Circadian time- and sleep-dependent modulation of cortical parvalbumin-positive inhibitory neurons.

Parvalbumin-positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time- and sleep-dependent manner throughout the 24-h day. We first show that PV-evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus-evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Evaluation of combining ultrapulse CO2 with fractional CO2 laser for the treatment of atrophic scars in Asians.

Various treatment modalities have been applied to atrophic scars. Fractional CO2 laser treatment has attracted increasingly more attention because of its quicker recovery time and fewer side effects. However, its limitation of sculpting the edge is an urgent shortcoming. In order to achieve a more effective result with fewer complications, we have integrated ultrapulse CO2 and fractional CO2 lasers to for the treatment of facial atrophic scars. The study included 25 patients (10 males and 15 females) diagnosed with moderate to severe atrophic scars between August 2020 and July 2022. All subjects underwent the same surgical treatment. The effects were assessed at baseline, 1 week, 1 month, and 3 months using photographic evidence. Objective evaluation of the results was conducted using a quartile grading scale, while the subjects' satisfaction and any adverse events were also recorded. The patients in the study underwent more than two laser sessions (2-5), resulting in substantial improvement in their appearance. The time interval between each session was 3-6 months. The majority of the patients (19/25, 76%) had a significant or even excellent improvement. Any adverse events observed, such as erythema, superficial crusting, and PIH, were of a mild nature and temporary in duration. This treatment combined two CO2 lasers is an effective and safe choice for atrophic scars in Asians.

Sequential-Dependent Synthesis of Bimetallic Silver-Chromium Nanoparticles for Multichannel Sensing, Logic Computing, and 3 in 1 Information Protection.

Bimetallic nanomaterials (BNMs) have been used in sensing, biomedicine, and environmental remediation, but their multipurpose and comprehensive applications in molecular logic computing and information security protection have received little attention. Herein, This synthesis method is achieved by sequentially adding reactants under ice bath conditions. Interestingly, Ag-Cr NPs can dynamically selectively sense anions and reductants in multiple channels. Especially, ClO- can be quantitatively detected by oxidizing Ag-Cr NPs with detection limits of 98.37 nM (at 270 nm) and 31.83 nM (at 394 nm). Based on sequential-dependent synthesis process of Ag-Cr NPs, Boolean logic gates and customizable molecular keypad locks are constructed by setting the reactants as the inputs, the states of the resulting solutions as the outputs. Furthermore, dynamically selective response patterns of the Ag-Cr NPs can be converted into binary strings to exploit molecular crypto-steganography to encode, store, and hide information. By integrating the three dimensions of authorization, encryption, and steganography, 3 in 1 advanced information protection based on Ag-Cr nanosensing system can be achieved, which can enhance the anti-cracking ability of information. This research will promote the development and application of nanocomposites in the field of information security and deepen the connection between molecular sensing and the information world.

Multifunctional Carbon Nanocomposites as Nanoneurons from Multimode and Multianalyte Sensing to Molecular Logic Computing, Steganography, and Cryptography.

Inspired by information exchange and logic functions of life based on molecular recognition and interaction networks, ongoing efforts are directed toward development of molecular or nanosystems for multiplexed chem/biosensing and advanced information processing. However, because of their preparation shortcomings, poor functionality, and limited paradigms, it is still a big challenge to develop advanced nanomaterials-based systems and comprehensively realize neuron-like functions from multimode sensing to molecular information processing and safety. Herein, using fish scales derived carbon nanoparticles (FSCN) as a reducing agent and stabilizer, a simple one-step synthesis method of multifunctional silver-carbon nanocomposites (AgNPs-FSCN) is developed. The prepared AgNPs-FSCN own wide antibacterial and multisignal response abilities in five channels (including color, Tyndall, absorption and fluorescence intensities, and absorption wavelength) for quantitative colorimetric and fluorescence sensing of H2 O2 , ascorbic acid, and dopamine. Benefiting from its multicoding stimuli-responsive ability, molecular concealment, and programmability, AgNPs-FSCN can be abstracted as nanoneurons for implementing batch and parallel molecular logic computing, steganography, and cryptography. This research will promote the preparation of advanced multifunctional nanocomposites and the development of their multipurpose applications, including the multireadout-guided multianalyte intelligent sensing and sophisticated molecular computing, communication, and security.

Nerve biopsy: Current indications and decision tools.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

The efficacy of fractional CO2 laser in acne scar treatment: A meta-analysis.

Fractional CO2 laser is a good option for treating acne scars. However, the clinical efficacy of this treatment modality requires further evidence. To perform a meta-analysis to assess clinical improvements in acne scars with fractional CO2 laser and non-CO2 laser therapies. Databases (PubMed, Embase, Cochrane Library) were searched using the search strategy to identify eligible studies. All statistical analyses were performed using the Review Manager 5.0, and a meta-analysis was conducted to assess the effects of fractional CO2 laser used as a treatment for acne scars. Eight studies were included for further analysis. There was no significant difference between fractional CO2 laser and non-CO2 laser therapies in terms of clinical improvement, observer assessment (P = .19), patient assessment (P = .91), and incidence of post-inflammatory hyperpigmentation (P = .69). The subgroup analyses showed that the duration of follow-up had little effect on the evaluation of treatment effect. The efficacy of fractional CO2 laser therapy in acne scars appeared to be equal to that of non-CO2 laser therapies. More well designed randomized controlled trials and more credible and standard evaluation criteria are needed, and the efficiency of combination therapy requires further analysis.

TGFß2-mediated epithelial-mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance.

Osimertinib (AZD9291) has been widely used for the treatment of EGFR mutant non-small cell lung cancer. However, resistance to osimertinib is inevitable. In this study we elucidated the molecular mechanisms of resistance in osimertinib-resistant NCI-H1975/OSIR cells. We showed that NCI-H1975/OSIR cells underwent epithelial-mesenchymal transition (EMT), which conferred sensitivity to the GPX4 inhibitor 1S, 3R-RSL3 to induce ferroptotic cell death. The EMT occurrence resulted from osimertinib-induced upregulation of TGFß2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-κB pathway for survival, since treatment with the NF-κB pathway inhibitor BAY 11-7082 or genetic silence of p65 caused much greater cell death as compared with the parental NCI-H1975 cells. In NCI-H1975 cells, osimertinib activated NF-κB pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGFß2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-κB pathway. In addition, coexistence of EMT and activation of NF-κB pathway was observed in several NCI-H1975/OSIR clones. These findings shed new light on distinct roles of TGFß2 in osimertinib-resistant cells and provide new strategies for treatment of this resistant status.

Challenges in diagnosing hydroxychloroquine myopathy during the COVID-19 pandemic.

Hydroxychloroquine is being used for COVID-19 symptoms and in clinical trials, but can cause a toxic myopathy that leads to muscle weakness. A review of skeletal muscle biopsies from patients with hydroxychloroquine myopathy gives pointers of steps that can be taken to diagnose this toxic myopathy early and help differentiate it from COVID-19-related muscle weakness.

[Effects of combination of dihydroartemisinin and Huobahua on expression of p-p38 MAPK and ICAM-1 in mice with delayed-type hypersensitivity].

The aim of this paper was to investigate the immunosuppressive effects of dihydroartemisinin and Huobahua compatibility in mice with delayed hypersensitivity and explore its possible mechanism. The delayed-type hypersensitivity(DTH) model in mice was established to observe the immunosuppressive effects of dihydroartemisinin and Huobahua compatibility in DTH mice. ELISA assay was used to detect the contents of interferon(IFN-γ); histopathological changes and degree of mononuclear infiltration of right ear tissues were examined by HE staining; the expression level of intercellular cell adhesion molecule-1(ICAM-1) in the right ear of mice was detected by immunohistochemistry; the protein expression levels of p38 phospho mitogen activated protein kinase(p-p38 MAPK) was detected by Western blot analysis. As compared with the control group, the degree of ear swelling, thymus/spleen index, serum IFN-γ as well as the number and degree of infiltration of monocytes were significantly increased in the model group. As compared with the model group, the degree of ear swelling and thymus/spleen index of the mice in the combination group were significantly reduced; the number and degree of infiltration of monocytes were significantly relieved; the serum levels of IFN-γ and the expression levels of p-p38 MAPK and ICAM-1 proteins in the right ear were also significantly reduced. The combination of dihydroartemisinin and Huobahua can significantly inhibit the DTH response, and it may regulate the production and secretion of related inflammatory factor IFN-γ by inhibiting the phosphorylation activity of p38 MAPK, thereby further reducing the expression of ICAM-1 and thus exerting the immunosuppressive effect.

The source of ACE during scar formation is from both bone marrow and skin tissue.

Angiotensin-converting enzyme (ACE) has been found in the pathogenesis of various fibrosis diseases, and ACE inhibitor (ACEI) may affect wound healing and cutaneous fibrosis. However, there is no scientific evidence as to where the ACE is produced during scar formation. Whether it is from the cutaneous tissue or the bone marrow, or both remains unknown. In this study, we investigated the source of ACE using bone marrow transplantation in genetically modified mice, analyzed the inflammatory milieu and some growth factors in the middle of the wound healing period (4 d after the wound was induced). After having deleted the ACE from bone marrow or skin tissue, the wound/scar width in the low-ACE groups were narrower than those in wild-type (WT) controls. Loosely arranged collagen deposition and reduced vessel density were also detected in ACE-deficient mice. Lower ACE levels during scar formation were also accompanied by lower levels of TGF-ß1. In the middle of the wound healing period, ACE levels affected the inflammatory cells significantly. In the mice with a deficiency in ACE, the expression of TGF-ß1 and TNF-α decreased, but not that of IL-4. Our findings indicate that both bone marrow and skin tissue release ACE during scar formation. Deleting either of them can affect the inflammatory cells and growth factors and reduce the expression of TGF-ß1, resulting in a decreased level of scarring.-Fang, Q.-Q., Wang, X.-F., Zhao, W.-Y., Chen, C.-Y., Zhang, M.-X., Shi, B.-H., Zhang, L.-Y., Tan, W.-Q. The source of ACE during scar formation is from both bone marrow and skin tissue.

Vasculitic neuropathy: Comparison of clinical predictors with histopathological outcome.

INTRODUCTION: To improve diagnostic accuracy, in this study we compared prebiopsy clinical parameters with subsequent pathological confirmation of peripheral nerve vasculitis. METHODS: Clinical, laboratory, and neurophysiological parameters were analyzed for consecutive patients referred for nerve biopsy with suspected vasculitis. Patients were assigned pathological categories of definite, probable, possible, or absent vasculitis using validated guidelines. Patients with definite or probable vasculitis were considered to have pathologically confirmed vasculitis. RESULTS: From a cohort of 78 patients, biopsy confirmed vasculitis in 29.5%. Parameters that best differentiated between pathologically confirmed and pathologically unlikely vasculitis were stepwise clinical progression (34.8% vs. 5.6%), the presence of serum anti-myeloperoxidase antibody (28.6% vs. 2.2%) and rheumatoid factor seropositivity (38.1% vs. 10.7%). Pathologically absent vasculitis was frequent in patients with normal (100%) or primarily demyelinating (87.5%) nerve conduction studies. DISCUSSION: Factoring the negative predictors of pathologically confirmed vasculitis into decision-making can reduce the frequency of diagnostically unhelpful nerve biopsies. Muscle Nerve 59:643-649, 2019.

Computed Tomography-Assisted Auricular Cartilage Graft for Depression of the Alar Base in Secondary Unilateral Cleft Lip Repair: A Preliminary Report.

OBJECTIVES: To evaluate the feasibility, effectiveness, and safety of computed tomography-assisted auricular cartilage grafting for treating alar base depression secondary to unilateral cleft lip. DESIGN AND SETTING: For patients with obvious depression of the alar base, the difference in heights of the alar base and the piriform margin between the cleft side and the noncleft side were measured with computed tomography. If both were >3.0 mm, the cartilage was harvested postauricularly and subdivided into 2 to 4 pieces. A multiple layer graft was inserted under the depressed alar base. The procedure was performed from 2006 to 2013, and the follow-up period was 3 to 15 months. PARTICIPANTS: Chinese patients with alar base depression secondary to unilateral cleft lip were selected. INTERVENTION: Suture and cartilage graft techniques. MAIN OUTCOMES MEASURES: Differences in bilateral alar base heights and piriform apertures. RESULTS: There was no wound dehiscence, exposure of bone, or donor site morbidity. The difference in heights in the bilateral alar bases and piriform apertures decreased. There were no obvious scars in any of the cases. CONCLUSIONS: This technique has several advantages including ease of operation, minimal trauma, satisfactory outcomes, and useful references for operation provided by computed tomography. It is a superior alternative for reconstruction of secondary alar depression.

Anncaliia algerae Microsporidial Myositis, New South Wales, Australia.

We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.

MLKL mediates apoptosis via a mutual regulation with PERK/eIF2α pathway in response to reactive oxygen species generation.

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a core effector of necroptosis, and its function in necroptosis is widely studied. However, the function of MLKL in apoptosis remains unclear. In the present study, the role of MLKL in chelerythrine (CHE)-promoted apoptosis was studied. A special band of MLKL (i.e., *MLKL) was observed after treatment with CHE. MLKL and *MLKL were accumulated in the nucleus upon treatment with CHE and MLKL silencing reversed the CHE-induced apoptosis. Blockade of CHE-triggered reactive oxygen species (ROS) generation or inhibition of CHE-activated protein kinase-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α subunit (eIF2α) pathway reversed the apoptosis. A decreased ROS level inhibited CHE-mediated nuclear translocation of MLKL and *MLKL and the activation of eIF2α, whereas MLKL or eIF2α silencing did not affect the CHE-triggered ROS generation. Furthermore, MLKL silencing prevented the CHE-activated eIF2α signal, and eIF2α silencing blocked the CHE-induced nuclear translocation of MLKL and *MLKL. Our studies suggested that CHE possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK-eIF2α pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis.

Clinical Application of 3-Dimensional Continuous Suturing Technique for Triangular Wounds.

BACKGROUND: Although there are numerous skin closure methods, there is no special method for suturing triangular skin wounds. The authors have summarized and modified their experience with a 3-dimensional (3D) continuous suturing technique for triangular wounds. METHODS: From December 2015 to September 2017, the 3D continuous suturing technique for triangular wounds has been used in 32 cleft lip repairs (48 surgical triangular incisions) and 11 cases of facial trauma (15 traumatic triangular wounds). The patients, 3 months to 39 years of age, had triangular flaps designed for esthetic purposes or triangular defects secondary to accidents. To evaluate the effectiveness of this technique, the mean follow-up was 7 months (range, 1-15 months). RESULTS: The 3D continuous suturing technique for triangular wounds can shorten the suturing time, decrease the number of thread knots, and shorten the time of surgery. All patients healed well and the stitches were removed 7 days postoperatively. The wound on both sides of the triangle was well arranged, with a good appearance and no scar hyperplasia. CONCLUSIONS: Our experience showed that the 3D continuous suturing technique for triangular wounds is a time-saving and convenient method and can make the wounds closed tighter, more stable, and reliable. The technique can be applied to any type of triangular wounds or incisions and is not limited to the clinical scenarios described in this article.

Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells.

Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-l-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells.

Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells. Pretreatment with the N-linked glycosylation inhibitor tunicamycin, osimertinib clearly decreased the production of new PD-L1 protein probably due to a reduction in mRNA. After blocking transcription and translation processes with actinomycin D and cycloheximide, respectively, osimertinib continued to reduce the expression of PD-L1, demonstrating that osimertinib might degrade PD-L1 at the post-translational level, which was confirmed by a cycloheximide chase assay, revealing that osimertinib (125 nmol/L) decreased the half-life of PD-L1 from approximately 17.8 h and 13.8 h to 8.6 h and 4.6 h, respectively, in NCI-H1975 and HCC827 cells. Pretreatment with the proteasome inhibitors (MG-132 or bortezomib) blocked the osimertinib-induced degradation of PD-L1, but an inhibitor of autophagy (chloroquine) did not. In addition, inhibition of GSK3ß by LiCl prevented osimertinib-induced PD-L1 degradation. The results demonstrate that osimertinib reduces PD-L1 mRNA expression and induces its protein degradation, suggesting that osimertinib may reactivate the immune activity of T cells in the tumor microenvironment in EGFR-mutated NSCLC patients.

Retrograde laparoscopic resection of left side of the liver: a safe and effective way.

OBJECTIVE: The safety and feasibility of retrograde laparoscopic resection of the left side of the liver. METHODS: Ninety-three laparoscopic left hepatic lobe cases were selected between August 2010 and August 2014 from our institution. A retrospective cohort study was performed between the antegrade partial hepatectomy group (47 cases; dissection from the first porta hepatis to the second) and the retrograde partial hepatectomy group (46 cases; dissection from the second porta hepatis to the first), to compare the length of time needed for resection, the amount of bleeding, post-operative time in the hospital, and the incidence of major complications, such as bile leakage, abdominal abscess, and post-hepatectomy hemorrhage. RESULTS: All of the cases had a successful laparoscopic partial hepatectomy without the need for an intraoperative blood transfusion. Patients were able to ambulate on post-operative day 1 and tolerated a liquid diet on post-operative day 1 or 2. There were no statistical differences of post-operative hospital length of stay or incidence of major complications between the two groups. Both duration of resection and the amount of bleeding were less in the retrograde group than of those in the antegrade group, due to the lower incidence of hepatic vein injury in the retrograde group. CONCLUSION: Occlusion of both the inflow and outflow hepatic vessels combined with retrograde hepatectomy from the second porta hepatis to the first, demonstrated less hemorrhage and lower incidence of hepatic veins injury during laparoscopic partial hepatectomy.

[Food-borne Parasitic Infection in Intermediate Hosts in Ninghai County of Zhejiang Province].

To understand the status of food-borne parasitic infection in intermediate hosts in Ninghai County of Zhejiang Province, freshwater crabs were collected from 4 towns of the County to detect the infection with metacercariae of Paragonimus, and frogs were collected from 8 towns to examine the infection with plerocercoid of Spirometra mansoni from May to September, 2015. Among the 339 freshwater crabs collected, the infection rate was 9.1%（31/339）, with each crab containing 6.7 metacercariae of Paragonimus on average. Among the 348 frogs collected, the infection rate was 11.5%（40/348）, with each frog containing 2.2 plerocercoids on average. In conclusion, there is a high rate of food-borne parasitic infection in intermediate hosts in Ninghai County. Comprehensive prevention and control measures are needed.