Impdh2 deficiency suppresses osteoclastogenesis through mitochondrial oxidative phosphorylation and alleviates ovariectomy-induced osteoporosis.

Abnormalities in osteoclastic generation or activity disrupt bone homeostasis and are highly involved in many pathologic bone-related diseases, including rheumatoid arthritis, osteopetrosis, and osteoporosis. Control of osteoclast-mediated bone resorption is crucial for treating these bone diseases. However, the mechanisms of control of osteoclastogenesis are incompletely understood. In this study, we identified that inosine 5'-monophosphate dehydrogenase type II (Impdh2) positively regulates bone resorption. By histomorphometric analysis, Impdh2 deletion in mouse myeloid lineage cells (Impdh2LysM-/- mice) showed a high bone mass due to the reduced osteoclast number. qPCR and western blotting results demonstrated that the expression of osteoclast marker genes, including Nfatc1, Ctsk, Calcr, Acp5, Dcstamp, and Atp6v0d2, was significantly decreased in the Impdh2LysM-/- mice. Furthermore, the Impdh inhibitor MPA treatment inhibited osteoclast differentiation and induced Impdh2-cytoophidia formation. The ability of osteoclast differentiation was recovered after MPA deprivation. Interestingly, genome-wide analysis revealed that the osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation, were impaired in the Impdh2LysM-/- mice. Moreover, the deletion of Impdh2 alleviated ovariectomy-induced bone loss. In conclusion, our findings revealed a previously unrecognized function of Impdh2, suggesting that Impdh2-mediated mechanisms represent therapeutic targets for osteolytic diseases.

A p38 MAP kinase inhibitor suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss through the inhibition of bone turnover.

Inhibition of excessive osteoclastic activity is an efficient therapeutic strategy for many bone diseases induced by increased bone resorption, such as osteoporosis. BMS-582949, a clinical p38α inhibitor, is a promising drug in Phase II studies for treating rheumatoid arthritis. However, its function on bone resorption is largely unknown. In this study, we find that BMS-582949 represses RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, BMS-582949 inhibits osteoclastic F-actin ring formation and osteoclast-specific gene expression. Mechanically, BMS-582949 treatment attenuates RANKL-mediated osteoclastogenesis through mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) signaling pathways without disturbing nuclear factor-κB (NF-κB) signaling. Interestingly, BMS-582949 impairs osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation (OXPHOS). Furthermore, BMS-582949 administration prevents bone loss in ovariectomized mouse mode by inhibiting both bone resorption and bone formation in vivo. Taken together, these findings indicate that BMS-582949 may be a potential and effective drug for the therapy of osteolytic diseases.

Deletion of Impdh2 in adipocyte precursors limits the expansion of white adipose tissue and enhances metabolic health with overnutrition.

The equilibrium between the hypertrophic growth of existing adipocytes and adipogenesis is vital in managing metabolic stability in white adipocytes when faced with overnutrition. Adipogenesis has been established as a key player in combating metabolic irregularities caused by various factors. However, the benefits of increasing adipogenesis-mediated white adipose tissue (WAT) expansion for metabolic health regulation remain uncertain. Our findings reveal an increase in Impdh2 expression during the adipogenesis phase, both in vivo and in vitro. Xmp enhances adipogenic potential by fostering mitotic clonal expansion (MCE). The conditional knockout of Impdh2 in adipocyte progenitor cells(APCs) in adult and aged mice effectively curbs white adipose tissue expansion, ameliorates glucose tolerance, and augments energy expenditure under high-fat diet (HFD). However, no significant difference is observed under normal chow diet (NCD). Concurrently, the knockout of Impdh2 in APCs significantly reduces the count of new adipocytes induced by HFD, without affecting adipocyte size. Mechanistically, Impdh2 regulates the proliferation of APCs during the MCE phase via Xmp. Exogenous Xmp can significantly offset the reduction in adipogenic abilities of APCs due to Impdh2 deficiency. In summary, we discovered that adipogenesis-mediated WAT expansion, induced by overnutrition, also contributes to metabolic abnormalities. Moreover, the pivotal role of Impdh2 in regulating adipogenesis in APCs offers a novel therapeutic approach to combat obesity.

Oxidative Cascade Iodocyclization of 1,n-Dienes: Synthesis of Iodinated Benzo[b]azepine and Benzo[b]azocine Derivatives.

An oxidative cascade iodocyclization of 1,7- or 1,8-dienes has been realized under mild conditions. By employing I2 as an iodine source, this protocol provides a concise and efficient approach to a great deal of biologically significant iodinated benzo[b]azepine and benzo[b]azocine derivatives in moderate to good yields. The gram-scale synthesis and further transformation of products render the approach practical and attractive. Radical trapping and deuterium-labeling experiments help to understand the mechanism.

Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis.

In this study, we aimed to assess the analgesic efficacy of a thermoresponsive polymeric dexamethasone (Dex) prodrug (ProGel-Dex) in a mouse model of osteoarthritis (OA). At 12 weeks post model establishment, the OA mice received a single intra-articular (IA) injection of ProGel-Dex, dose-equivalent Dex, or Saline. Comparing to Saline and Dex controls, ProGel-Dex provided complete and sustained pain relief for >15 weeks according to incapacitance tests. In vivo optical imaging confirmed the continuous presence of ProGel-Dex in joints for 15 weeks post-injection. According to micro-CT analysis, ProGel-Dex treated mice had significantly lower subchondral bone thickness and medial meniscus bone volume than Dex and Saline controls. Except for a transient delay of body weight increase and slightly lower endpoint liver and spleen weights, no other adverse effect was observed after ProGel-Dex treatment. These findings support ProGel-Dex's potential as a potent and safe analgesic candidate for management of OA pain.

Near-Infrared Photothermal Manipulates Cellular Excitability and Animal Behavior in Caenorhabditis elegans.

Near-infrared (NIR) photothermal manipulation has emerged as a promising and noninvasive technology for neuroscience research and disease therapy for its deep tissue penetration. NIR stimulated techniques have been used to modulate neural activity. However, due to the lack of suitable in vivo control systems, most studies are limited to the cellular level. Here, a NIR photothermal technique is developed to modulate cellular excitability and animal behaviors in Caenorhabditis elegans in vivo via the thermosensitive transient receptor potential vanilloid 1 (TRPV1) channel with an FDA-approved photothermal agent indocyanine green (ICG). Upon NIR stimuli, exogenous expression of TRPV1 in AFD sensory neurons causes Ca2+ influx, leading to increased neural excitability and reversal behaviors, in the presence of ICG. The GABAergic D-class motor neurons can also be activated by NIR irradiation, resulting in slower thrashing behaviors. Moreover, the photothermal manipulation is successfully applied in different types of muscle cells (striated muscles and nonstriated muscles), enhancing muscular excitability, causing muscle contractions and behavior changes in vivo. Altogether, this study demonstrates a noninvasive method to precisely regulate the excitability of different types of cells and related behaviors in vivo by NIR photothermal manipulation, which may be applied in mammals and clinical therapy.

Electroacupuncture Pretreatment at Zusanli (ST36) Ameliorates Hepatic Ischemia/Reperfusion Injury in Mice by Reducing Oxidative Stress via Activating Vagus Nerve-Dependent Nrf2 Pathway.

Background and Purpose: Current pharmacological approaches to prevent hepatic ischemia/reperfusion injury (IRI) are limited. To mitigate hepatic injury, more research is needed to improve the understanding of hepatic IRI. Depending on traditional Chinese medicine (TCM) theory, acupuncture therapy has been used for the treatment of ischemic diseases with good efficacy. However, the efficacy and mechanism of acupuncture for hepatic IRI are still unclear. Methods: Blood provided to the left and middle lobe of mice livers was blocked with a non-invasive clamp and then the clamps were removed for reperfusion to establish a liver IRI model. Quantitative proteomics approach was used to evaluate the impact of EA pretreatment on liver tissue proteome in the IRI group. Serum biochemistry was used to detect liver injury, inflammation, and oxidative stress levels. H&E staining and TUNEL staining were used to detect hepatocyte injury and apoptosis. Immunohistochemistry and ELISA were used to detect the degree of inflammatory cell infiltration and the level of inflammation. The anti-inflammatory and antioxidant capacities were detected by Quantitative RT-PCR and Western blotting. Results: We found that EA at Zusanli (ST36) has a protective effect on hepatic IRI in mice by alleviating oxidative stress, hepatocyte death, and inflammation response. Nuclear factor E2-related factor 2 (Nrf2) as a crucial target was regulated by EA and was then successfully validated. The Nrf2 inhibitor ML385 and cervical vagotomy eliminated the protective effect in the EA treatment group. Conclusion: This study firstly demonstrated that EA pretreatment at ST36 significantly ameliorates hepatic IRI in mice by inhibiting oxidative stress via activating the Nrf2 signal pathway, which was vagus nerve-dependent.

Polymeric dexamethasone prodrugs attenuate lupus nephritis in MRL/lpr mice with reduced glucocorticoid toxicity.

Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.

Irrigation and debridement for knee osteoarthritis patients with suspected infection by intra-articular injection before total knee arthroplasty: a retrospective study.

BACKGROUND: Patients suffer from knee osteoarthritis (KOA) pain may seek for intra-articular injections before total knee arthroplasty (TKA), which have a possibility of causing the joint sepsis. However, the management and clinical outcomes of these patients following TKA remain uncertain. METHODS: Patients with a history of intra-articular injection, in which a joint sepsis was suspected, were included. The patients received joint irrigation and debridement (I&D) and antibiotic treatment until serum inflammatory indicators returned to normal level before TKA. The information of joint fluid routine and culture, synovium section and culture, and serum inflammatory indicator values were collected. Range of motion, Knee Society Scores (KSS) and Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) were used for functional evaluations. RESULTS: A total of 17 patients with 17 knee joints were included, all with elevated C-reactive protein (CRP) levels (23.5 ± 8.7 mg/L) as well as increased number of white blood cells (WBC) in the aspiration (50.8 ± 15.3) × 109/L, but no positive cultures were found. The culture of synovium detected three positive results: two Staphylococcus epidermidis and one S. aureus. I&D treatment had no obvious effect on the functional outcomes of KOA, but alleviated the joint pain (p < 0.01). Furthermore, we found that I&D pretreatment could increase the operation time with about 10 min longer than the primary TKA (p < 0.01). With respect to TKA outcomes, I&D had a slight influence on the knee flexion (p < 0.01), but no significant difference was identified between the two groups for KSS and WOMAC (all p values > 0.05). In addition, there was no significant difference in complication rates between the two groups in the last follow-up. CONCLUSION: I&D treatment is a valuable procedure for suspected knee infection, which has a higher incidence of detecting microorganisms while does not influence the functional outcomes and complication rates of TKA. However, further larger studies are required to confirm these findings.

The Therapeutic Effects of Acupuncture and Electroacupuncture on Cancer-related Symptoms and Side-Effects.

In addition to cancer-related death, malignant progression also leads to a series of symptoms and side-effects, which would detrimentally affect cancer patients' the quality of life, adversely influence their adherence to treatments, and, therefore, negatively affect their long-term survival. Acupuncture and electroacupuncture (EA), as two classic treatment methods in traditional Chinese medicine, have been widely employed to cure various diseases. Recently, the clinical application of acupuncture and EA in cancer patients has received great attention. In this review, we summarized the clinical application of acupuncture and EA in alleviating the cancer symptoms, reducing the cancer treatment-related side-effects, and relieving the cancer pain. The symptoms and side-effects discussed in this review include fatigue, insomnia, chemotherapy-associated dyspepsia syndrome (CADS), pain, xerostomia, and anxiety and depression. The underlying mechanisms of the therapeutic effects of acupuncture and EA might be related to the regulation of the mitochondrial function, coordination of the activity of the nervous system, adjustment of the production of neurotransmitters, and alleviation of the immune responses. In conclusion, acupuncture and EA have been proved to be beneficial for cancer patients. More research, however, is required to clarify the potential mechanisms behind acupuncture and EA for widespread adoption in clinical application.

Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.

Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in ∼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.

Hepatotoxicity of FDA-approved small molecule kinase inhibitors.

Introduction: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians.Areas covered: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms.Expert opinion: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.

Cell-derived decellularized extracellular matrix scaffolds for articular cartilage repair.

Articular cartilage repair remains a great clinical challenge. Tissue engineering approaches based on decellularized extracellular matrix (dECM) scaffolds show promise for facilitating articular cartilage repair. Traditional regenerative approaches currently used in clinical practice, such as microfracture, mosaicplasty, and autologous chondrocyte implantation, can improve cartilage repair and show therapeutic effect to some degree; however, the long-term curative effect is suboptimal. As dECM prepared by proper decellularization procedures is a biodegradable material, which provides space for regeneration tissue growth, possesses low immunogenicity, and retains most of its bioactive molecules that maintain tissue homeostasis and facilitate tissue repair, dECM scaffolds may provide a biomimetic microenvironment promoting cell attachment, proliferation, and chondrogenic differentiation. Currently, cell-derived dECM scaffolds have become a research hotspot in the field of cartilage tissue engineering, as ECM derived from cells cultured in vitro has many advantages compared with native cartilage ECM. This review describes cell types used to secrete ECM, methods of inducing cells to secrete cartilage-like ECM and decellularization methods to prepare cell-derived dECM. The potential mechanism of dECM scaffolds on cartilage repair, methods for improving the mechanical strength of cell-derived dECM scaffolds, and future perspectives on cell-derived dECM scaffolds are also discussed in this review.

Dexamethasone prodrug nanomedicine (ZSJ-0228) treatment significantly reduces lupus nephritis in mice without measurable side effects - A 5-month study.

Lupus nephritis (LN) is a major cause of morbidity and mortality among systemic lupus erythematosus patients. Glucocorticoids (GCs) are uniformly used in clinical LN management. Their notorious toxicities, however, have hampered the long-term clinical application. To circumvent GC side effects while maintaining their potent therapeutic efficacy, we have developed a macromolecular prodrug nanomedicine based on dexamethasone (ZSJ-0228). The focus of this study was to investigate its long-term efficacy and, most importantly, safety in the lupus-prone NZB/W F1 mouse. Monthly ZSJ-0228 treatment for five months significantly reduced the incidence of nephritis in NZB/W F1 mice with an improved survival rate. In contrast to treatment with dose equivalent daily free dexamethasone, long-term monthly ZSJ-0228 did not result in any measurable GC-associated side effects. With its outstanding efficacy and exceptional safety, it is anticipated that ZSJ-0228 may be a novel therapy for long-term clinical management of LN.

Quantitative Characterization of Bone Viability of Femoral Head and Subchondral Bone by Using Single Photon Emission Computerized Tomography/Computerized Tomography (SPECT/CT).

BACKGROUND Vascularized fibular grafting (VFG) has been successfully employed for treating avascular necrosis of the femoral head (ANFH). In this study, we aimed to evaluate the bone viability of the femoral head and subchondral bone following VFG by using single photon emission computerized tomography and computerized tomography (SPECT/CT). MATERIAL AND METHODS Between March 2011 and June 2014, 14 ANFH patients (17 hips) treated with VFG at Zhongshan Hospital, Fudan University, were prospectively enrolled. The patients included 9 males and 5 females with an average age of 26.6 years (range, 18-34 years). According to the ARCO (Association Research Circulation Osseous) stage criteria, 3 hips corresponded to stage IIA, 4 hips to stage IIB, 2 hips to stage IIC, 5 hips to stage IIIA, and 3 hips to stage IIIB. A novel method based on SPECT/CT was developed to quantitative characterized the bone viability of femoral head and subchondral bone prior to surgery and at 3 months after VFG. All patients were followed for an average duration of 3.8 years (ranging 2.6-5.5 years). RESULTS The bone viability of the femoral head (Vfh) and subchondral bone (Vsb) of patients' hips at ARCO stage III was 58.9±7.6 and 48.9±6.1, respectively, which were significantly lower than the preoperative Vfh (78.1±5.2) and Vsb (69.8±4.3) of hips at stage II (P<0.05). The Vfh of hips at stage II improved to 104.0±9.7 at 3 months post-intervention, and there was no significant difference compared with the Vfh (97.3±7.4) of hips at stage III (P=0.15). The Vsb of hips at stage III improved to 80.4±7.3 at 3 months after VFG; however, this value was significantly lower than that of hips at stage II (92.7±5.5) (P<0.05). CONCLUSIONS The Vfh and Vsb of our patients were associated with their ARCO stages, and could be improved after vascularized fibular grafting procedure as measured by SPECT/CT.

In situ administration of cytokine combinations induces tumor regression in mice.

BACKGROUND: Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but the complex immunosuppressive microenvironment confines the therapeutic benefits to a minority of patients with solid tumors. METHODS: A lentivector-based inducible system was established to evaluate the therapeutic effect of cytokines in established tumors. Intratumoral injection of certain cytokine combination in syngeneic tumor models was conducted to assess the therapeutic potentials. FINDINGS: Doxycycline (Dox)-induced local expression of cytokine combinations exhibites a strong synergistic effect, leading to complete regression of tumors. Notably, IL12 + GMCSF+IL2 expression induces eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of ~15 mm in diameter, and generates intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induce tumor elimination in most of mice. Moreover, intratumoral injection of chitosan/IL12 + GMCSF+IL2 solution induces a complete response in all the tested syngeneic tumor models, regardless of various tumor immunograms. INTERPRETATION: Administration of certain cytokine combinations in tumor microenvironment induces a strong synergistic antitumor response, including the recruitment of large amount of immune cells and the generation of systemic antitumor immunity. It provides a versatile method for the immunotherapy of intractable malignant neoplasms. FUND: There is no external funding supporting this study.

A Comparative Study of Behavior Problems among Left-Behind Children, Migrant Children and Local Children.

This study aims to estimate the prevalence of behavioral problems among left-behind children, migrant children and local children in China, and to compare the risks of behavioral problems among the three types of children. Data on 4479 children aged 6-16 used in this study were from a survey conducted in China in 2017. The school-age version of the Children Behavior Checklist was used to measure children's behavioral problems. Descriptive analysis, correlation analysis, and logistic regressions were conducted. The prevalence of behavioral problems was 18.80% and 13.59% for left-behind children and migrant children, respectively, both of which were higher than that of local children. Logistic regression analysis showed that after adjustments for individual and environmental variables, the likelihood of total, internalizing and externalizing behavior problems for left-behind children and migrant children were higher than those for local children; left-behind children had a higher likelihood of internalizing problems than externalizing problems, while migrant children had a higher prevalence of externalizing problems. Left-behind children had a higher prevalence of each specific syndrome than migrant and local children. Both individual and environmental factors were associated with child behavioral problems, and family migration may contribute to the increased risks. Left-behind and migrant children were more vulnerable than local children to behavioral problems.

A comparative study of unintentional injuries among schooling left-behind, migrant and residential children in China.

BACKGROUND: Children who suffer from parental migration have been manifested to exhibit physical and mental impairments at higher rates. This current study aims to explore unintentional injury disparity among schooling left-behind children, migrant children and residential children in China, and to examine the risk factors of unintentional injury among the three types of children based on a multi-level system framework. This study will fill the gaps of this topic for China and contribute to the world literature in the context of countries with frequent population migration. METHODS: Data for 4479 children aged 6-16 of a representative population sample were obtained from a survey conducted in China in 2017. Child's unintentional injury in this survey was measured based on the definition and classification of ICD-10. Descriptive analysis, multivariable logistic regression and zero-inflated negative binomial regression were employed in this study. RESULTS: Left-behind children showed higher prevalence of total unintentional injury than migrant and residential children, as well as in 14 specific unintentional injuries. There was a statistical difference between left-behind and residential children's unintentional injuries, but no significant difference was found between migrant and residential children. Results also indicated that both individual and environmental factors constructed as a multi-level system were associated with children's unintentional injuries. CONCLUSIONS: Family migration may have contributed to the increased unintentional injury risks among children. Left-behind children were more vulnerable to suffer from unintentional injuries than migrant and residential children, and specific attentions should be paid to unique group of children, especially the left-behind children. Given the importance and serious consequences of children's unintentional injuries, the findings may provide implications for necessary intervention.

Dense Intra-adipose Sympathetic Arborizations Are Essential for Cold-Induced Beiging of Mouse White Adipose Tissue.

Efferent signals from the central nervous system represent a key layer of regulation of white adipose tissue (WAT). However, the mechanism by which efferent neural signals control WAT metabolism remains to be better understood. Here, we exploit the volume fluorescence-imaging technique to visualize the neural arborizations in mouse inguinal WAT at single-fiber resolution. The imaging reveals a dense network of sympathetic arborizations that had been previously undetected by conventional methods, with sympathetic fibers being in close apposition to > 90% of adipocytes. We demonstrate that these sympathetic fibers originate from the celiac ganglia, which are activated by cold challenge. Sympathetic-specific deletion of TrkA receptor or pharmacologic ablation by 6-hydroxydopamine abolishes these intra-adipose arborizations and, as a result, cold-induced beiging of inguinal WAT. Furthermore, we find that local sympathetic arborizations function through beta-adrenergic receptors in this beiging process. These findings uncover an essential link connecting efferent neural signals with metabolism of individual adipocytes.

Plexin B2 and Semaphorin 4C Guide T Cell Recruitment and Function in the Germinal Center.

Follicular T helper (TFH) cells orchestrate the germinal center (GC) response locally. TFH localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here. we define an antigen-independent, contact-dependent, adhesive guidance system for TFH cells. Unusual for amoeboid cell migration, the system is composed of transmembrane plexin B2 (PlxnB2) molecule, which is highly expressed by GC B cells, and its transmembrane binding partner semaphorin 4C (Sema4C), which is upregulated on TFH cells. Sema4C on TFH cells serves as a receptor to sense the GC-presented PlxnB2 cue and biases TFH migration inwards at the GC edge to promote GC access. The absence of PlxnB2 from the GC or Sema4C from TFH cells causes TFH accumulation along the GC border, impairs T-B cell interactions in the GC, and is associated with defective plasma cell production and affinity maturation. Therefore, Sema4C and PlxnB2 regulate GC TFH recruitment and function and optimize antibody responses.