obstacles inhibit the freely Rouse behavior of polymer chains; and the quasi-Rouse dynamics with D ∼ N-1 and τr ∼ N2.5 when the height of obstacles is smaller than twice the vertical size of polymer chains, where D, N, and τr are the diffusion coefficient, chain length, and end-to-end vector relaxation time of polymer chains, respectively. The long chains have sufficient conformation entropy to form loops to hop over short obstacles, which could dramatically reduce the confinement from obstacles on the rough surfaces and changes the diffusion and relaxation dynamics of polymer chains from the reptationlike dynamics to the quasi-Rouse dynamics. Our results reveal the whole diffusion dynamics of polymer chains strongly adsorbed on rough surfaces and clarify the corresponding transition mechanism, which is significant for the understanding of the physical nature and the development of the corresponding applications.

Effects of surface roughness on the self-diffusion dynamics of a single polymer.

We employ molecular dynamics simulations to simulate the diffusion dynamics of a single polymer adsorbed on surfaces with different roughnesses, which are characterized by the separation distance between obstacles and the height of obstacles. Our simulations demonstrate that for strong adsorption and when the confinement of obstacles is strong enough for all chains, the scaling exponent α of the diffusion coefficient on the chain length exhibits three cases with increase of the height of obstacles: a Rouse plateau with α ≈ -1 (the lateral motion of the polymer chains is free), a reptationlike plateau with α ≈ -1.5 (the polymer chains can hardly stride over the obstacles in the perpendicular direction) and a transition from the Rouse plateau to the reptationlike plateau with -1.5 < α < -1 (the obstacles hinder the lateral motion of the polymer chains). However, with increase of the separation distance between obstacles, the confinement from the obstacles exhibits a decrease (more lateral motions of the polymer chains are allowed), which results in a higher plateau (no longer separate reptationlike dynamics). Our results clarify the effects of surface roughness on the diffusion mechanism of polymer chains strongly adsorbed on solid surfaces in dilute solutions and the resulting transition mechanism from the Rouse scaling to the reptationlike scaling, which is significant for the understanding of the physical nature and the development of the corresponding applications.

7, 8, 3'-Trihydroxyflavone protects H/R-induced apoptosis and induces in vivo growth of human embryonic stem cell-derived cardiomyocytes.

BACKGROUND: Cellular therapy of human embryonic stem cell-derived cardiomyocytes (hES-CMs) holds great promise for regenerating infarcted cardiac tissues. Yet, the major challenge remains as little cells survived after grafting. In this study, we examined whether treating hES-CMs with 7, 8, 3'-Trihydroxyflavone (THF) may improve hES-CMs developments both in vitro and in vivo. METHOD: HES-CMs were differentiated in vitro, and treated with 5 µ59M THF for 24 h. The control hES-CMs were treated with PBS. Possible effect of THF on hES-CM differentiation was assessed by viability and western blot assays. HES-CMs were also treated with hypoxia/reoxygenation (H/R)-condition to induce apoptosis. The effect of THF on rescuing H/R-induced hES-CM apoptosis was assessed by TUNEL and western blot assays. HES-CMs were then grafted into infarcted rat hearts. The effect of THF on promoting in vivo growth of hES-CMs was examined by immunohistochemistry. RESULTS: THF pretreatment did not alter the differentiation process of hES-CMs. Under H/R condition, THF rescued hES-CM apoptosis, activated TrkA and TrkB signaling pathways through phosphorylation and induced VEGF production. In in vivo rat model of myocardial infarction, THF induced the growth of transplanted hES-CMs by promoting Cardiac Troponin I and CD31. CONCLUSION: THF has pro-cardiac effect on hES-CMs by protecting cells from H/R induced apoptosis and promoting in vivo growth of cell transplantation in infarcted hearts. These results may help optimizing the cellular therapy of using human embryonic stem cells to benefiting patients suffered from heart attack. This article is protected by copyright. All rights reserved.

Patient- and treatment-related risk factors associated with neck muscle spasm in nasopharyngeal carcinoma patients after intensity-modulated radiotherapy.

BACKGROUND: To evaluate the incidence of neck muscle spasm in nasopharyngeal carcinoma (NPC) patients that received intensity-modulated radiotherapy (IMRT), and to analyse the patient- and treatment-related risk factors associated with neck muscle spasm. METHODS: A sample of 152 IMRT-treated, biopsy-proven, nondisseminated NPC patients were retrospectively analysed. All had documented IMRT treatment plans and had returned for follow-up review at 4 years post-radiotherapy. Spasm of the sternocleidomastoid (SCM) muscle was graded from 0 to 3 (absent to severe) and this grade served as the clinical endpoint. Risk factors were identified using logistic regression analysis. RESULTS: Within 4 years of radiotherapy, neck muscle spasm developed in 23.68% of the patients; Grades 0, 1, 2 and 3 were respectively assigned to 83.55, 7.57, 6.58 and 2.30% of assessed SCMs. Multivariate analysis indicated that gender, N stage, V60 (percentage of SCM volume that received >60 Gy) were independent prognostic variables, and that the optimal threshold for using V60 to predict neck muscle spasm was 61.92% (sensitivity = 0.900, specificity = 0.953). CONCLUSIONS: Gender, N stage and V60 were independent predictive factors for post-radiotherapy neck muscle spasm, and a V60 of ≤61.92% in the SCM was relatively safe.

Anaerobic co-digestion of corn straw, sewage sludge and fresh leachate: Focusing on synergistic/antagonistic effects and microbial mechanisms.

Effects of sewage sludge (SS) and fresh leachate (FL) addition on corn straw (CS) digestion and underlying mechanisms were investigated. Co-digestion of CS, SS and FL significantly increased cumulative methane production by 7.2-61.1%. Further analysis revealed that co-digestion acted mainly on slowly degradable substrates and exerted dual effects on methane production potential, which was closely related to the volatile solids (VS) content. Antagonistic effects of co-digestion resulted from the dominance of norank_c_Bathyarchaeia, a mixotrophic methanogen that may generate methane inefficiently and consume existing methane. The synergistic enhancement of methane production (0.7-12.7%) was achieved in co-digestion with 33.5-45.5% of total VS added as SS and FL. Co-digestion with more balanced nutrients and higher buffering capacity enriched Actinobacteriota, Firmicutes, and Synergistota, thereby facilitating the substrate degradation. Furthermore, the predominant acetoclastic methanogens, increased hydrogenotrophic methanogens, and decreased methylotrophic methanogens in the digester combined to prompt the synergy.

Differential effects of intra-RMTg infusions of pilocarpine or 4-DAMP on regulating depression- and anxiety-like behaviors.

Depression and anxiety are associated with dysfunction of the mesolimbic dopamine system. The rostromedial tegmental nucleus (RMTg) is predominantly composed of GABAergic neurons that exhibit dense projections and strongly inhibit mesolimbic dopaminergic neurons, proposed as a major "brake" for the system. Consequently, the RMTg may be a crucial brain region for regulating these emotions. The central cholinergic system, particularly the muscarinic receptors, plays an important regulatory role in depression and anxiety. M3 muscarinic receptors are distributed on GABAergic neurons in the RMTg, but their involvement in the regulation of depression and anxiety remains uncertain. This study aimed to examine the effects of RMTg M3 muscarinic receptors on regulating depression- and anxiety-like behaviors in adult male Wistar rats, as assessed through the forced swim, tail suspension, and elevated plus maze tests. The results showed that intra-RMTg injections of the M1/M3 muscarinic receptors agonist, pilocarpine (3, 10, and 30 µg/side), or the M3 muscarinic receptors antagonist, 4-DAMP (0.5, 1, and 2 µg/side), did not alter the immobility time in the forced swim and tail suspension tests. Additionally, pilocarpine (30 µg/side) decreased time spent in open arms and increased time in closed arms in the elevated plus maze; while 4-DAMP (1 and 2 µg/side) played the opposite role by increasing time spent in open arms and decreasing time in closed arms. These findings suggest that RMTg M3 muscarinic receptors have differential effects on regulating depression- and anxiety-like behaviors. Enhancing or inhibiting these receptors can produce anxiogenic or anxiolytic effects, but have no impact on depression-like behavior. Therefore, RMTg M3 muscarinic receptors are involved in regulating anxiety and may be a potential therapeutic target for anxiolytic drugs.

Study on Synergistic Effects of Nanohydroxyapatite/High-Viscosity Carboxymethyl Cellulose Scaffolds Stimulated by LIPUS for Bone Defect Repair of Rats.

Despite the self-healing capacity of bone, the regeneration of critical-size bone defects remains a major clinical challenge. In this study, nanohydroxyapatite (nHAP)/high-viscosity carboxymethyl cellulose (hvCMC, 6500 mPa·s) scaffolds and low-intensity pulsed ultrasound (HA-LIPUS) were employed to repair bone defects. First, hvCMC was prepared from ramie fiber, and the degree of substitution (DS), purity, and content of NaCl of hvCMC samples were 0.91, 99.93, and 0.017%, respectively. Besides, toxic metal contents were below the permissible limits for pharmaceutically used materials. Our results demonstrated that the hvCMC is suitable for pharmaceutical use. Second, nHAP and hvCMC were employed to prepare scaffolds by freeze-drying. The results indicated that the scaffolds were porous, and the porosity was 35.63 ± 3.52%. Subsequently, the rats were divided into four groups (n = 8) randomly: normal control (NC), bone defect (BD), bone defect treated with nHAP/hvCMC scaffolds (HA), and bone defect treated with nHAP/hvCMC scaffolds and stimulated by LIPUS (HA-LIPUS). After drilling surgery, nHAP/hvCMC scaffolds were implanted in the defect region of HA and HA-LIPUS rats. Meanwhile, HA-LIPUS rats were treated by LIPUS (1.5 MHz, 80 mW cm-2) irradiation for 2 weeks. Compared with BD rats, the maximum load and bone mineral density of HA-LIPUS rats were increased by 20.85 and 51.97%, respectively. The gene and protein results indicated that nHAP/hvCMC scaffolds and LIPUS promoted the bone defect repair and regeneration of rats significantly by activating Wnt/ß-catenin and inhibiting OPG/RANKL signaling pathways. Overall, compared with BD rats, nHAP/hvCMC scaffolds and LIPUS promoted bone defect repair significantly. Furthermore, the research results also indicated that there are synergistic effects for bone defect repair between the nHAP/hvCMC scaffolds and LIPUS.

The effect of bacteria on uranium sequestration stability by different forms of phosphorus.

Immobilisation of uranium (U (VI)) by direct precipitation of uranyl phosphate (U-P) exhibits a great potential application in the remediation of U (VI)-contaminated environments. However, phosphorus, vital element of bacteria's decomposition, absorption and transformationmay affect the stability of U (VI) with ageing time. The main purpose of this work is to study the effect of bacteria on uranium sequestration mechanism and stability by different forms of phosphorus in a water sedimentary system. The results showed that phosphate effectively enhanced the removal of U (VI), with 99.84%. X-Ray Diffraction (XRD), Scanning Electron Microscopy and Energy Dispersive Spectrometer (SEM-EDS), and X-ray Photoelectron Spectroscopy (XPS) analyses imply that U (VI) and U (IV) co-exist on the surface of the samples. Combined with BCR results, it demonstrated that bacteria and phosphorus have a synergistic effect on the removal of U (VI), realising the immobilisation of U (VI) from a transferable phase to a stable phase. However, from a long-term perspective, the redissolution and release of uranium immobilisation of U (VI) by pure bacteria with ageing time are worthy of attention, especially in uranium mining environments rich in sensitive substances. This observation implies that the stability of the uranium may be impacted by the prevailing environmental conditions. The novel findings could provide theoretical evidence for U (VI) bio-immobilisation in U (VI)-contaminated environments.

Preparation of landscape gardening soil using undersized fraction from aged MSW by EDTA or citric acid coupled with humic acid: Effect assessment, properties, and optimization.

Undersized fraction from aged municipal solid waste (UFAMSW), as a kind of soil-like material, has been proved effective in providing a large amount of organic matter and nutrients for soil and plants. The characteristics and effectiveness of heavy metal pollution removal in UFAMSW attracted tremendous research interest from scientists recently. In this study, the heavy metal removal efficiencies and bioavailability of washing on contaminated UFAMSW were evaluated with three washing reagents including ethylene diamine tetra acetic acid (EDTA), citric acid (CA), and humic acid (HA). The effects of chelating agent concentration, pH, and washing time on metal removal were investigated and response surface methodology (RSM) was employed to optimize the washing conditions. The results indicated that the removal efficiencies of Cu, Zn, and Mn could be 53.68%, 52.12%, and 30.63% by EDTA/HA washing and 42.36%, 39.67% and 28.49% by CA/HA washing, respectively. The European Community Bureau of Reference (BCR) sequential extraction was applied to analyze the fraction change of heavy metals in UFAMSW before and after washing, and it was found that chelating agent combined with HA could contribute to the removal of the exchangeable fraction. Physical and chemical properties of UFAMSW were improved to some extent after washing with mixed HA and chelating agent and could achieve the quality standard of landscape gardening soil. Accordingly, the mixture of HA and other chelating agents could be a promising washing process for preparation of landscape gardening soil using UFAMSW.Implications: Our manuscript studies the removal of heavy metals from the contaminated undersized fraction from aged municipal solid waste (UFAMSW). UFAMSW, as a kind of soil-like material, has been proved effective in providing a large amount of organic matter and nutrients for soil and plants however often limited by heavy metal pollution. The UFAMSW used in this experiment was collected after the excavation and screening-sorting of aged refuse from Changshankou Domestic Waste Sanitary Landfill in Wuhan City, Hubei Province, Southern China. This study investigated the effects of EDTA, CA, HA, mixed EDTA/HA, and mixed CA/HA washing on heavy metal removal (Cu, Zn, and Mn), bioavailability of residual heavy metal and properties. The effects of chelating agent concentration, pH, and washing time on metal removal were investigated and then response surface methodology was employed to optimize the washing conditions. The results showed that washing by CA/HA and EDTA/HA, had a higher removal efficiency of heavy metals (Cu, Zn, and Mn) in UFAMSW compared to single HA. Meanwhile, HA has a higher removal for exchangeable fraction of heavy metals, the exchangeable concentration of Cu, Zn, and Mn in CA/HA and EDTA/HA washed UFAMSW were lower compared with UFAMSW washed by single CA and EDTA. Thus, mixing HA with EDTA or CA makes a less risk to environmental and the removal efficiency is acceptable. Additionally, CA/HA and EDTA/HA washing tend to improve soil physicochemical properties and soil fertility. Thus, mixing HA with different washing agent are potential methods for preparation of landscape gardening soil using UFAMSW.

The dynamic recruitment of LAB proteins senses meiotic chromosome axis differentiation in C. elegans.

During meiosis, cohesin and meiosis-specific proteins organize chromatin into an axis-loop architecture, coordinating homologous synapsis, recombination, and ordered chromosome segregation. However, how the meiotic chromosome axis is assembled and differentiated with meiotic progression remains elusive. Here, we explore the dynamic recruitment of two long arms of the bivalent proteins, LAB-1 and LAB-2, in Caenorhabditis elegans. LAB proteins directly interact with the axis core HORMA complexes and weak interactions contribute to their recruitment. LAB proteins phase separate in vitro, and this capacity is promoted by HORMA complexes. During early prophase, synapsis oppositely regulates the axis enrichment of LAB proteins. After the pachytene exit, LAB proteins switch from a reciprocal localization pattern to a colocalization pattern, and the normal dynamic pattern of LAB proteins is altered in meiotic mutants. We propose that LAB recruitment senses axis differentiation, and phase separation of meiotic structures helps subdomain establishment and accurate segregation of the chromosomes.

Bioactive fiber-reinforced hydrogel to tailor cell microenvironment for structural and functional regeneration of myotendinous junction.

Myotendinous junction (MTJ) injuries are prevalent in clinical practice, yet the treatment approaches are limited to surgical suturing and conservative therapy, exhibiting a high recurrence rate. Current research on MTJ tissue engineering is scarce and lacks in vivo evaluation of repair efficacy. Here, we developed a three-dimensional-printed bioactive fiber-reinforced hydrogel containing mesenchymal stem cells (MSCs) and Klotho for structural and functional MTJ regeneration. In a rat MTJ defect model, the bioactive fiber-reinforced hydrogel promoted the structural restoration of muscle, tendon, and muscle-tendon interface and enhanced the functional recovery of injured MTJ. In vivo proteomics and in vitro cell cultures elucidated the regenerative mechanisms of the bioactive fiber-reinforced hydrogel by modulating oxidative stress and inflammation, thus engineering an optimized microenvironment to support the survival and differentiation of transplanted MSCs and maintain the functional phenotype of resident cells within MTJ tissues, including tendon/muscle cells and macrophages. This strategy provides a promising treatment for MTJ injuries.

CD4 T cells and CD8α+ lymphocytes are necessary for intravenous BCG-induced protection against tuberculosis in macaques.

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose of BCG vaccination from 5×105 CFU ID to 5×107 CFU intravenous (IV) resulted in prevention of infection and disease in a rigorous, highly susceptible non-human primate model of TB. Identifying the immune mechanisms of protection for IV BCG will facilitate development of more effective vaccines against TB. Here, we depleted select lymphocyte subsets in IV BCG vaccinated macaques prior to Mtb challenge to determine the cell types necessary for that protection. Depletion of CD4 T cells or all CD8α expressing lymphoycytes (both innate and adaptive) resulted in loss of protection in most macaques, concomitant with increased bacterial burdens (~4-5 log10 thoracic CFU) and dissemination of infection. In contrast, depletion of only adaptive CD8αß+ T cells did not significantly reduce protection against disease. Our results demonstrate that CD4 T cells and innate CD8α+ lymphocytes are critical for IV BCG-induced protection, supporting investigation of how eliciting these cells and their functions can improve future TB vaccines.