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Recent studies in mouse models have shown that gut microbiota significantly influences bone health. We demonstrated that 2-week oral treatment with broad spectrum antibiotics followed by 4 weeks of recovery of the gut microbiota results in dysbiosis (microbiota imbalance)-induced bone loss in mice. Because gut microbiota is critical for the development of the immune system and since both microbiota and the immune system can regulate bone health, in this study, we tested the role of the immune system in mediating post-antibiotic dysbiosis-induced bone loss. For this, we treated wild-type (WT) and lymphocyte deficient Rag2 knockout (KO) mice with ampicillin/neomycin cocktail in water for 2 weeks followed by 4 weeks of water without antibiotics. This led to a significant bone loss (31% decrease from control) in WT mice. Interestingly, no bone loss was observed in the KO mice suggesting that lymphocytes are required for dysbiosis-induced bone loss. Bray-Curtis diversity metrics showed similar microbiota changes in both the WT and KO post-antibiotic treated groups. However, several operational taxonomic units (OTUs) classified as Lactobacillales were significantly higher in the repopulated KO when compared to the WT mice, suggesting that these bacteria might play a protective role in preventing bone loss in the KO mice after antibiotic treatment. The effect of dysbiosis on bone was therefore examined in the WT mice in the presence or absence of oral Lactobacillus reuteri treatment for 4 weeks (post-ABX treatment). As hypothesized, mice treated with L. reuteri did not display bone loss, suggesting a bone protective role for this group of bacteria. Taken together, our studies elucidate an important role for lymphocytes in regulating post-antibiotic dysbiosis-induced bone loss.

In the pain matrix, the insular cortex (IC) is mainly involved in discriminative sensory and motivative emotion. Abnormal signal transmission from injury site causes neuropathic pain, which generates enhanced synaptic plasticity. The mammalian target of rapamycin (mTOR) complex is the key regulator of protein synthesis; it is involved in the modulation of synaptic plasticity. To date, there has been no report on the changes in optical signals in the IC under neuropathic condition after treatment with mTOR inhibitors, such as Torin1 and XL388. Therefore, we aimed to determine the pain-relieving effect of mTOR inhibitors (Torin1 and XL388) and observe the changes in optical signals in the IC after treatment. Mechanical threshold was measured in adult male Sprague-Dawley rats after neuropathic surgery, and therapeutic effect of inhibitors was assessed on post-operative day 7 following the microinjection of Torin1 or XL388 into the IC. Optical signals were acquired to observe the neuronal activity of the IC in response to peripheral stimulation before and after treatment with mTOR inhibitors. Consequently, the inhibitors showed the most effective alleviation 4 h after microinjection into the IC. In optical imaging, peak amplitudes of optical signals and areas of activated regions were reduced after treatment with Torin1 and XL388. However, there were no significant optical signal changes in the IC before and after vehicle application. These findings suggested that Torin1 and XL388 are associated with the alleviation of neuronal activity that is excessively manifested in the IC, and is assumed to diminish synaptic plasticity.

Developmental dyslexia, a severe deficit in literacy learning, is a neurodevelopmental learning disorder. Yet, it is not clear whether existing neurobiological accounts of dyslexia capture potential predispositions of the deficit or consequences of reduced reading experience. Here, we longitudinally followed 32 children from preliterate to school age using functional and structural magnetic resonance imaging techniques. Based on standardised and age-normed reading and spelling tests administered at school age, children were classified as 16 dyslexic participants and 16 controls. This longitudinal design allowed us to disentangle possible neurobiological predispositions for developing dyslexia from effects of individual differences in literacy experience. In our sample, the disorder can be predicted already before literacy learning from auditory cortex gyrification and aberrant downstream connectivity within the speech processing system. These results provide evidence for the notion that dyslexia may originate from an atypical maturation of the speech network that precedes literacy instruction.

Reviewer refusal is a phenomenon associated with different causes, including reviewer fatigue, lack of time, dissatisfaction with the editorial system, among other reasons. This article discusses the main factors involved in the reviewer refusal and the "peer-review crisis" from a broad perspective. In addition, reasons that make a researcher accept or not a review invitation are also described.

Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are produced when colonic bacteria in the human gastrointestinal tract ferment undigested fibers. Free fatty acid receptor 2 (FFA2) and FFA3 are G-protein-coupled receptors recently identified as SCFA receptors that may modulate inflammation. We previously showed through in vitro experiments that SCFAs activate FFA2 and FFA3, thereby mitigating inflammation in human renal cortical epithelial cells. This study used a murine model of adenine-induced renal failure to investigate whether or not SCFAs can prevent the progression of renal damage. We also examined whether or not these FFA2 and FFA3 proteins have some roles in this protective mechanism in vivo. Immunohistochemical analyses of mouse kidneys showed that FFA2 and FFA3 proteins were expressed mainly in the distal renal tubules and collecting tubules. First, we observed that the administration of propionate mitigated the renal dysfunction and pathological deterioration caused by adenine. Consistent with this, the expression of inflammatory cytokines and fibrosis-related genes was reduced. Furthermore, the mitigation of adenine-induced renal damage by the administration of propionate was significantly attenuated in FFA2-/- and FFA3-/- mice. Therefore, the administration of propionate significantly protects against adenine-induced renal failure, at least in part, via the FFA2 and FFA3 pathways. Our data suggest that FFA2 and FFA3 are potential new therapeutic targets for preventing or delaying the progression of chronic kidney disease.

NADP-dependent methylene-tetrahydromethanopterin (methylene-H4MPT) dehydrogenase (MtdA) catalyzes the reversible dehydrogenation of methylene-H4MPT to form methenyl-H4MPT+ by using NADP+ as a hydride acceptor. This hydride transfer reaction is involved in the oxidative metabolism from formaldehyde to CO2 in methylotrophic and methanotrophic bacteria. Here, we report on the crystal structures of the ternary MtdA-substrate complexes from Methylorubrum extorquens AM1 obtained in open and closed forms. Their conversion is accomplished by opening/closing the active site cleft via a 15° rotation of the NADP, relative to the pterin domain. The 1.08 Å structure of the closed and active enzyme-NADP-methylene-H4MPT complex allows a detailed geometric analysis of the bulky substrates and a precise prediction of the hydride trajectory. Upon domain closure, the bulky substrate rings become compressed resulting in a tilt of the imidazolidine group of methylene-H4MPT that optimizes the geometry for hydride transfer. An additional 1.5 Å structure of MtdA in complex with the nonreactive NADP+ and methenyl-H4MPT+ revealed an extremely short distance between nicotinamide-C4 and imidazoline-C14a of 2.5 Å, which demonstrates the strong pressure imposed. The pterin-imidazolidine-phenyl butterfly angle of methylene-H4MPT bound to MtdA is smaller than that in the enzyme-free state but is similar to that in H2- and F420-dependent methylene-H4MPT dehydrogenases. The concept of compression-driven hydride transfer including quantum mechanical hydrogen tunneling effects, which are established for flavin- and NADP-dependent enzymes, can be expanded to hydride-transferring H4MPT-dependent enzymes.

Studies have shown that obesity-induced hyperglycemia and hyperlipidemia could cause increased hippocampal endoplasmic reticulum (ER) stress and impaired cognition-related proteins expression, resulting in learning and memory impairment. Meanwhile, aerobic exercise could activate hippocampal nuclear factor erythroid 2-related factor 2 (Nrf2) reducing ER stress. This study investigated the underlying molecular mechanisms of this effect. In order to clarify the relationship among ER stress, Nrf2 signaling and cognition-related proteins expression in vitro, we respectively treated hippocampal cells with high glucose and palmitic acid (PA), ER stress inhibitor 4-phenylbutyrate (4-PBA), and Nrf2 activator Tert-Butylhydroquinone (TBHQ). Results showed that the expression levels of glucose transporter 3 (GLUT3), fatty acid transport protein 1 (FATP1), ER stress biomarkers (GRP78, p-PERK, p-IRE1α and p-eIF2α), ER stress-mediated apoptosis biomarkers (caspase-12, CHOP and Bax/Bcl-2), and the activity of NLRP3-IL-1β inflammatory pathway were significantly increased under high glucose and PA conditions, accompanied with depressed p38/ERK-CREB pathway and decreased levels of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN). On the other hand, both 4-PBA and TBHQ reduced ER stress and reversed the expression of the above-mentioned proteins. Our findings suggest that high glucose and PA could induce excessive ER stress and apoptosis via promoting the overexpression of GLUT3 and FATP1, and ER stress could suppress BDNF and SYN expression through negatively regulating p38/ERK-CREB pathway and positively regulating NLRP3-IL-1β pathway, which could be reversed by activated Nrf2-HO-1 pathway.

We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).

Tourette syndrome (TS) is a childhood-onset neurological disorder characterised by the occurrence of motor and vocal tics and the presence of premonitory sensory/urge phenomena. Functional neuroimaging studies in humans, and experimental investigations in animals, have shown that the genesis of tics in TS involve a complex interaction between cortical-striatal-thalamic-cortical brain circuits and additionally appears to involve the cerebellum. Furthermore, structural brain imaging studies have demonstrated alterations in grey matter (GM) volume in TS across a wide range of brain areas, including alterations in GM volume within the cerebellum. Until now, no study to our knowledge has yet investigated how GM structural covariance networks linked to the cerebellum may be altered in individuals with TS. In this study we employed voxel-based morphometry, and a 'seed-to-voxel' structural covariance network (SCN) mapping approach, to investigate alterations in GM cerebellar volume in people with TS, and alterations in cerebellar SCNs associated with TS. Data from 64 young participants was entered in the final analysis, of which 28 had TS while 36 were age-and sex-matched healthy volunteers. Using the spatially unbiased atlas template of the cerebellum and brainstem (SUIT) atlas, we found reduced GM volume in cerebellar lobule involved in higher-order cognitive functions and sensorimotor processing, in patients. In addition, we found that several areas located in frontal and cingulate cortices and sensorimotor network in addition to subcortical areas show altered structural covariance with our cerebellar seed compared to age-matched controls. These results add to the increasing evidence that cortico-basal ganglia-cerebellar interactions play an important role in tic symptomology.

Fibroblasts are a critical component of tumor microenvironments and associate with cancer cells physically and biochemically during different stages of the disease. Existing cell culture models to study interactions between fibroblasts and cancer cells lack native tumor architecture or scalability. We developed a scalable organotypic model by robotically encapsulating a triple negative breast cancer (TNBC) cell spheroid within a natural extracellular matrix containing dispersed fibroblasts. We utilized an established CXCL12 - CXCR4 chemokine-receptor signaling in breast tumors to validate our model. Using imaging techniques and molecular analyses, we demonstrated that CXCL12-secreting fibroblasts have elevated activity of RhoA/ROCK/myosin light chain-2 pathway and rapidly and significantly contract collagen matrices. Signaling between TNBC cells and CXCL12-producing fibroblasts promoted matrix invasion of cancer cells by activating oncogenic mitogen-activated protein kinase signaling, whereas normal fibroblasts significantly diminished TNBC cell invasiveness. We demonstrated that disrupting CXCL12 - CXCR4 signaling using a molecular inhibitor significantly inhibited invasiveness of cancer cells, suggesting blocking of tumor-stromal interactions as a therapeutic strategy especially for cancers such as TNBC that lack targeted therapies. Our organotypic tumor model mimics native solid tumors, enables modular addition of different stromal cells and extracellular matrix proteins, and allows high throughput compound screening against tumor-stromal interactions to identify novel therapeutics.

Cisplatin is used to treat a variety of solid tumors in both children and adults. However, cisplatin has serious side-effects, some of which may permanently affect patients' quality of life following treatment, such as ototoxicity. There is currently no FDA-approved therapy for the prevention or treatment of cisplatin-induced hearing loss. Herein we examine the potential for statins to prevent cisplatin-induced ototoxicity. Statins, a class of drugs commonly used to prevent or manage hypercholesterolemia, have been of clinical utility for decades with dependable outcomes and reliable safety profiles in humans. Statins are known to be protective in animal models of noise-induced and age-related hearing loss. Moreover, studies have demonstrated an additive benefit of statins in cancer treatment. In the current study, lovastatin reduces cisplatin-induced hearing loss in adult mice. Lovastatin-mediated protection was significantly greater among female than male mice, and the dose of lovastatin required for protection was different between the sexes. Taken together our data indicate that lovastatin reduces cisplatin-induced hearing loss in mice and suggest that concurrent statin and cisplatin therapy may represent a feasible clinical strategy for reducing cisplatin-induced ototoxicity that should be explored for future clinical use.

Progressive peritoneal fibrosis is a common complication in patients on long-term peritoneal dialysis (PD). PD-associated peritonitis is a major exacerbating factor. We investigated the anti-fibrotic properties of decorin secreted by peritoneal mesothelial cells.

Seizures that occur during early development are associated with adverse neurodevelopmental outcomes. Causation and mechanisms are currently under investigation. Induction of an early life seizure by kainic acid (KA) in immature rats on post-natal day (P) 7 results in behavioral changes in the adult rat that reflect social and intellectual deficits without overt cellular damage. Our previous work also demonstrated increased expression of CA1 hippocampal long-term potentiation (LTP) and reduced desensitization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPA-R) one week following a kainic acid induced seizure (KA-ELS). Here we used RNA sequencing (RNAseq) of mRNA from dorsal hippocampal CA1 to probe changes in mRNA levels one week following KA-ELS as a means to investigate the mechanisms for these functional changes. Ingenuity pathway analysis (IPA) confirmed our previous results by predicting an up-regulation of the synaptic LTP pathway. Differential gene expression results revealed significant differences in 7 gene isoforms. Additional assessments included AMPA-R splice variants and adenosine deaminase acting on RNA 2 (ADAR2) editing sites as a means to determine the mechanism for reduced AMPA-R desensitization. Splice variant analysis demonstrated that KA-ELS result in a small, but significant decrease in the "flop" isoform of Gria3, and editing site analysis revealed significant changes in the editing of a kainate receptor subunit, Grik2, and a serotonin receptor, Htr2c. While these specific changes may not account for altered AMPA-R desensitization, the differences indicate that KA-ELS alters gene expression in the hippocampal CA1 one week after the insult.

The RET proto-oncogene encodes receptor tyrosine kinase, expressed primarily in tissues of neural crest origin. De-regulation of RET signaling is implicated in several human cancers. Recent phosphatome interactome analysis identified PTPRA interacting with the neurotrophic factor (GDNF)-dependent RET-Ras-MAPK signaling-axis. Here, by identifying comprehensive interactomes of PTPRA and RET, we reveal their close physical and functional association. The PTPRA directly interacts with RET, and using the phosphoproteomic approach, we identify RET as a direct dephosphorylation substrate of PTPRA both in vivo and in vitro. The protein phosphatase domain-1 is indispensable for the PTPRA inhibitory role on RET activity and downstream Ras-MAPK signaling, whereas domain-2 has only minor effect. Furthermore, PTPRA also regulates the RET oncogenic mutant variant MEN2A activity and invasion capacity, whereas the MEN2B is insensitive to PTPRA. In sum, we discern PTPRA as a novel regulator of RET signaling in both health and cancer.

Tourette syndrome is a neurodevelopmental disorder putatively associated with a hyperdopaminergic state. Therefore, it seems plausible that excessive dopamine transmission in Tourette syndrome alters the ability to learn based on rewards and punishments. We tested whether Tourette syndrome patients exhibited altered reinforcement learning and corresponding feedback-related EEG deflections.

We studied 156 individuals with acute, right hemisphere ischemic stroke on a battery of hemispatial neglect tests to distinguish between viewer-centered and stimulus-centered neglect and MRI diffusion weighted imaging. We identified the relative contributions of age, total lesion volume, and damage to subcortical and cortical grey matter regions as well as white matter tracts to both the severity and presence of significant viewer-centered and stimulus-centered neglect, using multivariable regression tests. We found that age, volume of lesion, and percent damage to the regions of interest were each independently associated with the severity of viewer-centered neglect (r2 = .31; p < .0001). However, only age (t = 3.20; p = .002) and percent damage to the angular gyrus (t = 2.63, p = .010), a dorsal stream area, predicted severity of viewer-centered neglect independently of the other variables. The same variables predicted the presence of significant viewer-centered neglect. In contrast, these variables did not significantly predict the severity of stimulus-centered neglect. However, we found that percent damage to ventral stream regions of interest (middle temporal gyrus, inferior temporal gyrus, fusiform gyrus, inferior frontal occipital gyrus, sagittal stratum, along with total infarct volume were associated with the presence of significant stimulus-centered neglect (pseudo r2 = .70, p < .0004). Only percent damage to right inferior temporal gyrus predicted stimulus-centered neglect independently of the other variables (p = .018).

Engineering a pro-regenerative immune response following scaffold implantation is integral to functional tissue regeneration. The immune response to implanted biomaterials is determined by multiple factors, including biophysical cues such as material stiffness, topography and particle size. In this study we developed an immune modulating scaffold for bone defect healing containing bone mimetic nano hydroxyapatite particles (BMnP). We first demonstrate that, in contrast to commercially available micron-sized hydroxyapatite particles, in-house generated BMnP preferentially polarize human macrophages towards an M2 phenotype, activate the transcription factor cMaf and specifically enhance production of the anti-inflammatory cytokine, IL-10. Furthermore, nano-particle treated macrophages enhance mesenchymal stem cell (MSC) osteogenesis in vitro and this occurs in an IL-10 dependent manner, demonstrating a direct pro-osteogenic role for this cytokine. BMnPs were also capable of driving pro-angiogenic responses in human macrophages and HUVECs. Characterization of immune cell subsets following incorporation of functionalized scaffolds into a rat femoral defect model revealed a similar profile, with micron-sized hydroxyapatite functionalized scaffolds eliciting pro-inflammatory responses characterized by infiltrating T cells and elevated expression of M1 macrophages markers compared to BMnP functionalized scaffolds which promoted M2 macrophage polarization, tissue vascularization and increased bone volume. Taken together these results demonstrate that nano-sized Hydroxyapatite has immunomodulatory potential and is capable of directing anti-inflammatory innate immune-mediated responses that are associated with tissue repair and regeneration.

Adolescence is a period when complex interactions occur between mental health risk factors. The Longitudinal Adolescent Brain Study (LABS) commenced in 2018, to monitor environmental and psychosocial factors thought to influence mental health in 500 young people. Participants commence at 12 years of age, via a community-based recruitment model, and data is collected at 15 time-points over five years. This study examines demographic and psychosocial self-report data from time-point 1, for the first 50 participants. Here we investigate associations between environmental and psychosocial factors, considered as measures of intrinsic homeostasis and extrinsic modulation. Numerous strong correlations were found. Findings indicate that sleep dysfunction and social connectedness were strongly associated external modulators of intrinsic homeostasis in this sample of 12-year old participants. To successfully address the increase in mental health problems in young people, comprehensive evaluation of lifestyle and environmental risk factors is recommended in addition to medicalised approaches. Interventions to promote mental health wellbeing in young adolescents should include a focus on sleep quality and patterns and the positive and negative aspects of social connectedness.

Tourette syndrome (TS) is commonly comorbid with obsessive-compulsive disorder (OCD) and many phenomenological similarities exist between tics and obsessive-compulsive symptoms (OCS). Therefore, due to the clinical importance of comorbid OCD, the goal of this study was to investigate the neural substrates of OCS in TS using functional magnetic resonance imaging.