Seed-Coat Pigmentation Plays a Crucial Role in Partner Selection and N2 Fixation in Legume-Root-Microbe Associations in African Soils.

Legume-rhizobia symbiosis is the most important plant-microbe interaction in sustainable agriculture due to its ability to provide much needed N in cropping systems. This interaction is mediated by the mutual recognition of signaling molecules from the two partners, namely legumes and rhizobia. In legumes, these molecules are in the form of flavonoids and anthocyanins, which are responsible for the pigmentation of plant organs, such as seeds, flowers, fruits, and even leaves. Seed-coat pigmentation in legumes is a dominant factor influencing gene expression relating to N2 fixation and may be responsible for the different N2-fixing abilities observed among legume genotypes under field conditions in African soils. Common bean, cowpea, Kersting's groundnut, and Bambara groundnut landraces with black seed-coat color are reported to release higher concentrations of nod-gene-inducing flavonoids and anthocyanins compared with the Red and Cream landraces. Black seed-coat pigmentation is considered a biomarker for enhanced nodulation and N2 fixation in legumes. Cowpea, Bambara groundnut, and Kersting's bean with differing seed-coat colors are known to attract different soil rhizobia based on PCR-RFLP analysis of bacterial DNA. Even when seeds of the same legume with diverse seed-coat colors were planted together in one hole, the nodulating bradyrhizobia clustered differently in the PCR-RFLP dendrogram. Kersting's groundnut, Bambara groundnut, and cowpea with differing seed-coat colors were selectively nodulated by different bradyrhizobial species. The 16S rRNA amplicon sequencing also found significant selective influences of seed-coat pigmentation on microbial community structure in the rhizosphere of five Kersting's groundnut landraces. Seed-coat color therefore plays a dominant role in the selection of the bacterial partner in the legume-rhizobia symbiosis.

Fecal transplant from vaginally seeded infants decreases intraabdominal adiposity in mice.

Exposing C-section infants to the maternal vaginal microbiome, coined "vaginal seeding", partially restores microbial colonization. However, whether vaginal seeding decreases metabolic disease risk is unknown. Therefore, we assessed the effect of vaginal seeding of human infants on adiposity in a murine model. Germ-free mice were colonized with transitional stool from human infants who received vaginal seeding or control (placebo) seeding in a double-blind randomized trial. There was a reduction in intraabdominal adipose tissue (IAAT) volume in male mice that received stool from vaginally seeded infants compared to control infants. Higher levels of isoleucine and lower levels of nucleic acid metabolites were observed in controls and correlated with increased IAAT. This suggests that early changes in the gut microbiome and metabolome caused by vaginal seeding have a positive impact on metabolic health.

Chitosan-grafted folic acid decorated one-dimensional GONS: A biocompatible drug cargo for targeted co-delivery of anticancer agents.

In conventional chemotherapy, the cancer cells can become highly resilient due to a phenomenon known as multi-drug resistance (MDR). The co-delivery of chemotherapeutic agents assisted with novel nanocarrier-based targeted DDS may counter the MDR issues and subsequently improve their therapeutic efficacy. In line with this, the present work deals with the development of 1D graphene oxide nanoscrolls (GONS)-based nano delivery system for co-delivery of chemosensitizer along with the chemotherapeutic agent. Herein, the 1D GONS nanocarrier was initially functionalized with chitosan (CS) biopolymer and folic acid (FA) further to enhance their biocompatibility and target-specific co-delivery. The resultant GONS-CS-FA (GCF) nanocarriers were co-loaded with doxorubicin (DOX) and caffeic acid (CA) at different weight proportions with respect to nanocarrier and drug composition. The optimum loading efficiency of 51.14 ± 1.47 % (DOX) and 49.70 ± 1.19 % (CA) was observed for GCF: drug ratio of 2.5 with drug composition of 1:1. In vitro release at pH 5 yielded ~83 % DOX and 75 % CA, compared to ~71 % DOX and 61 % CA at pH 7.4 over 7 days, suggesting a higher and targeted drug release in the cancer microenvironment. Cytotoxicity tests revealed selective apoptosis in cancer cells (A549) while maintaining cytocompatibility with normal cells (HEK293).

Knockdown of SCN5A alters metabolic-associated genes and aggravates hypertrophy in the cardiomyoblast.

SCN5A mutations have been reported to cause various cardiomyopathies in humans. Most of the SCN5A mutations causes loss of function and thereby, alters the overall cellular function. Therefore, to understand the loss of SCN5A function in cardiomyocytes, we have knocked down the SCN5A gene (SCN5A-KD) in H9c2 cells and explored the cell phenotype and molecular behaviors in the presence and absence of isoproterenol (ISO), an adrenergic receptor agonist that induces cardiac hypertrophy. Expression of several genes related to hypertrophy, inflammation, fibrosis, and energy metabolism pathways were evaluated. It was found that the mRNA expression of hypertrophy-related gene, brain (B-type) natriuretic peptide (BNP) was significantly increased in SCN5A-KD cells as compared to 'control' H9c2 cells. There was a further increase in the mRNA expressions of BNP and ßMHC in SCN5A-KD cells after ISO treatment compared to their respective controls. Pro-inflammatory cytokine, tumor necrosis factor-alpha expression was significantly increased in 'SCN5A-KD' H9c2 cells. Further, metabolism-related genes like glucose transporter type 4, cluster of differentiation 36, peroxisome proliferator-activated receptor alpha, and peroxisome proliferator-activated receptor-gamma were significantly elevated in the SCN5A-KD cells as compared to the control cells. Upregulation of these metabolic genes is associated with increased ATP production. The study revealed that SCN5A knock-down causes alteration of gene expression related to cardiac hypertrophy, inflammation, and energy metabolism pathways, which may promote cardiac remodelling and cardiomyopathy.

Distinguishing Molecular Properties of OAT, OATP, and MRP Drug Substrates by Machine Learning.

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood-brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut-liver-kidney axis, gut-brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug-drug interactions and drug-metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs.

Synthesis and characterization of a pH/temperature-dual responsive hydrogel with promising biocompatibility features for stimuli-responsive 5-FU delivery.

The tunable properties of stimuli-responsive copolymers or hydrogels enable their application in different fields such as biomedical engineering, tissue engineering, or even drug release. Here we introduce a new PNIPAM-based triblock copolymer material comprising a controlled amount of a novel hydrophobic crosslinker 2,4'-diacryloyloxy benzophenone (DABP) and acrylic acid (AAc) to achieve lower critical solution temperature (LCST) between ambient and body temperatures. The dual stimuli-responsive p(NIPAM-co-DABP-co-AAc) triblock copolymer material and hydrogel were synthesized, and their temperature and pH-responsive behaviors were systematically investigated. The hydrogel exhibited excellent temperature and pH-responsive properties with an LCST of around 30 °C. Moreover, the synthesized copolymer has been demonstrated to be nontoxic both in vitro and in vivo. When the hydrogel was preloaded with the model drug 5-fluorouracil (5-FU), the designed hydrogel released the drug in a temperature and pH-controlled fashion. It was observed that the prepared hydrogel has the ability to entrap 5-FU, and the loading is more than 85%. In the case of temperature-controlled release, we observed almost complete release of 5-FU at lower temperatures and sustained release behavior at higher temperatures. In addition, the hydrogel matrix was able to retard the release of 5-FU in an acidic environment and selectively release 5-FU in a basic environment. By realizing how the hydrogel properties influence the release of drugs from preloaded hydrogels, it is possible to design new materials with myriad applications in the drug delivery field.

Advancing sustainable agriculture: Evaluation of Poly (lactic acid) (PLA) based mulch films and identification of biodegrading microorganisms among soil microbiota.

Non-biodegradable polyolefin based plastic mulch residues in agricultural fields after the end of a crop cycle have raised several concerns as an environmental pollutant in recent years. This study explores the potential of Poly (lactic acid) (PLA) and Poly (butylene adipate-co-terephthalate) (PBAT) based compostable films reactively blended with compatibilizers and chain extenders as a promising solution to environmental challenges associated with traditional plastic mulch films. Epoxidized soybean oil (ESO) and Epoxy-functionalized styrene acrylic copolymer (ESA) have been used as reactive compatibilizers and chain extenders respectively. In-depth analysis of the mechanical, thermal, and barrier properties of the developed films, revealed that the PLA/PBAT blend films at 75:25 weight ratio in the presence of 5 phr ESO and 0.5 phr ESA exhibit improved performance characteristics for application as mulch films. Furthermore, the films were subjected to 360-h UV exposure to gauge their stability under prolonged exposure, specifically investigating changes in the carbonyl index. Additionally, a rigorous real-time field trial of the mulch films spanning eight months with various crops was carried out to understand their performance in practical agricultural settings. The study also involved the identification of microorganisms responsible for the degradation of the developed mulch films employing 16S rRNA sequencing.

Compressive Myelopathy Secondary to TRPV4 Skeletal Dysplasia: Spondylometaphyseal Dysplasia, Kozlowski Type.

Transient receptor potential vanilloid 4 channel ( TRPV4 ) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4 , which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

Out-of-pocket payment and financial risk protection for breast cancer treatment: a prospective study from India.

Background: Available data on cost of cancer treatment, out-of-pocket payment and reimbursement are limited in India. We estimated the treatment costs, out-of-pocket payment, and reimbursement in a cohort of breast cancer patients who sought treatment at a publicly funded tertiary cancer care hospital in India. Methods: A prospective longitudinal study was conducted from June 2019 to March 2022 at Tata Memorial Centre (TMC), Mumbai. Data on expenditure during each visit of treatment was collected by a team of trained medical social workers. The primary outcome variables were total cost (TC) of treatment, out-of-pocket payment (OOP), and reimbursement. TC included cost incurred by breast cancer patients during treatment at TMC. OOP was defined as the total cost incurred at TMC less of reimbursement. Reimbursement was any form of financial assistance (cashless or repayment), including social health insurance, private health insurance, employee health schemes, and assistance from charitable trusts, received by the patients for breast cancer treatment. Findings: Of the 500 patients included in the study, 45 discontinued treatment (due to financial or other reasons) and 26 died during treatment. The mean TC of breast cancer treatment was ₹258,095/US$3531 (95% CI: 238,225, 277,934). Direct medical cost (MC) accounted for 56.3% of the TC. Systemic therapy costs (₹50,869/US$696) were higher than radiotherapy (₹33,483/US$458) and surgery costs (₹25,075/US$343). About 74.4% patients availed some form of financial assistance at TMC; 8% patients received full reimbursement. The mean OOP for breast cancer treatment was ₹186,461/US$2551 (95% CI: 167,666, 205,257), accounting for 72.2% of the TC. Social health insurance (SHI) had a reasonable coverage (33.1%), followed by charitable trusts (29.6%), employee health insurance (5.1%), private health insurance (4.4%) and 25.6% had no reimbursement. But SHI covered only 40.1% of the TC of treatment compared to private health insurance that covered as much as 57.1% of it. Both TC and OOP were higher for patients who were younger, belonged to rural areas, had a comorbidity, were diagnosed at an advanced stage, and were from outside Maharashtra. Interpretation: In India, the cost and OOP for breast cancer treatment are high and reimbursement for the treatment flows from multiple sources. Though many of the patients receive some form of reimbursement, it is insufficient to prevent high OOP. Hence both wider insurance coverage as well as higher cap of the insurance packages in the health insurance schemes is suggested. Allowing for the automatic inclusion of cancer treatment in SHI can mitigate the financial burden of cancer patients in India. Funding: This work was funded by an extramural grant from the Women's Cancer Initiative and the Nag Foundation and an intramural grant from the International Institute of Population Sciences, Mumbai.

Socioeconomic gradient of lean diabetes in India: Evidence from National Family Health Survey, 2019-21.

Diabetes is a global public health challenge, particularly in India, affecting millions. Among diabetic patients, lean type 2 diabetes is a severe subtype with higher microvascular complication risks. While studies on the prevalence, variations and risk factors of diabetes are increasingly available, there has been limited research on the prevalence, variations, and socioeconomic disparities of lean diabetes in India. This study used NFHS-5 microdata, and lean diabetes is defined as those with a BMI level of under 25 and random blood glucose levels of over 200 or under diabetic medication. Descriptive and multivariate analyses were conducted to understand lean diabetes variations and related factors. Socioeconomic disparities were measured using concentration curves and the concentration index. The study unveiled important insights into lean diabetes in India. 8.2% of men and 6.0% of women had elevated blood glucose levels, indicating a significant diabetes burden. Notably, 2.9% of men and 2.4% of women were diagnosed with lean diabetes. Among type 2 diabetics, 52.56% of males and 43.57% of females had lean type 2 diabetes. Lean diabetes prevalence varied from 11.6% in the poorest quintile to 1.1% in the richest. The odds of lean type 2 diabetes among those in the poorest quintile was 6.7 compared to the richest quintile. The concentration index of lean type 2 diabetes was -0.42 for men and -0.39 for women, suggesting a disproportionate impact on lower socioeconomic groups. This study advances our understanding of the complex interplay between socioeconomic factors and lean type 2 diabetes in India. To address the rising burden of lean diabetes among lower socioeconomic strata, policymakers and healthcare professionals must prioritise initiatives enhancing healthcare access, promoting healthy lifestyles, and ensuring effective diabetes management. By addressing socioeconomic disparities and implementing interventions for vulnerable populations, India can reduce diabetes-related mortality and enhance its citizens' overall health.

One-Pot Synthesis of Vinylogous Cyano Aminoaryls (VinCAs) as Benzenic Fluorophores: Tailoring Diverse Emission Colors for White Light Emitting Materials and Cell Imaging.

Donor-acceptor-based organic small molecules with an electronic push-pull effect can demonstrate intramolecular charge transfer to show interesting photoluminescence properties. This is an essential criterion for designing fluorogenic probes for cell imaging studies and the development of organic light-emitting diodes. Now, to design such optical materials sometimes it is necessary to tune the band gap by controlling the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital. Typically, the band gaps could be modulated by installing unsaturated handles between electron-rich donors and electron-deficient acceptors. However, these methods are often synthetically and economically challenging due to the involvement of expensive catalysts and difficult reaction setups. In our present study, we show a straightforward, cost-effective method for obtaining a series of donor-acceptor-type Vinylogous Cyano Aminoaryls (VinCAs) with diverse emission colors. Further studies reveal that these VinCAs can serve as effective cell imaging agents, showcasing potential use in chemical biology. Additionally, these molecules could be further used to generate white light emission (WLE), showing their potential utility in advanced lighting technologies.

Influence of the configuration of metal sensing layers on the performance of a bimetallic (Ag-Cu) surface plasmon resonance biosensor.

Bimetallic surface plasmon resonance (SPR) sensors have the potential to overcome the drawbacks of individual metals, but the effect of the configuration of the two metallic layers on the performance of the sensors has not been explored. This study examines the influence of different positions of a thin layer of silver in relation to a copper layer on the sensitivity of such a bimetallic SPR sensor. The design of this configuration aims to improve the SPR reflectance curve and strengthen the evanescent electric field to improve the sensor efficiency. Our findings indicate that, by optimizing the architectures of SPR sensors and using a silver-copper bimetallic structure, we can achieve superior performance compared to devices that utilize only silver or copper. The optimized Ag (5 nm)/Cu (55 nm) sensor design, with the best sensitivity of 299.09° RIU-1, can detect a change of 0.43°/(g dl-1) for hemoglobin in blood, 0.35°/(g dl-1) for glucose in urine, and 0.1°/(%) for methanol in ethanol. We also demonstrate the importance of signal quality by introducing two new parameters that offer a better quantitative indication of the efficiency of a sensor than is obtained by using only sensitivity.

The Spectrum of Central Nervous System Tumors at a Tertiary Care Center Primarily Serving a Rural Population.

Background Central nervous system (CNS) tumors cause significant mortality and morbidity in all age groups. There was no data about the histological spectrum of all CNS tumors in the tertiary care center serving primarily the rural population of Uttar Pradesh. Aims and objectives The present study aimed to describe the histopathological spectrum of all CNS tumors reported in a rural tertiary care center at Saifai, Uttar Pradesh. It also aimed to provide an overview of the descriptive epidemiology of CNS tumors. Material and methods This was a retrospective, cross-sectional study. The study duration was three years. A total of 115 cases of CNS tumors were studied during that period. Cases were classified according to their histological types, and results were analyzed. Results The most common histological group was neuroepithelial tumors, with 53 cases (46.08%). This group had 36 cases of astrocytic tumors (31.3%), three cases of oligodendroglial tumors (2.6%), five cases of oligoastrocytic tumors (4.34%), five cases of ependymal tumors (4.34%), and four cases of embryonal tumors (3.47%). The second most common tumor was meningeal tumors, with 32 cases (27.82%). The male/female ratio (M/F) ratio was 0.7. Females were found to be more affected by almost all histologic categories. Most meningiomas (89.6%) were of World Health Organization (WHO) grade I (26 cases out of 29). Astrocytic tumors showed WHO grade I, II, III, and IV tumors in two cases (5.5%), twelve cases (33.3%), four cases (11.1%), and eighteen cases (50%), respectively. In the younger age group (0-20 years), ependymoma and medulloblastoma were most common, followed by pilocytic astrocytoma and schwannoma. Conclusion In this region, neuroepithelial tumors were seen more commonly than meningioma. Females were found to be more affected by CNS tumors. This study has provided relevant data, which can be used for research and better patient management. Further studies with the incorporation of advanced radiological investigation and immunohistochemistry have been recommended.

Low-Temperature Synthesis of WSe2 by the Selenization Process under Ultrahigh Vacuum for BEOL Compatible Reconfigurable Neurons.

Low-temperature large-area growth of two-dimensional (2D) transition-metal dichalcogenides (TMDs) is critical for their integration with silicon chips. Especially, if the growth temperatures can be lowered below the back-end-of-line (BEOL) processing temperatures, the Si transistors can interface with 2D devices (in the back end) to enable high-density heterogeneous circuits. Such configurations are particularly useful for neuromorphic computing applications where a dense network of neurons interacts to compute the output. In this work, we present low-temperature synthesis (400 °C) of 2D tungsten diselenide (WSe2) via the selenization of the W film under ultrahigh vacuum (UHV) conditions. This simple yet effective process yields large-area, homogeneous films of 2D TMDs, as confirmed by several characterization techniques, including reflection high-energy electron diffraction, atomic force microscopy, transmission electron microscopy, and different spectroscopy methods. Memristors fabricated using the grown WSe2 film are leveraged to realize a novel compact neuron circuit that can be reconfigured to enable homeostasis.

Strategic Design of Non-d10 Luminescent Metal-Organic Frameworks as Dual-Mode Ultrafast and Selective Sensing Platforms for Aldehydes at the ppb Level.

Utilizing a cautious design of luminescent MOFs of non-d10 divalent transition metals based on two factors (metal nodes in an octahedral geometry to minimize nonradiative energy dissipation and tailored organic chromophores), this work reports {[Ni2(oxdz)2(tpbn)]}n (1), {[Ni2(oxdz)2(tphn)]}n (2), and {[Ni2(oxdz)2(tpon)]}n (3), synthesized at room temperature, varying the spacer length of tpbn/tphn/tpon (four, six, and eight CH2 groups, respectively). This subtle change in 1-3 is correlated to their hydrophobicity and polarizing power via water vapor sorption and selective and sensitive detection of aldehydes at the ppb level, respectively. A decrease in water vapor uptake (14.8, 8.95, and 3.19 mmol g-1 for 1-3, respectively) is observed with an increase in their hydrophobicity. On the other hand, the solution phase detection limits of acetaldehyde and benzaldehyde (2.42 and 6.71 ppb for 1, 2.77 and 4.08 ppb for 2, and 10.35 and 10.4 ppb for 3, respectively) show a similar trend for their polarizing power. The best performance of 1 is expanded to the vapor-phase detection of acetaldehyde (297% luminescence enhancement) under different pH conditions. The second mode of detection of acetaldehyde via the metal-centered electrochemical behavior of 1 provides detection limits of 38.2 and 71.5 ppb at pH 7 and 13, respectively.

Trametes versicolor Laccase-Based Magnetic Inorganic-Protein Hybrid Nanobiocatalyst for Efficient Decolorization of Dyes in the Presence of Inhibitors.

In the present investigation, an ecofriendly magnetic inorganic-protein hybrid system-based enzyme immobilization was developed using partially purified laccase from Trametes versicolor (TvLac), Fe3O4 nanoparticles, and manganese (Mn), and was successfully applied for synthetic dye decolorization in the presence of enzyme inhibitors. After the partial purification of crude TvLac, the specific enzyme activity reached 212 U∙mg total protein-1. The synthesized Fe3O4/Mn3(PO4)2-laccase (Fe3O4/Mn-TvLac) and Mn3(PO4)2-laccase (Mn-TvLac) nanoflowers (NFs) exhibited encapsulation yields of 85.5% and 90.3%, respectively, with relative activities of 245% and 260%, respectively, compared with those of free TvLac. One-pot synthesized Fe3O4/Mn-TvLac exhibited significant improvements in catalytic properties and stability compared to those of the free enzyme. Fe3O4/Mn-TvLac retained a significantly higher residual activity of 96.8% over that of Mn-TvLac (47.1%) after 10 reuse cycles. The NFs showed potential for the efficient decolorization of synthetic dyes in the presence of enzyme inhibitors. For up to five reuse cycles, Fe3O4/Mn-TvLac retained a decolorization potential of 81.1% and 86.3% for Coomassie Brilliant Blue R-250 and xylene cyanol, respectively. The synthesized Fe3O4/Mn-TvLac showed a lower acute toxicity towards Vibrio fischeri than pure Fe3O4 nanoparticles did. This is the first report of the one-pot synthesis of biofriendly magnetic protein-inorganic hybrids using partially purified TvLac and Mn.

Nerve injury inhibits Oprd1 and Cnr1 transcription through REST in primary sensory neurons.

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1, Oprd1, Oprl1, Oprk1) and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression of Rest and downregulated mRNA levels of all 4 opioid receptor and Cnr1 genes, but Oprm1 was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription of Oprd1 and Cnr1 via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice.

The biosynthesis of C-reactive protein (CRP) in the liver is increased in inflammatory diseases including rheumatoid arthritis. Previously published data suggest a protective function of CRP in arthritis; however, the mechanism of action of CRP remains undefined. The aim of this study was to evaluate the effects of human CRP on the development of collagen-induced arthritis (CIA) in mice which is an animal model of autoimmune inflammatory arthritis. Two CRP species were employed: wild-type CRP which binds to aggregated IgG at acidic pH and a CRP mutant which binds to aggregated IgG at physiological pH. Ten CRP injections were given on alternate days during the development of CIA. Both wild-type and mutant CRP reduced the incidence of CIA, that is, reduced the number of mice developing CIA; however, CRP did not affect the severity of the disease in arthritic mice. The serum levels of IL-17, IL-6, TNF-α, IL-10, IL-2 and IL-1ß were measured: both wild-type and mutant CRP decreased the level of IL-17 and IL-6 but not of TNF-α, IL-10, IL-2 and IL-1ß. These data suggest that CRP recognizes and binds to immune complexes, although it was not clear whether CRP functioned in its native pentameric or in its structurally altered pentameric form in the CIA model. Consequently, ligand-complexed CRP, through an as-yet undefined mechanism, directly or indirectly, inhibits the production of IL-17 and eventually protects against the initiation of the development of arthritis. The data also suggest that IL-17, not TNF-α, is critical for the development of autoimmune inflammatory arthritis.