Restoration of Visual Function by Enhancing Conduction in Regenerated Axons.

Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.

Casein kinase 1 gamma regulates oxidative stress response via interacting with the NADPH dual oxidase complex.

Oxidative stress response is a fundamental biological process mediated by conserved mechanisms. The identities and functions of some key regulators remain unknown. Here, we report a novel role of C. elegans casein kinase 1 gamma CSNK-1 (also known as CK1γ or CSNK1G) in regulating oxidative stress response and ROS levels. csnk-1 interacted with the bli-3/tsp-15/doxa-1 NADPH dual oxidase genes via genetic nonallelic noncomplementation to affect C. elegans survival in oxidative stress. The genetic interaction was supported by specific biochemical interactions between DOXA-1 and CSNK-1 and potentially between their human orthologs DUOXA2 and CSNK1G2. Consistently, CSNK-1 was required for normal ROS levels in C. elegans. CSNK1G2 and DUOXA2 each can promote ROS levels in human cells, effects that were suppressed by a small molecule casein kinase 1 inhibitor. We also detected genetic interactions between csnk-1 and skn-1 Nrf2 in oxidative stress response. Together, we propose that CSNK-1 CSNK1G defines a novel conserved regulatory mechanism for ROS homeostasis.

Differential modulation of C. elegans motor behavior by NALCN and two-pore domain potassium channels.

Two-pore domain potassium channels (K2P) are a large family of "background" channels that allow outward "leak" of potassium ions. The NALCN/UNC80/UNC79 complex is a non-selective channel that allows inward flow of sodium and other cations. It is unclear how K2Ps and NALCN differentially modulate animal behavior. Here, we found that loss of function (lf) in the K2P gene twk-40 suppressed the reduced body curvatures of C. elegans NALCN(lf) mutants. twk-40(lf) caused a deep body curvature and extended backward locomotion, and these phenotypes appeared to be associated with neuron-specific expression of twk-40 and distinct twk-40 transcript isoforms. To survey the functions of other less studied K2P channels, we examined loss-of-function mutants of 13 additional twk genes expressed in the motor circuit and detected defective body curvature and/or locomotion in mutants of twk-2, twk-17, twk-30, twk-48, unc-58, and the previously reported twk-7. We generated presumptive gain-of-function (gf) mutations in twk-40, twk-2, twk-7, and unc-58 and found that they caused paralysis. Further analyses detected variable genetic interactions between twk-40 and other twk genes, an interdependence between twk-40 and twk-2, and opposite behavioral effects between NALCN and twk-2, twk-7, or unc-58. Finally, we found that the hydrophobicity/hydrophilicity property of TWK-40 residue 159 could affect the channel activity. Together, our study identified twk-40 as a novel modulator of the motor behavior, uncovered potential behavioral effects of five other K2P genes and suggests that NALCN and some K2Ps can oppositely affect C. elegans behavior.

The reverse TRBV30 gene of mammals: a defect or superiority in evolution?

At the 3' end of the C2 gene in the mammalian TRB locus, a distinct reverse TRBV30 gene (named TRBV31 in mice) has been conserved throughout evolution. In the fully annotated TRB locus of 14 mammals (including six orders), we observed noteworthy variations in the localization and quality of the reverse V30 genes and Recombination Signal Sequences (RSSs) in the gene trees of 13 mammals. Conversely, the forward V29 genes and RSSs were generally consistent with the species tree of their corresponding species. This finding suggested that the evolution of the reverse V30 gene was not synchronous and likely played a crucial role in regulating adaptive immune responses. To further investigate this possibility, we utilized single-cell TCR sequencing (scTCR-seq) and high-throughput sequencing (HTS) to analyze TCRß CDR3 repertoires from both central and peripheral tissues of Primates (Homo sapiens and Macaca mulatta), Rodentia (Mus musculus: BALB/c, C57BL/6, and Kunming mice), Artiodactyla (Bos taurus and Bubalus bubalis), and Chiroptera (Rhinolophus affinis and Hipposideros armige). Our investigation revealed several novel observations: (1) The reverse V30 gene exhibits classical rearrangement patterns adhering to the '12/23 rule' and the 'D-J rearrangement preceding the V-(D-J) rearrangement'. This results in the formation of rearranged V30-D2J2, V30-D1J1, and V30-D1J2. However, we also identified 'special rearrangement patterns' wherein V30-D rearrangement preceding D-J rearrangement, giving rise to rearranged V30-D2-J1 and forward Vx-D2-J. (2) Compared to the 'deletional rearrangement' (looping out) of forward V1-V29 genes, the reverse V30 gene exhibits preferential utilization with 'inversional rearrangement'. This may be attributed to the shorter distance between the V30 gene and D gene and the 'inversional rearrangement' modes. In summary, in the mammalian TRB locus, the reverse V30 gene has been uniquely preserved throughout evolution and preferentially utilized in V(D)J recombination, potentially serving a significant role in adaptive immunity. These results will pave the way for novel and specialized research into the mechanisms, efficiency, and function of V(D)J recombination in mammals.

Simultaneous Dual-Gene Test of Methicillin-Resistant Staphylococcus Aureus using an Argonaute-Centered Portable and Visual Biosensor.

The development of novel method for drug-resistant bacteria detection is imperative. A simultaneous dual-gene Test of methicillin-resistant Staphylococcus aureus (MRSA) is developed using an Argonaute-centered portable biosensor (STAR). This is the first report concerning Argonaute-based pathogenic bacteria detection. Simply, the species-specific mecA and nuc gene are isothermally amplified using loop-mediated isothermal amplification (LAMP) technique, followed by Argonaute-based detection enabled by its programmable, guided, sequence-specific recognition and cleavage. With the strategy, the targeted nucleic acid signals gene are dexterously converted into fluorescent signals. STAR is capable of detecting the nuc gene and mecA gene simultaneously in a single reaction. The limit of detection is 10 CFU/mL with a dynamic range from 10 to 107 CFU/mL. The sample-to-result time is <65 min. This method is successfully adapted to detect clinical samples, contaminated foods, and MRSA-infected animals. This work broadens the reach of Argonaute-based biosensing and presents a novel bacterial point-of-need (PON) detection platform.

Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K-AKT pathway.

Synovial inflammation and fibrosis are important pathological changes associated with osteoarthritis (OA). Herein, we investigated if nintedanib, a drug specific for pulmonary fibrosis, plays a positive role in osteoarthritic synovial inflammation and fibrosis. We assessed the effect of nintedanib on osteoarthritic synovial inflammation and fibrosis in a mouse model of OA created by destabilization of the medial meniscus and a macrophage M1 polarization model created by stimulating RAW264.7 cells with lipopolysaccharide. Histological staining showed that daily gavage administration of nintedanib significantly alleviated articular cartilage degeneration, reduced the OARSI score, upregulated matrix metalloproteinase-13 and downregulated collagen II expression, and significantly reduced the synovial score and synovial fibrosis in a mouse OA model. In addition, immunofluorescence staining showed that nintedanib significantly decreased the number of M1 macrophages in the synovium of a mouse model of OA. In vitro results showed that nintedanib downregulated the phosphorylation levels of ERK, JNK, p38, PI3K, and AKT while inhibiting the expression of macrophage M1 polarization marker proteins (CD86, CD80, and iNOS). In conclusion, this study suggests that nintedanib is a potential candidate for OA treatment. The mechanisms of action of nintedanib include the inhibition of M1 polarization in OA synovial macrophages via the MAPK/PI3K-AKT pathway, inhibition of synovial inflammation and fibrosis, and reduction of articular cartilage degeneration.

Circular RNA DLGAP4 alleviates sevoflurane-induced neurotoxicity by regulating miR-9-5p/Sirt1/BDNF pathway.

BACKGROUND: Sevoflurane is a widely used anesthetic in infants. However, long and repeated exposure to this drug can cause developmental neurotoxicity. This study aimed to investigate the role and mechanism of circular RNA DLGAP4 (circDLGAP4) in sevoflurane-induced neurotoxicity. METHODS: Neonatal mice and mouse hippocampal neuronal cell line HT22 were used to construct sevoflurane-induced nerve injury models. The role of circDLGAP4 in sevoflurane-induced neurotoxicity was evaluated by gain-and/or loss-of-function methods. Pathological alterations in hippocampus were analyzed by hematoxylin-eosin and Tunel staining. Cell injury was assessed by cell viability and apoptosis, which was detected by CCK-8 and flow cytometry. The expression of circDLGAP4 and miR-9-5p was determined by real-time PCR. Sirt1 and BDNF levels were measured by Western blot. Productions of TNF-α and IL-6 were examined by ELISA. Dual-luciferase reporter assay and/or RNA pull-down assay were used to confirm the direct binding among circDLGAP4, miR-9-5p, and Sirt1. Rescue experiments were used to further verify the mechanism of circDLGAP4. RESULTS: CircDLGAP4 expression was decreased by sevoflurane both in vivo and in vitro. Overexpression of circDLGAP4 elevated cell viability, reduced apoptosis and levels of TNF-α and IL-6, while circDLGAP4 knockdown showed the opposite effects in sevoflurane-induced HT22 cells. Mechanically, circDLGAP4 functioned via directly binding to and regulating miR-9-5p, followed by targeting the Sirt1/BDNF pathway. Additionally, circDLGAP4 upregulation relieved sevoflurane-induced nerve injury, reduced levels of TNF-α, IL-6 and miR-9-5p, but increased the expression of Sirt1 and BDNF in hippocampus. CONCLUSIONS: Our studies found that circDLGAP4 relieved sevoflurane-induced neurotoxicity by sponging miR-9-5p to regulate Sirt1/BDNF pathway.

Ion transport through short nanopores modulated by charged exterior surfaces.

Short nanopores find extensive applications, capitalizing on their high throughput and detection resolution. Ionic behaviors through long nanopores are mainly determined by charged inner-pore walls. When pore lengths decrease to sub-200 nm, charged exterior surfaces provide considerable modulation to ion current. We find that the charge status of inner-pore walls affects the modulation of ion current from charged exterior surfaces. For 50-nm-long nanopores with neutral inner-pore walls, the charged exterior surfaces on the voltage (surfaceV) and ground (surfaceG) sides enhance and inhibit the ion transport by forming ion enrichment and depletion zones inside nanopores, respectively. For nanopores with both charged inner-pore and exterior surfaces, continuous electric double layers enhance the ion transport through nanopores significantly. The charged surfaceV results in higher ion current by simultaneously weakening the ion depletion at pore entrances and enhancing the intra-pore ion enrichment. The charged surfaceG expedites the exit of ions from nanopores, resulting in a decrease in ion enrichment at pore exits. Through adjustment in the width of charged-ring regions near pore boundaries, the effective charged width of the charged exterior is explored at ∼20 nm. Our results may provide a theoretical guide for further optimizing the performance of nanopore-based applications, such as seawater desalination, biosensing, and osmotic energy conversion.

Single-Cell Quantitative Proteomic Analysis of Human Oocyte Maturation Revealed High Heterogeneity in In Vitro-Matured Oocytes.

Oocyte maturation is pertinent to the success of in vitro maturation (IVM), which is used to overcome female infertility, and produced over 5000 live births worldwide. However, the quality of human IVM oocytes has not been investigated at single-cell proteome level. Here, we quantified 2094 proteins in human oocytes during in vitro and in vivo maturation (IVO) by single-cell proteomic analysis and identified 176 differential proteins between IVO and germinal vesicle oocytes and 45 between IVM and IVO oocytes including maternal effect proteins, with potential contribution to the clinically observed decreased fertilization, implantation, and birth rates using human IVM oocytes. IVM and IVO oocytes showed separate clusters in principal component analysis, with higher inter-cell variability among IVM oocytes, and have little correlation between mRNA and protein changes during maturation. The patients with the most aberrantly expressed proteins in IVM oocytes had the lowest level of estradiol per mature follicle on trigger day. Our data provide a rich resource to evaluate effect of IVM on oocyte quality and study mechanism of oocyte maturation.

Association between CBS gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region and coronary artery disease: a meta-analysis.

BACKGROUND: Several studies indicate that the cystathionine ß-synthase (CBS) gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region may be correlated with coronary artery disease (CAD) susceptibility, but the results have been inconsistent and inconclusive. Thus, a meta-analysis was conducted to provide a comprehensive estimate of these associations. METHODS: On the basis of searches in the PubMed, EMBASE, Cochrane Library, Wanfang, VIP, and CNKI databases, we selected 14 case - control studies including 2123 cases and 2368 controls for this meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated accordingly using a fixed-effect or random-effect model. RESULTS: The results indicated an increased risk between the CBS T833C gene polymorphisms and susceptibility to CAD under the dominant model (CC+CT vs. TT: OR = 1.92, 95% CI: 1.11 ~ 3.32), recessive model (CC vs. CT+TT: OR = 1.88, 95% CI: 1.17 ~ 3.03), and homozygous model (CC vs. TT: OR = 2.46, 95% CI: 1.04 ~ 5.83). In these three genetic models, no significant association was identified for CBS G919A (AA+AG vs. GG: OR = 1.48, 95% CI: 0.45 ~ 4.82),(AA vs. AG+GG: OR = 1.58, 95% CI: 0.93 ~ 2.70),(AA vs. GG: OR = 1.66, 95% CI: 0.40 ~ 6.92) or CBS 844ins68 (II+ID vs. DD: OR = 1.04, 95% CI: 0.80 ~ 1.35),(II vs. ID+DD: OR = 1.09, 95% CI: 0.51 ~ 2.36),(II vs. DD: OR = 1.10, 95% CI: 0.51 ~ 2.39). CONCLUSIONS: This meta-analysis suggests that the CBS T833C gene polymorphism is significantly associated with the risk of CAD and it shows a stronger association in Asian populations. Individuals with the C allele of the CBS gene T833C polymorphism might be particularly susceptible to CAD.

Dissecting the manipulation of lufenuron on chitin synthesis in Helicoverpa armigera.

Lufenuron, a benzoylurea chitin synthesis inhibitor, is effective against many insect pests. However, the insecticidal activity of lufenuron has not been completely elucidated, nor has its disturbing effect on chitin synthesis genes. In this study, bioassay results demonstrated an outstanding toxicity of lufenuron against Helicoverpa armigera larvae. The treated larvae died from abortive molting and metamorphosis defects, and severe separation of epidermis and subcutaneous tissues was observed. Treatment of 3rd- and 4th-instar larvae with LC25 lufenuron significantly extended the duration of larval and pupal stage, reduced the rates of pupation and emergence, and adversely affected pupal weight. Besides, lufenuron can severely reduce chitin content in larval integument, and the lufenuron-treated larvae showed reduced trehalose content in their hemolymph. Further analysis using RNA sequencing revealed that five chitin synthesis genes were down-regulated, whereas the expressions of two chitin degradation genes were significantly enhanced. Knockdown of chitin synthase 1 (HaCHS1), uridine diphosphate-N-acetylglucosamine-pyrophosphorylase (HaUAP), phosphoacetyl glucosamine mutase (HaPGM), and glucosamine 6-phosphate N-acetyl-transferase (HaGNPAT) in H. armigera led to significant increase in larval susceptibilities to LC25 lufenuron by 75.48%, 65.00%, 68.42% and 28.00%, respectively. Our findings therefore revealed the adverse effects of sublethal doses of lufenuron on the development of H. armigera larvae, elucidated the perturbations on chitin metabolism, and proved that the combination of RNAi and lufenuron would improve the control effect of this pest.

Geochemical behavior of rare earth elements in agricultural soils along the Syr Darya River within the Aral Sea Basin.

The widespread use of rare earth elements (REEs) across various industries makes them a new type of pollutant. Additionally, REEs are powerful indicators of geochemical processes. As one of the two main rivers in the Aral Sea, identifying the geochemical behavior of REEs in agricultural soils of the Syr Darya River is of great significance for subsequent indicative studies. In this study, the geochemical characteristics, influencing factors, and potential application significance of REEs in agricultural soils from three sampling areas along the Syr Darya River were analyzed using soil geography and elemental geochemical analyses. The results showed that the highest total concentration of REEs in the agricultural soil was in Area I, with a mean value of 142.49 µg/g, followed by Area III with a mean value of 124.56 µg/g, and the lowest concentration was in Area II with a mean value of 122.48 µg/g. The agricultural soils in the three regions were enriched in light rare earth elements (LREEs), with mean L/H values of 10.54, 10.13, and 10.24, respectively. The differentiation between light and heavy rare earth elements (HREEs) was also high. The concentration of REEs in agricultural soil along the Syr Darya River was primarily influenced by minerals such as monazite and zircon, rather than human activities (the pollution index of all REEs was less than 1.5). The relationship between Sm and Gd can differentiate soils impacted by agricultural activities from natural background soils. The results of this study can serve as a basis for indicative studies of REEs in Central Asia.

The effect of budesonide combined with bifidobacteria and lactobacilli on lung function and gut microbiota of patients with chronic obstructive pulmonary disease.

Objective: To explore the effects of budesonide combined with Bifidobacteria and Lactobacilli on the lung function and intestinal microbiota of patients with chronic obstructive pulmonary disease (COPD). Methods: Clinical data of 124 COPD patients admitted to Fengcheng Hospital, Fengxian District, Shanghai from February 2021 to February 2023 were retrospectively analyzed. Patients either received budesonide treatment alone (n=59, control group) or budesonide combined with Bifidobacteria and Lactobacilli (n=65, observation group). Levels of lung function indicators, symptom relief time, gut microbiota levels, and quality of life were compared between the two groups before and after the treatment. Results: After two weeks of treatment, the improvement of lung function in the observation group was better than that in the control group (P<0.05). Compared to budesonide treatment alone, combined budesonide, Bifidobacteria, and Lactobacilli treatment were associated with shorter symptom relief time (P<0.05), and with more significant improvement of intestinal microbiota level (P<0.05) and the quality of life (P<0.05). Conclusions: Budesonide combined with Bifidobacteria and Lactobacilli can effectively alleviate clinical symptoms, regulate intestinal microbiota, improve lung function and the quality of life of COPD patients.

Clinical study of Microendoscopic Discectomy + Fibrous Ring Suture Versus Microendoscopic Discectomy alone in the treatment of lumbar disc herniation in young and middle-aged patients.

Objective: To compare the clinical efficacy of microendoscopic discectomy + fibrous ring suture versus microendoscopic discectomy alone in the treatment of lumbar disc herniation (LDH) in young and middle-aged patients. Methods: A retrospective analysis was performed on the clinical data of 66 young and middle-aged patients with single-segment LDH diagnosed in Orthopedic Hospital of Henan Province from October 2019 to October 2022. All patients were divided into two groups: the microendoscopic discectomy + fibrous ring suture group and the microendoscopic discectomy alone group, with 33 cases in each group. The Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) scores of the two groups were recorded before surgery and six and twelve months after surgery. Results: Both groups completed the surgery and postoperative follow-up successfully and showed no statistically significant differences in terms of incision length, duration of surgery, intraoperative blood loss and length of hospital stay (all P>0.05). VAS, ODI and JOA scores were significantly improved in both groups at 6 and 12 months after surgery compared with those before surgery (all P<0.05). The two groups were similar in terms of excellent and good rates of postoperative modified MacNab Evaluation Criteria, with no statistically significant differences. No serious complications were observed in the two groups during and after surgery. Conclusion: Both of the two surgical methods are effective in the treatment of LDH in young and middle-aged patients, and microendoscopic discectomy + fibrous ring suture in particular may be preferred because it results in significant improvement in patients' VAS and ODI scores.

A Double-ligand Chelating Strategy to Iron Complex Anolytes with Ultrahigh Cyclability for Aqueous Iron Flow Batteries.

Aqueous all-iron flow batteries (AIFBs) are attractive for large-scale and long-term energy storage due to their extremely low cost and safety features. To accelerate commercial application, a long cyclable and reversible iron anolyte is expected to address the critical barriers, namely iron dendrite growth and hydrogen evolution reaction (HER). Herein, we report a robust iron complex with triethanolamine (TEA) and 2-methylimidazole (MM) double ligands. By introducing two ligands into one iron center, the binding energy of the complex increases, making it more stable in the charge-discharge reactions. The Fe(TEA)MM complex achieves reversible and stable redox between Fe3+ and Fe2+ , without metallic iron growth and HER. AIFBs based on this anolyte perform a high energy efficiency of 80.5 % at 80 mA cm-2 and exhibit a record durability among reported AIFBs. The efficiency and capacity retain nearly 100 % after 1,400 cycles. The capital cost of this AIFB is $ 33.2 kWh-1 (e.g., 20 h duration), cheaper than Li-ion battery and vanadium flow battery. This double-ligand chelating strategy not only solves the current problems faced by AIFBs, but also provides an insight for further improving the cycling stability of other flow batteries.

Highly Stable Photo-Assisted Zinc-Ion Batteries via Regulated Photo-Induced Proton Transfer.

Photo-assisted ion batteries utilize light to boost capacity but face cycling instability due to complex charge/ion transfer under illumination. This study identified photo-induced proton transfer (photo-induced PT) as a significant process in photo-(dis)charging of widely-used V2O5-based zinc-ion batteries, contributing to enhanced capacity under illumination but jeopardizing photo-stability. Photo-induced PT occurs at 100 ps after photo-excitation, inducing rapid proton extraction into V2O5 photoelectrode. This process creates a proton-deficient microenvironment on surface, leading to repetitive cathode dissolution and anode corrosion in each cycle. Enabling the intercalated protons from photo-induced PT to be reversibly employed in charge-discharge processes via the anode-alloying strategy achieves high photo-stability for the battery. Consequently, a ~54 % capacity enhancement was achieved in a V2O5-based zinc-ion battery under illumination, with ~90 % capacity retention after 4000 cycles. This extends the photo-stability record by 10 times. This study offers promising advancements in energy storage by addressing instability issues in photo-assisted ion batteries.

Dual-Modal Biosensor for Staphylococcus aureus Detection Based on a Porphyrin-Based Porous Organic Polymer FePor-TPA with Excellent Peroxidase-like, Catalase-like, and Photoelectrochemical Properties.

Bacterial infections seriously harm human health and cause many severe diseases, which triggered urgent demands to exploit specific and sensitive biosensor strategies for Staphylococcus aureus detection. Here, a colorimetric and photoelectrochemical dual-mode biosensor for S. aureus assay based on FePor-TPA was constructed. 2D FePor-TPA thin film and its bulk powder (FePor-TPA) were synthesized by in situ growth on ITO and a solvothermal condition, respectively, both of which exhibited excellent peroxidase-like and catalase-like activity, originating from their metalloporphyrin linkers. Benefiting from the in situ growth on ITO electrodes, the 2D FePor-TPA thin film also possessed a more ordered stacking mode and in turn exhibited good electrical conductivity, stable initial photocurrent, and high sensitivity to O2. As for bulk FePor-TPA, its porous structure and high specific surface area make it a possible scaffold to load an amount of AuNPs, the rabbit anti-Staphylococcus aureus Rosenbach tropina antibody (Ab2), and GOx for constructing the signal probe (GOx/Ab2@Au@FePor-TPA) and realizing catalytic amplification. With these satisfactory features in mind, the 2D FePor-TPA thin film and its bulk powder (FePor-TPA) were utilized to construct a dual and signal-on bioplatform for sensitively and selectively detecting S. aureus, which, as far as we know, has not been reported.

PER1 promotes functional recovery of mice with hindlimb ischemia by inducing anti-inflammatory macrophage polarization.

Hindlimb ischemia (HLI) is an arterial occlusive disease that exposes the patients to the risk of limb gangrene and loss. Polarization of macrophages is related to HLI-induced inflammation. Period circadian regulator 1 (PER1) is a core component of the circadian clock. We first showed, based upon bioinformatics analysis of microarray data, that PER1 expression was reduced in monocytes from patients with critical limb ischemia. The proximal femoral artery in the left hindlimb of male mice was ligated and then the femoral artery and its collateral branches were removed to establish the HLI mouse model. After modeling, a single intramuscular injection of 1 × 109 pfu Ad-PER1 was performed at the adductor and gastrocnemius muscles. The gastrocnemius muscle tissues were collected at day 0, 3, 7, 14, 21 post-HLI. There was obvious pathological necrosis, accompanied with reduced expression of PER1 in the muscle tissues of HLI mice. Expression of CD68 and CD31 seemed to be corresponded to PER1 in gastrocnemius muscle, implying the potential of PER1 in regulating macrophage-related inflammation and angiogenesis. PER1 overexpression diminished myocyte damage, promoted blood flow restoration and improved behavioral scores of HLI mice. Immunostaining of CD31 and α-SMA revealed that PER1 upregulation reversed HLI-induced decreases in capillary and arteriole density. In vitro, RAW264.7 cells were cultured in hypoxia (1% O2) for 24 h. The percentage of pro-inflammatory CD86+ macrophages (M1 type) was decreased and that of anti-inflammatory CD206+ macrophages (M2 type) was increased when PER1 was overexpressed. Moreover, the expression levels of TNF-α, IL-6 and M1-type marker iNOS were decreased, and levels of IL-10 and M2-type marker Arg-1 were increased by PER1 in gastrocnemius muscle of HLI mice and hypoxia-treated RAW264.7 cells. PER1 might reduce M1 macrophage polarization and promote M2 macrophage polarization, and thus exert anti-inflammatory and pro-angiogenic actions. Our findings suggest that PER1 overexpression promotes functional recovery of mice with HLI through regulating macrophage polarization.

Turning whispering-gallery-mode responses through Fano interferences in coupled all-dielectric block-disk cavities.

Here, we theoretically demonstrate a strategy for efficiently turning whispering-gallery-mode (WGM) responses of a subwavelength dielectric disk through their near-field couplings with common low-order electromagnetic resonances of a dielectric block. Both simulations and an analytical coupled oscillator model show that the couplings are Fano interferences between dark high-quality WGMs and bright modes of the block. The responses of a WGM in the coupled system are highly dependent on the strengths and the relative phases of the block modes, the coupling strength, and the decay rate of the WGM. The WGM responses of coupled systems can exceed that of the individual disk. In addition, such a configuration will also facilitate the excitation of WGMs by a normal incident plane wave in experiments. These results could enable new applications for enhancing light-matter interactions.

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.