Challenges of mesenchymal stem cells in the clinical treatment of COVID-19.

The 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought an enormous public health burden to the global society. The duration of the epidemic, the number of infected people, and the widespread of the epidemic are extremely rare in modern society. In the initial stage of infection, people generally show fever, cough, and dyspnea, which can lead to pneumonia, acute respiratory syndrome, kidney failure, and even death in severe cases. The strong infectivity and pathogenicity of SARS-CoV-2 make it more urgent to find an effective treatment. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with the potential for self-renewal and multi-directional differentiation. They are widely used in clinical experiments because of their low immunogenicity and immunomodulatory function. Mesenchymal stem cell-derived exosomes (MSC-Exo) can play a physiological role similar to that of stem cells. Since the COVID-19 pandemic, a series of clinical trials based on MSC therapy have been carried out. The results show that MSCs are safe and can significantly improve patients' respiratory function and prognosis of COVID-19. Here, the effects of MSCs and MSC-Exo in the treatment of COVID-19 are reviewed, and the clinical challenges that may be faced in the future are clarified.

A review on wound management strategies in enhanced recovery after craniotomy: An in-depth analysis of their influence on patient recovery and surgical outcomes.

Craniotomy, an essential neurosurgical operation, poses distinct difficulties in the realm of post-operative care, specifically with regard to the management of wounds. Efficient wound management is critical in order to optimize the surgical outcomes, reduce complications and facilitate a speedier recovery. The purpose of this comprehensive review was to assess contemporary wound management approaches as they pertain to improved recovery following craniotomy. This was achieved by contrasting conventional methods with more recent and innovative techniques and analysing the effects of these approaches on patient recovery and surgical results. An exhaustive literature search was undertaken, comprising narrative reviews, clinical studies, peer-reviewed articles and expert opinions. The emphasis was on the evolution of wound management strategies and techniques utilized after cranial section, as well as their contributions to patient recovery. The analysis reveals that while conventional wound management methods, including suturing and antiseptics, continue to be essential, innovative strategies such as negative pressure wound therapy, skin adhesives and advanced pain management protocols are becoming increasingly recognized. It has been demonstrated that these novel approaches improve recovery by decreasing the incidence of infections, enhancing patient comfort and producing superior cosmetic results. Nevertheless, obstacles continue to endure, including patient-specific variables, technological and financial considerations and the enduring consequences of recovery. Thus the treatment of wounds during craniotomy recuperation necessitates an integrated strategy that incorporates conventional techniques alongside contemporary advancements. Progress in this domain necessitates the customization of approaches to suit the unique requirements of each patient, the resolution of identified obstacles and an emphasis on ongoing investigation and interdisciplinary cooperation. The ever-changing terrain of wound management approaches underscores the ever-changing character of neurosurgical treatment and the continuous endeavour to enhance patient results following cranial resection.

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

OBJECTIVE: ß-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe ß-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis.

Tumor metastasis is the major cause of breast cancer morbidity and mortality. It has been reported that the F-box protein FBXO3 functions as an E3 ubiquitin ligase in regulating various biological processes, including host autoimmune, antiviral innate immunity, and inflammatory response. However, the role of FBXO3 in tumor metastasis remains elusive. We have previously shown that ΔNp63α is a common inhibitory target in oncogene-induced cell motility and tumor metastasis. In this study, we show that FBXO3 plays a vital role in PI3K-mediated breast cancer metastasis independent of its E3 ligase activity and ΔNp63α in breast cancer cells and in mouse. FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis. Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation. Furthermore, p110αH1047R facilitates the phosphorylation and stabilization of FBXO3 in an ERK1-dependent manner. Knockdown of either FBXO3 or USP4 leads to significant inhibition of PI3K-induced breast cancer metastasis. Clinically, elevated expression of p110α/FBXO3/USP4/Twist1 is associated with poor overall survival (OS) and recurrence-free survival (RFS) of breast cancer patients. Taken together, this study reveals that the FBXO3-USP4-Twist1 axis is pivotal in PI3K-mediated breast tumor metastasis and that FBXO3/USP4 may be potential therapeutic targets for breast cancer treatment.

Burst of hopping trafficking correlated reversible dynamic interactions between lipid droplets and mitochondria under starvation.

Dynamic membrane contacts between lipid droplets (LDs) and mitochondria play key roles in lipid metabolism and energy homeostasis. Understanding the dynamics of LDs under energy stimulation is thereby crucial to disclosing the metabolic mechanism. Here, the reversible interactions between LDs and mitochondria are tracked in real-time using a robust LDs-specific fluorescent probe (LDs-Tags). Through tracking the dynamics of LDs at the single-particle level, spatiotemporal heterogeneity is revealed. LDs in starved cells communicate and integrate their activities (i.e., lipid exchange) through a membrane contact site-mediated mechanism. Thus the diffusion is intermittently alternated between active and confined states. Statistical analysis shows that the translocation of LDs in response to starvation stress is non-Gaussian, and obeys nonergodic-like behavior. These results provide deep understanding of the anomalous diffusion of LDs in living cells, and also afford guidance for rationally designing efficient transporter.

Quantitative Blood Oxygenation Level Dependent Magnetic Resonance Imaging for Estimating Intra-renal Oxygen Availability Demonstrates Kidneys Are Hypoxemic in Human CKD.

Introduction: Kidney blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI) has shown great promise in evaluating relative oxygen availability. This method is quite efficacious in evaluating acute responses to physiological and pharmacologic maneuvers. Its outcome parameter, R2∗ is defined as the apparent spin-spin relaxation rate measured in the presence of magnetic susceptibility differences and it is measured using gradient echo MRI. Although associations between R2∗ and renal function decline have been described, it remains uncertain to what extent R2∗ is a true reflection of tissue oxygenation. This is primarily because of not taking into account the confounding factors, especially fractional blood volume (fBV) in tissue. Methods: This case-control study included 7 healthy controls and 6 patients with diabetes and chronic kidney disease (CKD). Using data before and after administration of ferumoxytol, a blood pool MRI contrast media, the fBVs in kidney cortex and medulla were measured. Results: This pilot study independently measured fBV in kidney cortex (0.23 ± 0.03 vs. 0.17 ± 0.03) and medulla (0.36 ± 0.08 vs. 0.25 ± 0.03) in a small number of healthy controls (n = 7) versus CKD (n = 6). These were then combined with BOLD MRI measurements to estimate oxygen saturation of hemoglobin (StO2) (0.87 ± 0.03 vs. 0.72 ± 0.10 in cortex; 0.82 ± 0.05 vs. 0.72 ± 0.06 in medulla) and partial pressure of oxygen in blood (bloodPO2) (55.4 ± 6.5 vs. 38.4 ± 7.6 mm Hg in cortex; 48.4 ± 6.2 vs. 38.1 ± 4.5 mm Hg in medulla) in control versus CKD. The results for the first time demonstrate that cortex is normoxemic in controls and moderately hypoxemic in CKD. In the medulla, it is mildly hypoxemic in controls and moderately hypoxemic in CKD. Whereas fBV, StO2, and bloodPO2 were strongly associated with estimated glomerular filtration rate (eGFR), R2∗ was not. Conclusion: Our results support the feasibility of quantitatively assessing oxygen availability using noninvasive quantitative BOLD MRI that could be translated to the clinic.

Effective Solution toward the Issues of Zn-Based Anodes for Advanced Alkaline Ni-Zn Batteries.

Alkaline nickel-zinc (Ni-Zn) batteries, as traditional rechargeable aqueous batteries, possess an obvious advantage in terms of energy density, but their development has been hindered by the anode-concerned problems, Zn dendrites, self-corrosion, passivation, deformation, and hydrogen evolution reaction (HER). Herein, to solve these problems, a dual protective strategy is proposed toward the anode using ZnO as an initial active material, including a C coating on ZnO (ZnO@C) and a thin poly(vinyl alcohol) (PVA) layer coating on the electrode (ZnO@C-PVA). In a three-electrode configuration, the reversible capacity can reach 600 mAh g-1 for the ZnO@C-PVA. Using excessive commercial Ni(OH)2 as the cathode, the alkaline Ni-Zn cells exhibit good electrochemical performance: Discharge capacity can be as high as 640-650 mAh g-1 at 4 A g-1 with a Coulomb efficiency (CE) as high as 97-99% after activity, suggesting low self-corrosion and HER. Capacity retention is 97% after 1200 cycles, indicating rather good durability. The discharge capacity is even slightly increased with the increase of charge/discharge current density (≤8 A g-1), implying good rate performance. Additionally, the discharge voltage can reach 1.8 V (midpoint value) at various current densities, reflecting the fast reaction kinetics of the anode. Most importantly, no Zn dendrites and passivation are observed after long-term cycling. The strategy proposed here can solve the anode-concerned problems effectively, exhibiting a high application prospect.

FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and recurrence. Although chemotherapy has greatly improved the clinical outcome of TNBC patients, acquired drug resistance remains a huge challenge for TNBC treatment. Breast cancer stem cells (BCSCs) play a critical role in breast cancer development, metastasis, recurrence, and chemotherapy resistance. Thus, it is of great importance to decipher the underlying molecular mechanism of BCSCs regulation for TNBC drug resistance. In this study, we demonstrate that the F-box protein FBXL2 is a critical negative regulator of BCSCs stemness and that downregulation of FBXL2 plays a causal role in TNBC drug resistance. We show that expression levels of FBXL2 significantly influence CD44high/CD24low subpopulation and the mammosphere formation ability of TNBC cells. Ectopic expression of FBXL2 inhibits initiation of TNBC and overcomes paclitaxel resistance in vivo. In addition, activation of FBXL2 by nebivolol, a clinically used small-molecule inhibitor of the beta-1 receptor, markedly overcomes BCSCs-induced paclitaxel resistance. Mechanistically, we show that FBXL2 targets transcriptional factor E47 for polyubiquitin- and proteasome-mediated degradation, resulting in inhibition of BCSC stemness. Clinical analyses indicate that low expression of FBXL2 correlates with high expression of E47 as well as with high stemness features, and is associated with poor clinical outcomes of breast cancer patients. Taken together, these results highlight that the FBXL2-E47 axis plays a critical role in the regulation of BCSC stemness and paclitaxel resistance. Thus, targeting FBXL2 might be a potential therapeutic strategy for drug-resistant TNBC.

Fabrication of a Cation Exchange Membrane with Largely Reduced Anion Permeability for Advanced Aqueous K-ion Battery in an Alkaline-Neutral Electrolyte Decoupling System.

Herein, an efficient method to prepare sulfonated polyether ether ketone (SPEEK) based cation exchange membranes (CEMs) is developed, where polyethersulfone (PES) is used as an additive. The optimized membrane of 30 wt.%PES/SPEEK-M exhibits a rather low anion permeability and a high ionic conductivity of 9.52 mS cm-1 together with low volume swelling in water. Meanwhile, tensile strength of the membrane is as high as 31.4 MPa with a tensile strain of 162%. As separators for aqueous K-ion batteries (AKIBs) with decoupled gel electrolytes (Zn anode in alkaline and Prussian blue (FeHCF) cathode in neutral). Discharge voltage of the AKIB can reach 2.3 V. Meanwhile, Zn dendrites can be effectively suppressed in the gel anolyte. Specific capacities of the FeHCF cathode are 116.7 mAh g-1 at 0.3 A g-1 (close to its theoretical value), and 95.0 mAh g-1 at 1.0 A g-1 , indicating good rate performance. Capacity retention of the cathode is as high as 91.2% after 1000 cycles' cycling owing to the well remained neutral environment of the catholyte. There is almost no pH change for the catholyte after cycling, indicating good anion-blocking or cation-selecting ability of the 30 wt.%PES/SPEEK-M, much better than other membranes.

Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

Scientific Challenges and Improvement Strategies of Zn-Based Anodes for Aqueous Zn-Ion Batteries.

Aqueous zinc-ion batteries (ZIBs) have attracted widespread attention due to the intrinsic features of Zn-based anodes, mainly including high capacity, low cost, and low working potential together with high over-potential for hydrogen evolution reaction. Aqueous ZIBs are considered to be strong competitors and substitutes for lead-acid, nickel-metal hydrogen, nickel-cadmium, and even lithium-ion batteries. Great efforts have been made in the past few years towards the issues existed in aqueous ZIBs, mainly including alkaline and mild acidic systems. In this perspective, we illustrate the advantages, the main challenges, and the corresponding solution strategies of Zn-based anodes in various aqueous rechargeable ZIBs with alkaline and mild acidic electrolytes. Furthermore, feasible aqueous ZIBs for practical use are prospected.

Design of the Threshold-Controllable Memristor Emulator Based on NDR Characteristics.

Due to the high manufacturing cost of memristors, an equivalent emulator has been employed as one of the mainstream approaches of memristor research. A threshold-type memristor emulator based on negative differential resistance (NDR) characteristics is proposed, with the core part being the R-HBT network composed of transistors. The advantage of the NDR-based memristor emulator is the controllable threshold, where the state of the memristor can be changed by setting the control voltage, which makes the memristor circuit design more flexible. The operation frequency of the memristor emulator is about 250 kHz. The experimental results prove the feasibility and correctness of the threshold-controllable memristor emulator circuit.

The Comparative Efficacy of Non-ergot Dopamine Agonist and Potential Risk Factors for Motor Complications and Side Effects From NEDA Use in Early Parkinson's Disease: Evidence From Clinical Trials.

Background/Objectives: Non-ergot dopamine agonist (NEDA) are recommended as the first-line treatment for patients with early Parkinson's disease (PD) because of their efficacy in treating PD motor symptoms. However, systematic evaluations of the risk of motor complications induced by NEDA and risk factors potentially associated with motor complications are still lacking. Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched for potentially eligible randomized controlled trials. The incidence of motor complications (dyskinesia, motor fluctuations), impulsive-compulsive behaviors and adverse events and clinical disability rating scale (UPDRS) scores were evaluated using standard meta-analytic methods. Metaregression was conducted on the incidence of motor complications (dyskinesia) with treatment duration and NEDA dose as covariates. Results: Patients treated with NEDA had significantly lower UPDRS total scores, motor scores and activity of daily living (ADL) scores than those receiving a placebo (weighted mean difference (WMD) -4.81, 95% CI -6.57 to -3.05; WMD -4.901, 95% CI -7.03 to -2.77; WMD -1.52, 95% CI -2.19 to -0.84, respectively). Patients in the NEDA and NEDA+open Levodopa (LD) groups had lower odds for dyskinesia than patients in the LD group (OR = 0.21, 95% CI: 0.15-0.29; OR = 0.31, 95% CI 0.24-0.42, respectively). Metaregressions indicated that the mean LD dose of the NEDA group increased, and the odds of developing dyskinesia increased (p = 0.012). However, the odds of developing dyskinesia in the NEDA group were not related to treatment duration (p = 0.308). PD patients treated with NEDA or NEDA+open LD had a lower risk of wearing-off implications than those treated with LD (all p < 0.05). No significant difference was found between the NEDA and placebo groups in impulsive-compulsive behavior development (p > 0.05). Patients in the NEDA group were more likely to suffer somnolence, edema, constipation, dizziness, hallucinations, nausea and vomiting than those in the placebo or LD group. Conclusion: NEDA therapy reduces motor symptoms and improves ADLs in early PD. The odds of developing motor complications were lower with NEDA than with LD, and dyskinesia increased with increasing LD equivalent dose and was not influenced by NEDA treatment duration. Therefore, long-term treatment with an appropriate dosage of NEDA might be more suitable than LD for early PD patients. Registration: PROSPERO CRD42021287172.

Radiomics-Based Image Phenotyping of Kidney Apparent Diffusion Coefficient Maps: Preliminary Feasibility & Efficacy.

Given the central role of interstitial fibrosis in disease progression in chronic kidney disease (CKD), a role for diffusion-weighted MRI has been pursued. We evaluated the feasibility and preliminary efficacy of using radiomic features to phenotype apparent diffusion coefficient (ADC) maps and hence to the clinical classification(s) of the participants. The study involved 40 individuals (10 healthy and 30 with CKD (eGFR < 60 mL/min/1.73 m2)). Machine learning methods, such as hierarchical clustering and logistic regression, were used. Clustering resulted in the identification of two clusters, one including all individuals with CKD (n = 17), while the second one included all the healthy volunteers (n = 10) and the remaining individuals with CKD (n = 13), resulting in 100% specificity. Logistic regression identified five radiomic features to classify participants as with CKD vs. healthy volunteers, with a sensitivity and specificity of 93% and 70%, respectively, and an AUC of 0.95. Similarly, four radiomic features were able to classify participants as rapid vs. non-rapid CKD progressors among the 30 individuals with CKD, with a sensitivity and specificity of 71% and 43%, respectively, and an AUC of 0.75. These promising preliminary data should support future studies with larger numbers of participants with varied disease severity and etiologies to improve performance.

Apoptosis, rather than neurogenesis, induces significant hippocampal-dependent learning and memory impairment in chronic low Cd2+ exposure.

Cadmium (Cd), a ubiquitous toxic heavy metal, with the intractable trait of low degradation, can induce multiple organ damage. Whereas, far less is known about its neurotoxicity and the specific mechanism in the chronic low Cd exposure. To investigate the chronic neurotoxicity of Cd2+ , we traced its effects for up to 30 months in mice which were exposed to Cd2+ by drinking the mimicking Cd-polluted water. We found the toxicity of chronic Cd exposure was a process associated with the transition from autophagy to apoptosis, and the switch of autophagy-apoptosis was Cd dose-dependent with the threshold of [Cd2+ ] 0.04 mg/L. Furthermore, JNK was found to be a hub molecule orchestrated the switch of autophagy-apoptosis by interacting with Sirt1 and p53. At last, the hippocampus-dependent learning and memory was damaged by continuous neuron apoptosis rather than deficit of neurogenesis. Therefore, elucidation of the effect, process, and potential molecular mechanism of the chronic low Cd2+ exposure is important for controlling of the environmental-pollutant Cd.

The action of enhancing weak light capture via phototropic growth and chloroplast movement in plants.

To cope with fluctuating light conditions, terrestrial plants have evolved precise regulation mechanisms to help optimize light capture and increase photosynthetic efficiency. Upon blue light-triggered autophosphorylation, activated phototropin (PHOT1 and PHOT2) photoreceptors function solely or redundantly to regulate diverse responses, including phototropism, chloroplast movement, stomatal opening, and leaf positioning and flattening in plants. These responses enhance light capture under low-light conditions and avoid photodamage under high-light conditions. NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) and ROOT PHOTOTROPISM 2 (RPT2) are signal transducers that function in the PHOT1- and PHOT2-mediated response. NPH3 is required for phototropism, leaf expansion and positioning. RPT2 regulates chloroplast accumulation as well as NPH3-mediated responses. NRL PROTEIN FOR CHLOROPLAST MOVEMENT 1 (NCH1) was recently identified as a PHOT1-interacting protein that functions redundantly with RPT2 to mediate chloroplast accumulation. The PHYTOCHROME KINASE SUBSTRATE (PKS) proteins (PKS1, PKS2, and PKS4) interact with PHOT1 and NPH3 and mediate hypocotyl phototropic bending. This review summarizes advances in phototropic growth and chloroplast movement induced by light. We also focus on how crosstalk in signaling between phototropism and chloroplast movement enhances weak light capture, providing a basis for future studies aiming to delineate the mechanism of light-trapping plants to improve light-use efficiency.

Root-to-Shoot Long-Distance Mobile miRNAs Identified from Nicotiana Rootstocks.

Root-derived mobile signals play critical roles in coordinating a shoot's response to underground conditions. However, the identification of root-to-shoot long-distance mobile signals has been scant. In this study, we aimed to characterize root-to-shoot endogenous mobile miRNAs by using an Arabidopsis/Nicotiana interfamilial heterograft in which these two taxonomically distant species with clear genetic backgrounds had sufficient diversity in differentiating miRNA sources. Small RNA deep sequencing analysis revealed that 82 miRNAs from the Arabidopsis scion could travel through the graft union to reach the rootstock, whereas only a very small subset of miRNA (6 miRNAs) preferred the root-to-shoot movement. We demonstrated in an ex vivo RNA imaging experiment that the root-to-shoot mobile Nb-miR164, Nb-miR395 and Nb-miR397 were targeted to plasmodesmata using the bacteriophage coat protein MS2 system. Furthermore, the Nb-miR164 was shown to move from the roots to the shoots to induce phenotypic changes when its overexpressing line was used as rootstock, strongly supporting that root-derived Nb-miR164 was able to modify the scion trait via its long-distance movement.

The effects of neuromuscular joint facilitation treatment using neck patterns on the acoustic analysis of swallowing sounds in healthy adults.

[Purpose] We aimed to investigate the changes in the swallowing sounds of healthy adults during neuromuscular joint facilitation treatment using neck patterns. [Participants and Methods] A total of 20 healthy adults (10 males and 10 females; mean age, 29.2 ± 6.3 years) swallowed 10 mL of water four times under three conditions (after the neuromuscular joint facilitation neck-flexion resistance pattern, after the Shaker-type exercise, and during relaxed sitting without prior exercise [control]), randomly ordered with an interval greater than 3 days. Swallowing sounds for each water swallow were recorded using cervical auscultation. [Results] The mean amplitude of swallowing sound intensity and the mean spectral frequency were significantly higher after the neuromuscular joint facilitation neck-flexion resistance pattern and the Shaker-type exercise, in comparison with those in the control group. [Conclusion] Neuromuscular joint facilitation training with the neck-flexion resistance pattern influenced swallowing sounds to the same degree as the Shaker-type exercise, implying that this resistance pattern may enhance suprahyoid muscle contraction.

FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth.

Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.