Disruption of FLNB leads to skeletal malformation by interfering with skeletal segmentation through the HOX gene.

Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNBG1586R/G1586R and FLNBWT/G1586R mice, compared to FLNBWT/WT mice. Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNBG1586R/G1586R mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period.

TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.

BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells. METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1ß, IL-18, IL-6, and tumor necrosis factor-α (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively. RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1ß, IL-18, IL-6, and TNF-α, and promoted the expression of active IL-1ß, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells. CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.

A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

Effect of hematoma volume on the 30-day mortality rate of patients with primary hypertensive brainstem hemorrhage: a retrospective cohort study.

Objective: The purpose of this study is to investigate the effect of hematoma volume on the 30-Day Mortality Rate of patients with Primary Hypertensive Brainstem Hemorrhage (PHBH). Methods: Retrospective analysis was done on the clinical information of 74 patients who underwent treatment for primary hypertensive brainstem hemorrhage at the Department of Neurosurgery of the 908th Hospital of the Joint Logistic Support Force of the Chinese People's Liberation Army between January 2018 and December 2021. Both univariate and multivariate logistic regression were used to assess clinical signs and risk factors that affect 30-day mortality. Results: In the 74 patients with primary hypertensive brainstem hemorrhage included in this investigation, 46 patients died and 28 patients survived. The mortality rate at 30 days was 62.16%. A statistically significant difference was seen (P < 0.001) in the results of the univariate analysis, which suggested that hematoma volume may be a factor affecting the prognosis of patients with hypertensive brainstem hemorrhage. Hematoma volume was further demonstrated to be a risk factor and an independent factor impacting death in patients with brainstem hemorrhage (P < 0.001) by multivariate logistic regression analysis (OR: 2.6, 95% CI: 1.7-3.9, P < 0.001 Crude Model, OR: 3.6, 95% CI: 1.7-7.7, P < 0.001 Multivariate-Adjusted Model). After adjusting for confounding variables such as age, body mass index, sex, history of diabetes mellitus, history of hypertension, admission GCS score, stereotactic aspiration, combined hydrocephalus, admission systolic and diastolic blood pressure, the hematoma volume was revealed to be an independent predictor of 30-day death in patients with brainstem hemorrhage. We discovered by smooth curve fitting that hematoma volume increased in a non-linear manner with 30-day mortality. The 30-day mortality rate did not alter significantly when the hematoma volume was less than 4 ml. When the hematoma volume was greater than 4 ml, the 30-day mortality rate increased rapidly, and when the hematoma volume was 10 ml, the 30-day mortality rate reached the maximum. Conclusions: Hematoma volume is an independent factor affecting 30-day mortality in patients with primary hypertensive brainstem hemorrhage. The severe and extensive neurological damage caused by primary hypertensive brainstem hemorrhage is highly unlikely to be fundamentally altered by a single protocol, and new avenues need to be explored scientifically and continuously.

Hillock Related Degradation Mechanism for AlGaN-Based UVC LEDs.

Heteroepitaxial growth of high Al-content AlGaN often results in a high density of threading dislocations and surface hexagonal hillocks, which degrade the performance and reliability of AlGaN-based UVC light emitting diodes (LEDs). In this study, the degradation mechanism and impurity/defect behavior of UVC LEDs in relation to the hexagonal hillocks have been studied in detail. It was found that the early degradation of UVC LEDs is primarily caused by electron leakage. The prominent contribution of the hillock edges to the electron leakage is unambiguously evidenced by the transmission electron microscopy measurements, time-of-flight secondary ion mass spectrometry, and conductive atomic force microscopy. Dislocations bunching and segregation of impurities, including C, O, and Si, at the hillock edges are clearly observed, which facilitate the trap-assisted carrier tunneling in the multiple quantum wells and subsequent recombination in the p-AlGaN. This work sheds light on one possible degradation mechanism of AlGaN-based UVC LEDs.

Encapsulation of STING Agonist cGAMP with Folic Acid-Conjugated Liposomes Significantly Enhances Antitumor Pharmacodynamic Effect.

Background: 2',3'-cGAMP (2',3'-cyclic AMP-GMP) has been reported as an agonist of the STING (stimulator of interferon genes) signaling pathway. However, cGAMP has poor membrane permeability and can be hydrolyzed by ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), limiting its ability to activate the STING-IRF3 pathway. This study aimed to investigate that the folate-targeted liposomal cGAMP could overcome the defects of free cGAMP to enhance the antitumor effect. Materials and Methods: cGAMP was encapsulated in PEGylated folic acid-targeted liposomes to construct a carrier-delivered formulation. The particle size and morphology were detected by dynamic light scattering and transmission electron microscopy. The sustained-release ability was measured by drug release and pharmacokinetics. Animal models were applied to evaluate the tumor inhibition efficiency in vivo. Flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction were used to detect the expression of immune cells, secreted cytokines, and target genes. The activation of the STING-IRF3 pathway was evaluated by immunofluorescence. Results: Physical characters of liposomes revealed that the prepared liposomes were stable in neutral humoral environments and released more internal drugs in acidic tumor tissues. Systemic therapy with liposomes on Colorectal 26 tumor-bearing mice in vivo effectively inhibited tumor growth via stimulating the expression of CD8+ T cells and reversed the immunosuppressed tumor microenvironment (TME). Conclusions: The study suggests that the folic acid-targeted cGAMP-loaded liposomes deliver drugs to the TME to enhance the STING agonist activity, improving the efficiency of tumor therapy via the cGAMP-STING-IRF3 pathway.

TRIM46 upregulates Wnt/ß-catenin signaling by inhibiting Axin1 to mediate hypoxia-induced epithelial-mesenchymal transition in HK2 cells.

Hypoxia can cause Epithelial-mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family proteins, and mesenchymal markers under hypoxia. Our results showed that hypoxia significantly enhanced expression of TRIM46 in HK2 human renal proximal tubular epithelial cells. Our data further showed that hypoxia led to upregulated expression of mesenchymal markers including α-smooth muscle actin, vimentin, and Snail, and downregulated expression of epithelial marker E-cadherin, coupled with an increased abundance of nuclear ß-catenin. However, such effects were reversed when TRIM46 expression was knocked down. TRIM46 overexpression had similar effects as hypoxia exposure, and such effects were reversed when cells were treated with XAV-939, a selective inhibitor for ß-catenin. Furthermore, we found that TRIM46 promoted ubiquitination and proteasomal degradation of Axin1 protein, a robust negative regulator of Wnt/ß-catenin signaling activity. Finally, increased TRIM46 coupled with decreased Axin1 was observed in a rat renal fibrosis model. These data suggest a novel mechanism contributing to EMT that mediates hypoxia-induced renal fibrosis. Our results suggest that selectively inhibiting this pathway that activates fibrosis in human kidney may lead to development of a novel therapeutic approach for managing this disease.

Avoiding Misdiagnosis and Missed Diagnosis for Appropriately Treating Spinal Osteoid Osteomas: A Single-Center Experience.

OBJECTIVES: To analyze the causes of misdiagnosis and missed diagnosis in spinal osteoid osteoma, and to put forward solutions to improve diagnosis accuracy and treatment efficacy in patients. METHODS: We performed a retrospective cohort study on patients with spinal osteoid osteoma in Beijing Jishuitan Hospital from January 1983 to September 2019. All patients underwent surgery. The outcome measures were the extent of local pain, nocturnal pain, radicular symptoms of extremities after surgery, and reduction or disappearance of lesions on CT after surgery. RESULTS: Thirty-seven patients with spinal osteoid osteoma were recruited in the study. A total of 27% were female, and the mean (SD) age at diagnosis was 21.3 (8.7) years. A total of 87.0% of patients presented with nocturnal pain, and 94.7% of patients were responsive to NSAIDS treatment. The mean (SD) time from the initial onset of symptoms to the final diagnosis was 14.7 (12.5) months. Only four of 37 (10.8%) patients were correctly diagnosed with spinal osteoid osteoma on the first visit to the local hospital. CT is associated with a higher diagnosis rate than X-ray or MRI on the first visit. Surgical navigation was used in 88.9% of patients who underwent curettage resection, and in 10% of patients who underwent en bloc resection. A total of 37 of 37 patients (100%) reported relief of local pain and radicular symptoms of extremities after surgery, and no recurrence of tumors was found during follow-ups. CONCLUSIONS: Spinal CTs are recommended to be performed if osteoid osteoma is suspected based on clinical manifestation, including nocturnal pain and responsiveness to NSAIDS treatment, to avoid misdiagnosis and missed diagnosis of spinal osteoid osteoma.

Activation of STING by cGAMP Regulates MDSCs to Suppress Tumor Metastasis via Reversing Epithelial-Mesenchymal Transition.

The role of cGAMP stimulating cGAS-cGAMP-STING-IRF3 pathway to inhibit tumor growth was well-established. Herein, the efficiency and pharmacological mechanism of cGAMP on regulating tumor metastasis was investigated. The effects of cGAMP regulating CD8+ T cells and myeloid-derived suppressor cells (MDSCs) in tumor microenvironment was explored. In this study, we found that cGAMP boosted STING signaling pathway to activate the production of IFN-γ from CD8+ T cells, and decreased the population of MDSCs in vivo. The metastasis in CT26 tumor bearing mice was inhibited by cGAMP via regulating EMT process. cGAMP played an important role in suppressing the production of reactive oxygen species (ROS) and nitric oxide (NO) from MDSCs, abolished the suppressive function of MDSCs to the T cells. All in all, the results indicated that the STING agonist cGAMP activated the production of IFN-γ from CD8+ T cells to suppress MDSCs in vivo.

The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis.

Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

Pancreatic fistula after pancreaticoduodenectomy: Risk factors and preventive strategies.

PURPOSE: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is a worrisome and life-threatening complication. This study aimed to investigate the risk factors and preventive strategies for POPF after PD. MATERIALS AND METHODS: We retrospectively reviewed 301 consecutive patients who underwent PD at our hospitals between January 2011 and December 2017. We analyzed the pancreatic fistula rate according to the clinical characteristics, pathologic and laboratory findings, and the anastomotic methods and summarized the prevention measures. RESULTS: Postoperative morbidities included pancreatic leakage in 10.30% (31/301), delayed gastric emptying in 22.92% (69/301), abdominal infection in 6.98% (21/301), post-PD hemorrhage in 4.65% (14/301), and bile leakage in 4.98% (15/301), and the mortality rate was 2.33% (7/301). POPF was the most prominent factor for preoperative morbidity. Significant risk factors for pancreatic fistula were a soft pancreas, small pancreatic duct, tumor location, and interrupted anastomosis. Of these, soft texture, pancreatic duct <4 mm, and end-to-end anastomosis through hand suture closure were independent risk factors on multivariate analysis, while interrupted anastomosis, internal stent, and somatostatin use were risk factors in the high-risk pancreas subgroup. CONCLUSIONS: Our study demonstrated that pancreatic fistula is related to a soft texture and small pancreatic duct. The surgeon must consider these risk factors when performing PD. Thus, we propose a risk- and indication-adapted choice of anastomosis or an individualized approach for the pancreatic remnant to reduce the pancreatic fistula rate.

Efficacy and mechanism of cGAMP to suppress Alzheimer's disease by elevating TREM2.

Innate immune responses are considered to play crucial roles in the progression of Alzheimer's disease (AD). Recently, immunotherapy is emerging as an innovative and highly conceivable strategy for AD treatment. The cGAMP-STING-IRF3 signaling pathway plays a pivotal role in mediating innate immune responses. In this study, we provide pioneering investigation to find that the STING stimulator, cGAMP, significantly ameliorates cognitive deficits, improves pathological changes, decreases Aß plaque load and reduces neuron apoptosis in APP/PS1 transgenetic mice. The stimulation of cGAMP-STING-IRF3 pathway induces expression of triggering receptor expressed on myeloid cells 2 (TREM2), and the overexpression of TREM2 further decreases Aß deposition and neuron loss while improves AD pathomorphology and cognitive impairment. Additionally, TREM2 regulates microglia polarization from M1 towards M2 phenotype thereby achieves reduction of neuroinflammation in AD. These findings support that the enhancement of TREM2 exerts beneficial effects in ameliorating AD development. Taken together, our results demonstrate that cGAMP is a potential candidate for applications in Alzheimer's disease immunotherapy.

How to allocate discharge permits more fairly in China?-A new perspective from watershed and regional allocation comparison on socio-natural equality.

Equitable and efficient allocation of pollutant discharge permits is vital for controlling total pollutant amounts. However, the conventional water pollutant discharge permit allocation method is criticized for dividing the environmental attributes of water bodies, which is mainly based on administrative units. China is establishing a water ecological environment zoning management system to manage the water environment more scientifically, which may have a great impact on for controlling total pollutant amounts. Whether the ecological environment zoning management system can promote more equitable and efficient permit allocation remains unknown. In this paper, an environmental zoning system and "basin-region" correlation are established to take both regional and watershed allocation processes into consideration. Then, a multi-index Gini coefficient method is established to evaluate the equality of different allocating methods. The Gini coefficient is then combined with a linear interactive and general optimizer method to achieve an equitable allocation of ammonia nitrogen discharge permits in the Songhua River Basin from both watershed and regional perspectives. Forty-five water pollutant discharge allocation scenarios are considered to represent different manager tendencies. The results show that allocation based on watershed functional units is more equitable than that based on administrative units. The index weighting settings also have a large impact on regional and total equality and environmental efficiency. Midstream and downstream areas show large allocation differences, although no scenario can satisfy all watershed regions in terms of equality and environmental efficiency at the same time. Thus, more trade-offs are needed during decision making. By considering the coordination of social, environmental and economic development at the basin level, this study provides new insight into equitable and efficient allocation. Moreover, the findings suggest that an environmental zoning system should be considered for discharge permit allocation in water resource management.

Comparative analysis of the two extremes of FLNB-mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings.

Non-randomly distributed missense mutations of Filamin B (FLNB) can lead to a spectrum of autosomal dominant-inherited skeletal malformations caused by bone hypoplasia, including Larsen syndrome (LS), atelosteogenesi-I (AO-I), atelosteogenesi-I (AO-III) and boomerang dysplasia (BD). Among this spectrum of diseases, LS causes a milder hypoplasia of the skeletal system, compared to BD's much more severe symptoms. Previous studies revealed limited molecular mechanisms of FLNB-related diseases but most of them were carried out with HEK293 cells from the kidney which could not reproduce FLNB's specificity to skeletal tissues. Instead, we elected to use ATDC5, a chondrogenic stem cell line widely used to study endochondral osteogenesis. In this study, we established FLNB-transfected ATDC5 cell model. We reported a pedigree of LS with mutation of FLNBG1586R and reviewed a case of BD with mutation of FLNBL171R . Using the ATDC5 cell model above, we compared cellular and molecular phenotypes of BD-associated FLNBL171R and LS-associated FLNBG1586R . We found that while both phenotypes had an increased expression of Runx2, FLNBL171R-expressing ATDC5 cells presented globular aggregation of FLNB protein and increased cellular apoptosis rate while FLNBG1586R-expressing ATDC5 cells presented evenly distributed FLNB protein and decreased cellular migration. These findings support our explanation for the cause of differences in clinical phenotypes between LS and BD. Our study makes a comparative analysis of two extremes of the FLNB-mutated autosomal dominant spectrum, relating known clinical phenotypes to our new cellular and molecular findings. These results indicated next steps for future research on the role of FLNB in the physiological process of endochondral osteogenesis.

The Efficacy and Pharmacological Mechanism of Zn7MT3 to Protect against Alzheimer's Disease.

Alzheimer's disease (AD) is one of the leading causes of death for people over 65 years. Worse still, no completely effective therapeutic agent is available so far. One important pathological hallmark of AD is accumulated amyloid-ß (Aß) plaques with dysregulated metal homeostasis. Human metallothionin 3 (MT3), a regulator of metal homeostasis, is downregulated at least 30% in AD brain. So far, some in vitro studies demonstrated its multiple functions related to AD. However, it is a great pity that systematic in vivo studies of MT3 on AD model animals are still a blank so far. In this study, we treated APP/PS1 mice with sustained drug release of Zn7MT3 directly to the central nervous system, and investigated the role and molecular mechanism of Zn7MT3 to protect against AD mice systematically. The results demonstrated that Zn7MT3 can significantly ameliorate cognitive deficits, regulate metal homeostasis, abolish Aß plaque load, and reduce oxidative stress. Additionally, it has been confirmed that MT3 is penetrable to the blood brain barrier of AD mice. All these results support that Zn7MT3 is an effective AD suppressing agent and has potential for applications in Alzheimer's disease therapy.

Filamin B: The next hotspot in skeletal research?

Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Up to present, pathogenic mutations in FLNB are solely found to cause skeletal deformities, indicating the important role of FLNB in skeletal development. FLNB-related disorders are classified as spondylocarpotarsal synostosis (SCT), Larsen syndrome (LS), atelosteogenesis (AO), boomerang dysplasia (BD), and isolated congenital talipes equinovarus, presenting with scoliosis, short-limbed dwarfism, clubfoot, joint dislocation and other unique skeletal abnormalities. Several mechanisms of FLNB mutations causing skeletal malformations have been proposed, including delay of ossification in long bone growth plate, reduction of bone mineral density (BMD), dysregulation of muscle differentiation, ossification of intervertebral disc (IVD), disturbance of proliferation, differentiation and apoptosis in chondrocytes, impairment of angiogenesis, and hypomotility of osteoblast, chondrocyte and fibroblast. Interventions on FLNB-related diseases require prenatal surveillance by sonography, gene testing in high-risk carriers, and proper orthosis or orthopedic surgeries to correct malformations including scoliosis, cervical spine instability, large joint dislocation, and clubfoot. Gene and cell therapies for FLNB-related diseases are also promising but require further studies.

Polyanionic Antimicrobial Membranes: An Experimental and Theoretical Study.

Polycationic polymers have been widely used as antimicrobial materials because of their broad spectrum activity and potential use as new antibiotics. Herein, we report the synthesis of polyanionic antimicrobial membranes by in situ photo-cross-linking of a sulfate based anionic monomer, followed by cation-exchange with organic (quaternary ammonium or imidazolium) or metal (Ag+, Cu2+, Fe3+, Zn2+, Na+, K+) cations. The resultant polyanionic membranes show high and broad spectrum antibacterial activities against both bacteria (Escherichia coli, Staphylococcus aureus) and fungi (Candida albicans ). In addition, the polyanionic antimicrobial membranes efficiently inhibited the formation of biofilms by SC5314 and its crk1 gene deleted (Δcrk1) C. albicans strains. Furthermore, the synthesized polyanionic membranes exhibit good blood compatibility, low cytotoxicity and long-term antibacterial stability, demonstrating safe antimicrobial materials in the application of healthcare.

Flexible Light Emission Diode Arrays Made of Transferred Si Microwires-ZnO Nanofilm with Piezo-Phototronic Effect Enhanced Lighting.

Due to the fragility and the poor optoelectronic performances of Si, it is challenging and exciting to fabricate the Si-based flexible light-emitting diode (LED) array devices. Here, a flexible LED array device made of Si microwires-ZnO nanofilm, with the advantages of flexibility, stability, lightweight, and energy savings, is fabricated and can be used as a strain sensor to demonstrate the two-dimensional pressure distribution. Based on piezo-phototronic effect, the intensity of the flexible LED array can be increased more than 3 times (under 60 MPa compressive strains). Additionally, the device is stable and energy saving. The flexible device can still work well after 1000 bending cycles or 6 months placed in the atmosphere, and the power supplied to the flexible LED array is only 8% of the power of the surface-contact LED. The promising Si-based flexible device has wide range application and may revolutionize the technologies of flexible screens, touchpad technology, and smart skin.