Controlled Crystal Growth of All-Inorganic CsPbI2.2Br0.8 Thin Film via Additive Strategy for Air-Processed Efficient Outdoor/Indoor Perovskite Solar Cells.

The evolution of defects during perovskite film fabrication deteriorates the overall film quality and adversely affects the device efficiency of perovskite solar cells (PSCs). We endeavored to control the formation of defects by applying an additive engineering strategy using FABr, which retards the crystal growth formation of CsPbI2.2Br0.8 perovskite by developing an intermediate phase at the initial stage. Improved crystalline and pinhole-free perovskite film with an optimal concentration of FABr-0.8M% additive was realized through crystallographic and microscopic analysis. Suppressed non-radiative recombination was observed through photoluminescence with an improved lifetime of 125 ns for FABr-0.8M% compared to the control film (83 ns). The champion device efficiency of 17.95% was attained for the FABr-0.8M% PSC, while 15.94% efficiency was achieved in the control PSC under air atmospheric conditions. Furthermore, an impressively high indoor performance of 31.22% was achieved for the FABr-0.8M% PSC under 3200 K (1000 lux) LED as compared to the control (23.15%). With a realistic approach of air processing and controlling the crystallization kinetics in wide-bandgap halide PSCs, this investigation paves the way for implementing additive engineering strategies to reduce defects in halide perovskites, which can further benefit efficiency enhancements in outdoor and indoor applications.

In situ crystal reconstruction strategy-based highly efficient air-processed inorganic CsPbI2Br perovskite photovoltaics for indoor, outdoor, and switching applications.

All-inorganic CsPbI2Br (CPIB) perovskite has gained strong attention due to their favorable optoelectronic properties for photovoltaics. However, solution-processed CPIB films suffer from poor morphology due to the rapid crystallization process, which must be resolved for desirable photovoltaic performance. We introduced phenethylammonium iodide (PEAI) as an additive into a perovskite precursor that effectively controls the crystallization kinetics to construct the preferred quality α-CPIB film under ambient conditions. Various photophysical and structural characterization studies were performed to investigate the microstructural, morphological, and optoelectronic properties of the CPIB and PEAI-assisted perovskite films. We found that PEAI plays a vital role in decreasing pinholes, ensuring precise crystal growth, enhancing the crystallinity, improving the uniformity, and tailoring the film morphology by retarding the crystallization process, resulting in an improved device performance. The device based on the optimized PEAI additive (0.8 mg) achieved a respectably high power conversion efficiency (PCE) of 17.40% compared to the CPIB perovskite solar cell (PSC; 15.75%). Moreover, the CPIB + 0.8 mg PEAI PSC retained ∼87.25% of its original PCE, whereas the CPIB device retained ∼66.90% of the initial PCE after aging in a dry box at constant heating (85 °C) over 720 h, which revealed high thermal stability. Furthermore, the indoor photovoltaic performance under light-emitting diode (LED) lighting conditions (3200 K, 1000 lux) was investigated, and the CPIB + 0.8 mg PEAI PSC showed a promising PCE of 26.73% compared to the CPIB device (19.68%). In addition, we developed a switching function by employing the optimized PSC under LED lighting conditions, demonstrating the practical application of constructed indoor PSCs.

Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures.

Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.

EC-18 prevents autoimmune arthritis by suppressing inflammatory cytokines and osteoclastogenesis.

BACKGROUND: EC-18, a synthetic monoacetyldiaglyceride, exhibits protective effects against lung inflammation, allergic asthma, and abdominal sepsis. However, there have been no investigations to determine whether EC-18 has preventive potential in autoimmune diseases, especially rheumatoid arthritis (RA). METHODS: To investigate the efficacy of EC-18 on the development of RA, EC-18 was administered in a collagen-induced arthritis (CIA) murine model and disease severity and the level of inflammatory cytokines in the joint were investigated. The effect of EC-18 on the inflammation-related factors was investigated by flow cytometry, ELISA, western blot, and real-time PCR in splenocytes from mice and in peripheral blood mononuclear cells from healthy and patients with RA. The effect of EC-18 on osteoclastogenesis was investigated. RESULTS: EC-18 effectively reduced the clinical and histological severity of arthritis, similar to Janus kinase inhibitors include tofacitinib and baricitinib, in CIA. Furthermore, EC-18 exhibited a synergistic effect with methotrexate in preventing CIA. Treatment with EC-18 effectively reduced the production of inflammatory cytokines in immune cells and osteoclast differentiation in mice and patients with RA. CONCLUSION: These results suggest that EC-18 may be an effective strategy for RA.

Human visual consciousness involves large scale cortical and subcortical networks independent of task report and eye movement activity.

The full neural circuits of conscious perception remain unknown. Using a visual perception task, we directly recorded a subcortical thalamic awareness potential (TAP). We also developed a unique paradigm to classify perceived versus not perceived stimuli using eye measurements to remove confounding signals related to reporting on conscious experiences. Using fMRI, we discovered three major brain networks driving conscious visual perception independent of report: first, increases in signal detection regions in visual, fusiform cortex, and frontal eye fields; and in arousal/salience networks involving midbrain, thalamus, nucleus accumbens, anterior cingulate, and anterior insula; second, increases in frontoparietal attention and executive control networks and in the cerebellum; finally, decreases in the default mode network. These results were largely maintained after excluding eye movement-based fMRI changes. Our findings provide evidence that the neurophysiology of consciousness is complex even without overt report, involving multiple cortical and subcortical networks overlapping in space and time.

A machine-learning approach for predicting impaired consciousness in absence epilepsy.

Behavior during 3-4 Hz spike-wave discharges (SWDs) in absence epilepsy can vary from obvious behavioral arrest to no detectible deficits. Knowing if behavior is impaired is crucial for clinical care but may be difficult to determine without specialized behavioral testing, often inaccessible in practice. We aimed to develop a pure electroencephalography (EEG)-based machine-learning method to predict SWD-related behavioral impairment. Our classification goals were 100% predictive value, with no behaviorally impaired SWDs misclassified as spared; and maximal sensitivity. First, using labeled data with known behavior (130 SWDs in 34 patients), we extracted EEG time, frequency domain, and common spatial pattern features and applied support vector machines and linear discriminant analysis to classify SWDs as spared or impaired. We evaluated 32 classification models, optimized with 10-fold cross-validation. We then generalized these models to unlabeled data (220 SWDs in 41 patients), where behavior during individual SWDs was not known, but observers reported the presence of clinical seizures. For labeled data, the best classifier achieved 100% spared predictive value and 93% sensitivity. The best classifier on the unlabeled data achieved 100% spared predictive value, but with a lower sensitivity of 35%, corresponding to a conservative classification of 8 patients out of 23 as free of clinical seizures. Our findings demonstrate the feasibility of machine learning to predict impaired behavior during SWDs based on EEG features. With additional validation and optimization in a larger data sample, applications may include EEG-based prediction of driving safety, treatment adjustment, and insight into mechanisms of impaired consciousness in absence seizures.

Active Surveillance Versus Immediate Surgery for Low-Risk Papillary Thyroid Microcarcinoma Patients in South Korea: A Cost-Minimization Analysis from the MAeSTro Study.

Background: Active surveillance (AS) has been established as an alternative to immediate surgery for low-risk papillary thyroid microcarcinoma (PTMC). Nonetheless, it remains difficult to decide between AS and immediate surgery, since limited objective evidence exists regarding risks and benefits. The aim of study is to compare the cumulative costs of AS and immediate surgery. Methods: To estimate cumulative costs, a hypothetical model is simulated based on the Multicenter Prospective Cohort Study of Active Surveillance on Papillary Thyroid Micro-Carcinoma (MAeSTro) study, a multicenter prospective cohort study of AS for PTMC. Direct and indirect costs are estimated from diagnosis to the treatment decision and follow-up for 10 years and a longer period. In the case of the scenarios, AS, AS to surgery due to changing their mind, and lobectomy (analyzed regardless of levothyroxine [LT4] treatment, as well as subdivided into lobectomy/LT4[-] and lobectomy/LT4[+]) are considered. A sensitivity analysis is performed using different discount rates to address uncertainties in future time costs. To compare the cumulative costs, we referred to previous research conducted in Hong Kong, the United States, and Japan. Results: The initial cost of AS is estimated to be 5.6 times lower than that of lobectomy (regardless of LT4 use), while the 10-year cumulative costs of AS ($2545) and lobectomy regardless of LT4 ($3045) are similar under a discount rate of 3%. However, in the long-term follow-up period, immediate surgery is going to be estimated more economical than AS. The costs of the two management approaches are similar in Hong Kong, but substantially different in the United States and Japan, implying that it could be affected by each country's national health insurance coverage and the thyroid ultrasound interval during follow-up. Conclusion: Considering both direct and indirect costs, the cumulative costs of AS and immediate surgery in low-risk PTMC patients are similar during 10 years, and surgery could be more economical for patients with a life expectancy in long-term follow-up. However, careful interpretation is needed for long-term follow-up and the country's health care system and environment. Nevertheless, considering the representative protocols and objective costs in South Korea, it is expected to be a key to suggest the appropriate treatment for PTMC patients.

Advantages, Factors, Obstacles, Potential Solutions, and Recent Advances of Fish Germ Cell Transplantation for Aquaculture-A Practical Review.

Germ cell transplantation technology enables surrogate offspring production in fish. This technology has been expected to mitigate reproductive barriers, such as long generation time, limited fecundity, and complex broodstock management, enhancing seed production and productivity in aquaculture. Many studies of germ cell transplantation in various fish species have been reported over a few decades. So far, surrogate offspring production has been achieved in many commercial species. In addition, the knowledge of fish germ cell biology and the related technologies that can enhance transplantation efficiency and productivity has been developed. Nevertheless, the commercial application of this technology still seems to lag behind, indicating that the established models are neither beneficial nor cost-effective enough to attract potential commercial users of this technology. Furthermore, there are existing bottlenecks in practical aspects such as impractical shortening of generation time, shortage of donor cells with limited resources, low efficiency, and unsuccessful surrogate offspring production in some fish species. These obstacles need to be overcome through further technology developments. Thus, we thoroughly reviewed the studies on fish germ cell transplantation reported to date, focusing on the practicality, and proposed potential solutions and future perspectives.

A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells.

OBJECTIVE: The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two ß-subunits (p40 and EBI3). However, a ß-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation. METHODS: The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA. RESULTS: Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1ß, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner. CONCLUSION: In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Comparison of training effects between underwater treadmill gait training and overground gait training on the walking ability and respiratory function in patients with chronic severe hemiplegic stroke: A randomized, controlled, preliminary trial.

BACKGROUND: The need to develop a more effective intervention to obtain a functional recovery of stroke patients who are unable to perform land-based treadmill gait training has been widely reported. Thus, this pilot study aimed to identify a gait training type that could lead to improved gait and respiratory functioning in adult patients with chronic severe hemiplegic stroke. OBJECTIVES: To examine whether underwater treadmill or/and overground gait training could be more effective in stroke patients. METHODS: In this single-blinded, randomized, controlled, comparative study, 22 patients with severe hemiplegic stroke in a rehabilitation hospital were randomly assigned to the experimental (underwater treadmill gait training) or control group (overground gait training). All participants performed a 60-min neurodevelopmental treatment (five times/week for 12 weeks). Each group performed 30-min underwater or overground gait training (two times/week for 12 weeks). Gait and respiratory function were measured before and after the 12-week training. RESULTS: For the walking variables, step-time difference changes post-training showed significant differences between the groups (-.06 vs. +.04 s, p < .05). Both groups showed significant increases in the maximal voluntary volume (MVV) at post compared to pre training (p < .05). The post-training MVV values were significantly different between the two groups (+23.35 vs. +4.76 L, p < .05). CONCLUSIONS: In severe stroke patients, underwater treadmill gait training can be more effective in improving gait and respiratory function than overground gait training and could be an effective clinical intervention tool for the training of such patients.

Muscle activities of lower extremity and erector spinae muscles according to ankle joint position during squat exercise.

OBJECTIVE: The purpose of this study was to investigate the most effective ankle joint position for squat exercise by comparing muscle activities of lower extremity and erector spinae muscles in different ankle joint positions. METHODS: Thirty-seven normal healthy adults in their 20s participated in this study. Muscle activities of dominant vastus medialis oblique, vastus lateralis, biceps femoris, and erect spinae were measured in three ankle joint positions; dorsiflexion, neutral, and plantar flexion. RESULTS: Muscle activities of the vastus medialis oblique, vastus lateralis, and erector spinae muscles were statistically different in the three ankle joint positions during squat exercise (p< 0.05). Vastus medialis oblique muscles showed higher muscle activity in ankle plantar flexion than in the dorsiflexion or neutral positions (plantar flexion > neutral position, +3.3% of maximal voluntary isometric contraction (MVIC); plantar flexion > dorsiflexion, +12.2% of MVIC, respectively). Vastus lateralis muscles showed 7.1% of MVIC greater muscle activity in the neutral position than in dorsiflexion, and erector spinae muscles showed higher muscle activity in dorsiflexion than in plantar flexion or in the neutral position (dorsiflexion > neutral position, +4.3% of MVIC; dorsiflexion > plantar flexion, +7.1% of MVIC, respectively). CONCLUSION: In squat exercises designed to strengthen the vastus medialis oblique, ankle joint plantar flexion is probably the most effective ankle training position, and the dorsiflexion position might be the most effective exercise for strengthening the erector spinae muscle.

The pulse: transient fMRI signal increases in subcortical arousal systems during transitions in attention.

Studies of attention emphasize cortical circuits for salience monitoring and top-down control. However, subcortical arousal systems have a major influence on dynamic cortical state. We hypothesize that task-related increases in attention begin with a "pulse" in subcortical arousal and cortical attention networks, which are reflected indirectly through transient fMRI signals. We conducted general linear model and model-free analyses of fMRI data from two cohorts and tasks with mixed block and event-related design. 46 adolescent subjects at our center and 362 normal adults from the Human Connectome Project participated. We identified a core shared network of transient fMRI increases in subcortical arousal and cortical salience/attention networks across cohorts and tasks. Specifically, we observed a transient pulse of fMRI increases both at task block onset and with individual task events in subcortical arousal areas including midbrain tegmentum, thalamus, nucleus basalis and striatum; cortical-subcortical salience network regions including the anterior insula/claustrum and anterior cingulate cortex/supplementary motor area; in dorsal attention network regions including dorsolateral frontal cortex and inferior parietal lobule; as well as in motor regions including cerebellum, and left hemisphere hand primary motor cortex. The transient pulse of fMRI increases in subcortical and cortical arousal and attention networks was consistent across tasks and study populations, whereas sustained activity in these same networks was more variable. The function of the transient pulse in these networks is unknown. However, given its anatomical distribution, it could participate in a neuromodulatory surge of activity in multiple parallel neurotransmitter systems facilitating dynamic changes in conscious attention.

Cross training effects of non-paralytic dorsiflexion muscle strengthening exercise on paralytic dorsiflexor muscle activity, gait ability, and balancing ability in patients with chronic stroke: A randomized, controlled, pilot trial.

OBJECTIVE: To investigate the effects of non-paralytic dorsiflexion muscle strengthening exercise on functional abilities in chronic hemiplegic patients after stroke. METHODS: A total of 21 patients with chronic stroke underwent dorsiflexion muscle strengthening exercise (MST) 5 times a week for 6 weeks (the experimental group, MST to non-paralytic dorsiflexion muscles, n=11; the control group, MST to paralytic dorsiflexion muscles; n=10). Paralytic dorsiflexor muscle activities (DFA) and 10 m walking tests (10MWT) and timed up and go tests (TUG) were measured before and after intervention. RESULTS: A significant increase in DFA was observed after intervention in the experimental and control groups (p<0.05) (experimental 886.6% for reference voluntary contraction (RVC), control 931.6% for RVC). TUG and 10MWT results showed significant reductions post-intervention in the experimental and control groups (experimental group -5.6 sec, control -4.8 sec; experimental group -3.1 sec, control, -3.9 sec; respectively). No significant intergroup difference was observed between changes in DFA or between changes in TUG and 10MWT results after intervention (p>.05). CONCLUSION: Strengthening exercise performed on non-paralytic dorsiflexion muscles had positive cross-training effects on paralytic dorsiflexor muscle activities, balance abilities, and walking abilities in patients with chronic stroke.

Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach.

Encapsulated stem cells in various biomaterials have become a potentially promising cell transplantation strategy in the treatment of various neurologic disorders. However, there is no ideal cell delivery material and method for clinical application in brain diseases. Here we show silk fibroin (SF)-based hydrogel encapsulated engineered human mesenchymal stem cells (hMSCs) to overproduce brain-derived neurotrophic factor (BDNF) (BDNF-hMSC) is an effective approach to treat brain injury through trans-septal cell transplantation in the rat model. In this study, we observed SF induced sustained BDNF production by BDNF-hMSC both in 2D (9.367 ± 1.969 ng/ml) and 3D (7.319 ± 0.1025 ng/ml) culture conditions for 3 days. Through immunohistochemistry using α-tubulin, BDNF-hMSCs showed a significant increased average neurite length of co-cultured neuro 2a (N2a) cells, suggested that BDNF-hMSCs induced neurogenesis in vitro. Encapsulated BDNF-hMSC, pre-labeled with the red fluorescent dye PKH-26, exhibited intense fluorescence up to 14 days trans-septal transplantation, indicated excellent viability of the transplanted cells. Compared to the vehicle-treated, encapsulated BDNF- hMSC demonstrated significantly increased BDNF level both in the sham-operated and injured hippocampus (Hip) through immunoblot analysis after 7 days implantation. Transplantation of the encapsulated BDNF-hMSC promoted neurological functional recovery via significantly reduced neuronal death in the Hip 7 days post-injury. Using magnetic resonance imaging (MRI) analysis, we demonstrated that encapsulated BDNF-hMSC reduced lesion area significantly at 14 and 21 days in the damaged brain following trans-septal implantation. This stem cell transplantation approach represents a critical set up towards brain injury treatment for clinical application.

Enhanced Enrichment of Medaka Ovarian Germline Stem Cells by a Combination of Density Gradient Centrifugation and Differential Plating.

Fish ovarian germline stem cells (OGSCs) have great potential in various biological fields due to their ability to generate large numbers of mature eggs. Therefore, selective enrichment of OGSCs is a prerequisite for successful applications. To determine the optimal conditions for the enrichment of OGSCs from Japanese medaka (Oryzias latipes), we evaluated the effects of Percoll density gradient centrifugation (PDGC), differential plating (DP), and a combination of both methods. Based on cell morphology and gene expression of germ cell-specific Vasa and OGSC-specific Nanos2, we demonstrated that of seven density fractions obtained following PDGC, the 30-35% density fraction contained the highest proportion of OGSCs, and that Matrigel was the most effective biomolecule for the enrichment of Oryzias latipes OGSCs by DP in comparison to laminin, fibronectin, gelatin, and poly-l-lysine. Furthermore, we confirmed that PDGC and DP in combination significantly enhanced the efficiency of OGSC enrichment. The enriched cells were able to localize in the gonadal region at a higher efficiency compared to non-enriched ovarian cells when transplanted into the developing larvae. Our approach provides an efficient way to enrich OGSCs without using OGSC-specific surface markers or transgenic strains expressing OGSC-specific reporter proteins.

Lactobacillus sakei suppresses collagen-induced arthritis and modulates the differentiation of T helper 17 cells and regulatory B cells.

BACKGROUND: To evaluate the immunomodulatory effect of Lactobacillus sakei in a mouse model of rheumatoid arthritis (RA) and in human immune cells. METHODS: We evaluated whether L. sakei reduced the severity of collagen-induced arthritis (CIA) and modulated interleukin (IL)-17 and IL-10 levels, as well as whether it affected the differentiation of CD4+ T cells and regulatory B cells. We evaluated osteoclastogenesis after culturing bone marrow-derived mononuclear cells with L. sakei. RESULTS: The differentiation of T helper 17 cells and the serum level of IL-17 were suppressed by L. sakei in both human peripheral blood mononuclear cells and mouse splenocytes. The serum level of IL-10 was significantly increased in the L. sakei-treated group, whereas the regulatory T cell population was unchanged. The population of regulatory B cells significantly increased the in L. sakei-treated group. Oral administration of L. sakei reduced the arthritis incidence and score in mice with CIA. Finally, osteoclastogenesis and the mRNA levels of osteoclast-related genes were suppressed in the L. sakei-treated group. CONCLUSION: L. sakei exerted an anti-inflammatory effect in an animal model of RA, regulated Th17 and regulatory B cell differentiation, and suppressed osteoclastogenesis. Our findings suggest that L. sakei has therapeutic potential for RA.

Boosting the Conversion Efficiency Over 20% in MAPbI3 Perovskite Planar Solar Cells by Employing a Solution-Processed Aluminum-Doped Nickel Oxide Hole Collector.

Recently, nickel oxide (NiOx) thin films have been used as an efficient and robust hole transport layer (HTL) in inverted planar perovskite solar cells (IP-PSCs) to replace costly and unstable organic transport materials. However, the power conversion efficiency (PCE) of most IP-PSCs using NiOx HTLs is rather limited below 20% due to insufficient electronic conductivity of the NiOx. In this work, solution-processed Al-doped NiOx (ANO) films are suggested as HTLs for low-cost and stable IP-PSCs. The electrical conductivity of the NiOx film is significantly enhanced by Al doping, which effectively reduces the nonradiative recombination losses at the HTL-perovskite interfaces and boosts hole extraction/transportation. The device with undoped NiOx shows the best PCE of 16.56%, whereas ANO HTL (5% doping) contributes to achieving a PCE of 20.84%, which outperforms other CH3NH3PbI3 IP-PSCs with NiOx-based HTLs reported to date. Moreover, a reliability test (1728 h storage) shows that the performance stability is enhanced by approximately 11% by employing ANO HTLs. This investigation into ANO HTLs provides a new guideline for the further development of highly efficient and reliable IP-PSCs using low-cost and robust metal oxide HTLs.

Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome.

BACKGROUND: Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin-metformin combination therapy in obese mice with collagen-induced arthritis (CIA). METHODS: Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin-metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin-metformin daily for 10 weeks. RESULTS: Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin-metformin-treated cells. Moreover, rapamycin-metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin-metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo. CONCLUSIONS: These results suggest that rapamycin-metformin is a potential therapeutic option for autoimmune arthritis.

A bispecific soluble receptor fusion protein that targets TNF-α and IL-21 for synergistic therapy in inflammatory arthritis.

This study was aimed at investigating the therapeutic effects of BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, on the development of autoimmune arthritis in humans and mice. To verify the effects of BITRAP in human, peripheral blood mononuclear cells were cultured with BITRAP under IL-17-producing T (Th17) cell-polarizing conditions or osteoclast differentiation conditions. BITRAP treatment inhibited the production of IL-17 and vascular endothelial growth factor but increased the production of IL-10 in CD4+ T cells, as well as directly suppressed osteoclastogenesis. Collagen-induced arthritis (CIA) and IL-1R antagonist (IL-1Ra) knockout mice were treated with BITRAP. Following injection in CIA mice, BITRAP rapidly migrated into the inflamed joints and remained there for 72 hours. Application of BITRAP attenuated the severity of autoimmune arthritis in CIA and IL-1Ra knockout mice by reducing the numbers of inflammatory cytokine-expressing cells and Th17 cells and antibody secretion. Finally, BITRAP suppressed STAT3 phosphorylation, as well as production of IL-17 and TNF-α, in murine splenic CD4+ T cells. These findings suggest that BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, may be an effective treatment to overcome the limitations of anti-TNF therapy for patients with rheumatoid arthritis.

Endoscope-assisted transoral accessory parotid mass excision: Multicenter prospective observational study.

OBJECTIVE: Transoral surgery is gaining favor because it has the advantage of leaving no scar after surgery. The aim of this study was to evaluate the technical feasibility and safety of endoscope-assisted transoral accessory parotid mass excision. STUDY DESIGN: Multicenter, prospective, observational study. METHODS: This study was designed as a 7-year, prospective, multicenter evaluation of endoscope-assisted transoral accessory parotid mass excision. Clinical outcomes and complications related to the procedures were evaluated in patients. RESULTS: Twenty patients underwent endoscope-assisted transoral accessory parotid mass excisions, and 22 patients underwent conventional parotidectomy approach excisions. There was no significant difference with respect to overall demographic characteristics between the groups. However, the operation times were shorter in the transoral approach group (P = 0.001), and cosmetic satisfaction was much better in the transoral group (P < 0.001). CONCLUSION: Endoscope-assisted transoral accessory parotid mass excision is a potentially safe and effective procedure with excellent outcomes. LEVEL OF EVIDENCE: 2 Laryngoscope, 130:1218-1226, 2020.