MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work, we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with an unknown physiological substrate, displays an immune function by controlling inflammatory and type-I interferon (IFN) responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as an effector protein regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in the ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK inhibitor to ALS model mice can modulate Ser492-phospho-Brd4 levels, suppress microglial activation, and modify the disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.

Titanium Surface Characteristics Induce the Specific Reprogramming of Toll-like Receptor Signaling in Macrophages.

Most of the research on titanium-based dental implants (Ti-discs) is focused on how they are able to stimulate the formation of new tissue and/or cytotoxic studies, with very scarce data on their effects on functional responses by immunocompetent cells. In particular, the link between the rewiring of innate immune responses and surface biomaterials properties is poorly understood. To address this, we characterize the functional response of macrophage cultures to four different dental titanium surfaces (MA: mechanical abrasion; SB + AE: sandblasting plus etching; SB: sandblasting; AE: acid etching). We use different Toll-like receptor (TLR) ligands towards cell surface receptors (bacterial lipopolysaccharide LPS for TLR4; imiquimod for TLR7; synthetic bacterial triacylated lipoprotein for TLR2/TLR1) and endosomal membrane receptor (poly I:C for TLR3) to simulate bacterial (cell wall bacterial components) or viral infections (dsRNA and ssRNA). The extracellular and total LDH levels indicate that exposure to the different Ti-surfaces is not cytotoxic for macrophages under resting or TLR-stimulated conditions, although there is a tendency towards an impairment in macrophage proliferation, viability or adhesion under TLR4, TLR3 and TLR2/1 stimulations in SB discs cultures. The secreted IL-6 and IL-10 levels are not modified upon resting macrophage exposure to the Ti-surfaces studied as well as steady state levels of iNos or ArgI mRNA. However, macrophage exposure to MA Ti-surface do display an enhanced immune response to TLR4, TLR7 or TLR2/1 compared to other Ti-surfaces in terms of soluble immune mediators secreted and M1/M2 gene expression profiling. This change of characteristics in cellular phenotype might be related to changes in cellular morphology. Remarkably, the gene expression of Tlr3 is the only TLR that is differentially affected by distinct Ti-surface exposure. These results highlight the relevance of patterned substrates in dental implants to achieve a smart manipulation of the immune responses in the context of personalized medicine, cell-based therapies, preferential lineage commitment of precursor cells or control of tissue architecture in oral biology.

Distinct responses of human peripheral blood cells to different misfolded protein oligomers.

Increasing evidence indicates that peripheral immune cells play a prominent role in neurodegeneration connected to protein misfolding, which are associated with formation of aberrant aggregates, including soluble protein misfolded oligomers. The precise links, however, between the physicochemical features of diverse oligomers and their effects on the immune system, particularly on adaptive immunity, remain currently unexplored, due partly to the transient and heterogeneous nature of the oligomers themselves. To overcome these limitations, we took advantage of two stable and well-characterized types of model oligomers (A and B), formed by HypF-N bacterial protein, type B oligomers displaying lower solvent-exposed hydrophobicity. Exposure to oligomers of human peripheral blood mononuclear cells (PBMCs) revealed differential effects, with type B, but not type A, oligomers leading to a reduction in CD4+ cells. Type A oligomers promoted enhanced differentiation towards CD4+ CD25High FoxP3+ Tregs and displayed a higher suppressive effect on lymphocyte proliferation than Tregs treated with oligomers B or untreated cells. Moreover, our results reveal Th1 and Th17 lymphocyte differentiation mediated by type A oligomers and a differential balance of TGF-ß, IL-6, IL-23, IFN-γ and IL-10 mediators. These results indicate that type B oligomers recapitulate some of the biological responses associated with Parkinson's disease in peripheral immunocompetent cells, while type A oligomers resemble responses associated with Alzheimer's disease. We anticipate that further studies characterizing the differential effects of protein misfolded oligomers on the peripheral immune system may lead to the development of blood-based diagnostics, which could report on the type and properties of oligomers present in patients.

Modified level of miR-376a is associated with Parkinson's disease.

Parkinson's disease (PD) is a frequent progressive neurodegenerative disorder. Impaired mitochondrial function is a major feature of sporadic PD. Some susceptibility or causative genes detected in PD are strongly associated with mitochondrial dysfunction including PGC1α, TFAM and GSK3ß. microRNAs (miRNAs) are non-coding RNAs whose altered levels are proven in disparate PD models and human brains. Therefore, the aim of this study was to detect modulations of miRs upstream of PGC1α, TFAM and GSK3ß in association with PD onset and progress. In this study, a total of 33 PD subjects and 25 healthy volunteers were recruited. Candidate miRNA (miR-376a) was selected through target prediction tools and literature survey. Chronic and acute in vitro PD models were created by MPP+ -intoxicated SHSY5Y cells. The levels of miR-376a and aforementioned genes were assessed by RT-qPCR. The expression of target genes was decreased in chronic model while there were dramatically up-regulated levels of those genes in acute model of PD. miR-376a was strongly altered in both acute and chronic PD models as well as PBMCs of PD patients. Our results also showed overexpression of PGC1α, and TFAM in PBMCs is inversely correlated with down-regulation of miR-376a, suggesting that miR-376a possibly has an impact on PD pathogenesis through regulation of these genes which are involved in mitochondrial function. miR-376a expression in PD-derived PBMCs was also correlated with disease severity and may serve as a potential biomarker for PD diagnosis. This is the first study showing altered levels of miR-376a in PD models and PBMCs, suggesting the probable role of this miRNA in PD pathogenesis. The present study also proposed TFAM and PGC1α as target genes of miR-376a for the first time, through which it possibly can exert its impact on PD pathogenesis.

Multi-objective admission planning problem: a two-stage stochastic approach.

Effective admission planning can improve inpatient throughput and waiting times, resulting in better quality of service. The uncertainty in the patient arrival and the availability of resources makes the patient's allocation difficult to manage. Thus, in the admission process hospitals aim to accomplish targets of resource utilization and to lower the cost of service. Both objectives are related and in conflict. In this paper, we present a bi-objective stochastic optimization model to study the trade-off between the resource utilization and the cost of service, taking into account demand and capacity uncertainties. Real data from the surgery and medical areas of a Chilean public hospital are used to illustrate the approach. The results show that the solutions of our approach outperform the actual practice in the Chilean hospital.

Immunization with α-synuclein/Grp94 reshapes peripheral immunity and suppresses microgliosis in a chronic Parkinsonism model.

Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α-synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat-shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from αSyn/Grp94-immunized mice to recipient animals, and second, direct immunization with αSyn/Grp94, to study the effects in a chronic mouse MPTP-model of parkinsonism. We found that both approaches promoted a distinct profile in the peripheral system-supported by humoral and cellular immunity-consisting of a Th1-shifted αSyn-specific response accompanied by an immune-regulatory/Th2-skewed general phenotype. Remarkably, this mixed profile sustained by αSyn/Grp94 immunization led to strong suppression of microglial activation in the substantia nigra and striatum, pointing to a newly described positive effect of anti-αSyn Th1-responses in the context of PD. This strategy is the first to target αSyn and report the suppression of PD-associated microgliosis. Overall, we show that the αSyn/Grp94 combination supports a distinct and long-lasting immune profile in the peripheral system, which has an impact at the CNS level by suppressing chronic microglial activation in an MPTP model of PD. Furthermore, our study demonstrates that reshaping peripheral immunity by vaccination with appropriate misfolding protein/HSP combinations could be highly beneficial as a treatment for neurodegenerative misfolding diseases.

Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.

Dysregulated microglial responses are central in neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar disease (FTLD). Pathologic TDP-43, which is typically found in intracellular inclusions, is a misfolding protein with emerging roles in ALS and FTLD. Recently, TDP-43 species have been found in extracellular fluids of patients; however, the overall implications of TDP-43-mediated signaling linked to neuroinflammation are poorly understood. Our work-the first, to our knowledge, to focus on innate immunity responses to TDP-43 aggregates-shows that such species are internalized by microglia and cause abnormal mobilization of endogenous TDP-43. Exposure to TDP-43 aggregates elicited not only IL-1ß, but also NLRP3-dependent and noncanonical IL-18 processing. Moreover, we report a link between TDP-43 and neuronal loss via the apoptosis-independent emerging roles of caspase-3 in neurotoxic inflammation. Our results further support the view of noncell autonomous neurodegenerative mechanisms in ALS. Remarkably, we demonstrate that TDP-43 aggregates bind to and colocalize with MAPK/MAK/MRK overlapping kinase (MOK) and show that its phosphorylation status is disrupted. Finally, we show that this TDP-43-caused activation state can be altered by exogenous Hsp27 and Hsp70 chaperones. Our study provides new insight into the immune phenotype, mechanisms, and signaling pathways that operate in microglial neurotoxic activation in ALS.-Leal-Lasarte, M. M., Franco, J. M., Labrador-Garrido, A., Pozo, D., Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.

Chaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α-synuclein-elicited immune response.

We have investigated the potential role of molecular chaperones as modulators of the immune response by using α-synuclein (αSyn) as an aggregation-prone model protein. We first performed an in vitro immunoscreening with 21 preselected candidate chaperones and selected 2 from this set as displaying immunological activity with differential profiles, Grp94/Gp96 and FKBP4/52. We then immunized mice with both chaperone/α-synuclein combinations using monomeric or oligomeric α-synuclein (MαSyn or OαSyn, respectively), and we characterized the immune response generated in each case. We found that Grp94 promoted αSyn-specific T-helper (Th)1/Th17 and IgG1 antibody responses (up to a 3-fold increase) with MαSyn and OαSyn, respectively, coupled to a Th2-type general phenotype (generating 2.5-fold higher IgG1/IgG2 levels). In addition, we observed that FKBP4 favored a Th1-skewed phenotype with MαSyn but strongly supported a Th2-type phenotype with OαSyn (with a 3-fold higher IL-10/IFN-γ serum levels). Importantly, results from adoptive transfer of splenocytes from immunized animals in a Parkinson's disease mouse model indicates that these effects are robust, stable in time, and physiologically relevant. Taken together, Grp94 and FKBP4 are able to generate differential immune responses to α-synuclein-based immunizations, depending both on the nature of the chaperone and on the aggregation state of α-synuclein. Our work reveals that several chaperones are potential modulators of the immune response and suggests that different chaperones could be exploited to redirect the amyloid-elicited immunity both for basic studies of the immunological processes associated with neurodegeneration and for immunotherapy of pathologies associated with protein misfolding and aggregation.

Epigenetic Mechanisms of Gene Regulation in Amyotrophic Lateral Sclerosis.

Despite being clinically described 150 years ago, the mechanisms underlying amyotrophic lateral sclerosis (ALS) pathogenesis have not yet been fully understood. Studies in both animal models of ALS and human patients reveal a plethora of alterations such as increased glutamate-mediated excitotoxicity, redox stress, increased apoptosis, defective axonal transport, protein-misfolding events, mitochondrial impairment and sustained unregulated immune responses. Regardless of being sporadic or familiar ALS, the final outcome at the cellular level is the death of upper and lower motor neurons, and once diagnosed, ALS is typically lethal within the next 5 years. There are neither clear biomarkers nor therapeutic or disease-modifying treatments for ALS.Accumulating evidence supports the concept that epigenetic-driven modifications, including altered chromatin remodelling events, RNA editing and non-coding RNA molecules, might shed light into the pathogenic mechanisms underlying sporadic/familiar ALS onset and/or severity to facilitate the identification of effective therapies, early diagnosis and potentially early-stage therapeutic interventions to increase the survival outcome of ALS patients.

Iron oxide nanoparticles as magnetic relaxation switching (MRSw) sensors: Current applications in nanomedicine.

Since pioneering work in the early 60s on the development of enzyme electrodes the field of sensors has evolved to different sophisticated technological platforms. Still, for biomedical applications, there are key requirements to meet in order to get fast, low-cost, real-time data acquisition, multiplexed and automatic biosensors. Nano-based sensors are one of the most promising healthcare applications of nanotechnology, and prone to be one of the first to become a reality. From all nanosensors strategies developed, Magnetic Relaxation Switches (MRSw) assays combine several features which are attractive for nanomedical applications such as safe biocompatibility of magnetic nanoparticles, increased sensitivity/specificity measurements, possibility to detect analytes in opaque samples (unresponsive to light-based interferences) and the use of homogeneous setting assay. This review aims at presenting the ongoing progress of MRSw technology and its most important applications in clinical medicine.

Betalactam antibiotics affect human dendritic cells maturation through MAPK/NF-kB systems. Role in allergic reactions to drugs.

The mechanisms leading to drug allergy in predisposed patients, especially those related to T-cell-mediated drug hypersensitivity, are not well understood. A key event in allergic reactions to drugs is the maturation process undergone by dendritic cells (DCs). Although amoxicillin (AX) has been reported to interact and maturate DCs from patients with AX-induced delayed-type hypersensitivity, the cell signaling pathways related to AX-mediated DC maturation have not been elucidated. We sought to determine the role of the MAPK and NF-κΒ pathways on AX-induced DC maturation and functional status. For that purpose, in monocyte-derived-DCs from AX-delayed allergic patients and tolerant subjects, we analyzed the activation pattern of p38MAPK, JNK, and ERK signaling and the NF-κB, maturation markers as well as endocytosis and allostimulatory capacities driven by AX-stimulated-DCs. Our data reveal that AX induces an increase in the phosphorylation levels of the three MAPKs and activated NF-κB in DCs from allergic patients. Moreover, the inhibition of these pathways prevents the up-regulation of surface molecules induced by AX. Additionally, we observed that the allostimulatory capacity and the endocytosis down-regulation in AX-stimulated-DCs from allergic patients depend on JNK and NF-κB activities. Taken together, our data shed light for the first time on the main signaling pathways involved in DC maturation from AX-delayed allergic patient.

Functionally unicuspid aortic valve in an adult: Case report and literature review.

Aortic stenosis is one of the most prevalent cardiac valvular diseases throughout the world and has a significant impact on quality of life. While there are several etiologies, we will be discussing the case of a male in his mid-thirties of southeast Asian descent with a bicuspid aortic valve which was found to be functionally unicuspid and complicated by aortic dilation. Following a comprehensive review of literature, it appears this subset of aortic stenosis is not commonly encountered. In addition to presenting this fascinating case, we will review the epidemiology, classification and management of aortic stenosis. Furthermore, we will examine the latest evidence-based literature on bicuspid aortic valve and unicuspid aortic valve and discuss interventions and diagnostic tools that may improve clinical prognosis.

VEGF expression disparities in brainstem motor neurons of the SOD1G93A ALS model: Correlations with neuronal vulnerability.

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease characterized by severe muscle weakness mainly due to degeneration and death of motor neurons. A peculiarity of the neurodegenerative processes is the variable susceptibility among distinct neuronal populations, exemplified by the contrasting resilience of motor neurons innervating the ocular motor system and the more vulnerable facial and hypoglossal motor neurons. The crucial role of vascular endothelial growth factor (VEGF) as a neuroprotective factor in the nervous system is well-established since a deficit of VEGF has been related to motoneuronal degeneration. In this study, we investigated the survival of ocular, facial, and hypoglossal motor neurons utilizing the murine SOD1G93A ALS model at various stages of the disease. Our primary objective was to determine whether the survival of the different brainstem motor neurons was linked to disparate VEGF expression levels in resilient and susceptible motor neurons throughout neurodegeneration. Our findings revealed a selective loss of motor neurons exclusively within the vulnerable nuclei. Furthermore, a significantly higher level of VEGF was detected in the more resistant motor neurons, the extraocular ones. We also examined whether TDP-43 dynamics in the brainstem motor neuron of SOD mice was altered. Our data suggests that the increased VEGF levels observed in extraocular motor neurons may potentially underlie their resistance during the neurodegenerative processes in ALS in a TDP-43-independent manner. Our work might help to better understand the underlying mechanisms of selective vulnerability of motor neurons in ALS.

Chaperone proteostasis in Parkinson's disease: stabilization of the Hsp70/alpha-synuclein complex by Hip.

The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of alpha-synuclein (alphaSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation-prone polypeptides. We show a nucleotide-dependent interaction between Hsp70 and alphaSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with alphaSyn. Such a co-aggregation phenomenon can be prevented in vitro by the co-chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of alphaSyn aggregation. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration.

Herpes Simplex Encephalitis: Detection, Management, and Outcomes.

The pathophysiology of herpes simplex encephalitis (HSE) is incompletely understood and proposed to be secondary to the retrograde transport of the herpes simplex virus type 1 (HSV-1) via the trigeminal and/or olfactory nerves to the central nervous system (CNS). In this case report, we present a 68-year-old female who presents to our emergency department after a fall. Upon initial admission, her neurological examination was benign, and a computer tomography (CT) scan of her brain showed a subdural hematoma for which she was treated conservatively. Day 4 of her hospitalization marked a rapid decline in her course of illness, beginning with confusion and hallucinations, progressing to subclinical seizures, and culminating in irreversible brain damage and palliative extubation on day 16 of hospitalization. This case report discusses our insight into the challenges of early diagnosis and treatment of herpes encephalitis and their impact on improving patient outcomes.

Induction of alloantigen-specific human T regulatory cells by vasoactive intestinal peptide.

T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25- T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25(high) T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27(kip1). VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

Usefulness of endoscopic ultrasonography in the clinical suspicion of biliary disease.

BACKGROUND AND AIMS: endoscopic ultrasound (EUS) is a very sensitive and specific technique for the diagnosis of biliary diseases. This procedure has proven its usefulness in cases of high suspicion of biliary disease (history of gallstones and dilatation of the intrahepatic and/or extrahepatic bile ducts). We know less about its usefulness in cases of low suspicion of biliary pathology.The aim of this study was to assess the diagnostic accuracy of EUS in patients with low suspicion of biliary disease (patients with dilatation of the biliary tract were excluded). METHODS: 33 patients with low suspicion of biliary disease were recruited in 12 months. All of them had no biliary findings in a previous abdominal ultrasound and computer tomography scan. All of them underwent EUS and were studied prospectively. The diagnosis was confirmed by surgery and/or by ERCP in patients with positive EUS or clinical follow-up in those with normal EUS. Time of follow-up was 9 months (range, 3-12 months). RESULTS: seventeen patients (51.5%) presented with abnormal biliary findings on EUS (7 choledocholithiasis, 3 cholelithiasis, 2 choledocholithiasis + cholelithiasis and 5 microlithiasis). CONCLUSION: EUS is a useful and safe procedure for diagnosing patients with low suspicion of biliary disease.

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity.

Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.

Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies.

Dendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and possess the ability to activate T cells and stimulate the growth and differentiation of B cells. DCs provide a direct connection between innate and adaptive immune response, and arise from bone marrow precursors that are present in immature forms in peripheral tissues, where they are prepared to capture antigens. DCs migrate from the peripheral tissues to the closest lymph nodes through afferent lymphatic vessels to present the foreign antigens, stimulating T-cell activation and initiating a cellular immune response. Moreover, it is known that DCs have an important role in various diseases and conditions involving the immune system, particularly in cancer and autoimmune disorders. For these reasons, targeting nanoparticles (NPs) to DCs provides a promising strategy for developing an efficient balanced and protective immune response. NPs can modulate the immune response and might be potentially useful as effective vaccine adjuvants for infectious disease and cancer therapy. The objective of this review is to present the latest advances in NP delivery methods targeting DCs, the mechanisms of action, potential effects, and therapeutic results of these systems and their future applications, such as improved vaccination strategies, cancer immunotherapy, and immunomodulatory treatments. From the clinical editor: Dendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and activating T and B cells. The role of DC-s can be considered as a bridge between innate and adaptive immunity. Targeting nanoparticles (NPs) to DCs can modulate the immune response and might be useful as vaccine adjuvants in infectious disease and cancer therapy.

Validity and Reliability of the New Basic Functional Assessment Protocol (BFA).

The global evaluation of motion patterns can examine the synchrony of neuromuscular control, range of motion, strength, resistance, balance and coordination needed to complete the movement. Visual assessments are commonly used to detect risk factors. However, it is essential to define standardized field-based tests that can evaluate with accuracy. The aims of the study were to design a protocol to evaluate fundamental motor patterns (FMP), and to analyze the validity and reliability of an instrument created to provide information about the quality of movement in FMP. Five tasks were selected: Overhead Squat (OHS); Hurdle Step (HS); Forward Step Down (FSD); Shoulder Mobility (SM); Active Stretching Leg Raise (ASLR). A list of variables was created for the evaluation of each task. Ten qualified judges assessed the validity of the instrument, while six external observers performed inter-intra reliability. The results show that the instrument is valid according to the experts' opinion; however, the reliability shows values below those established. Thus, the instrument was considered unreliable, so it is recommended to repeat the reliability process by performing more training sessions for the external observers. The present study creates the basic functional assessment (BFA), a new protocol which comprises five tasks and an instrument to evaluate FMP.