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Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration, and cause oxidative stress. Blocking the MIC60-Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s Ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.

Summary The molecular mechanisms that restore microglial quiescence after acute stimulation remain largely unexplored, unlike those that drive microglial activation. In this issue of Immunity, Shemer et al. discover that the microglial IL-10 receptor counteracts the pro-inflammatory effects of TNF to allow restoration of microglial quiescence after peripheral endotoxin challenge.

This paper focuses on path tracing of a holonomic three wheel Omni drive system. Any path (curved, linear) is first sampled, where the coordinates of the path are stored in the local memory, at particular sampling rate which are then retrieved dynamically during the runtime to move the robot on the similar path. The task of moving the drive system from one coordinate to another is done by Deduced reckoning algorithm. This paper also proposes algorithm for minimizing overshoot (deviation from actual path) while moving in a curved trajectory. The proposed algorithm helps in keeping track of the robot very efficiently. The hardware employed to test the proposed algorithm used consists of a three wheeled Omni base, three high torque DC motors, three 6" Omni wheels, highly efficient DC motor drivers, high precision rotary encoders and a microcontroller powered by ARM® Cortex®-M3 processor(ARMv7-M,Thumb-2 instruction set architecture, Nested Vector Interrupt Control (NVIC),Memory Protection Unit (MPU), Advance High Performance Bus-lite (AHB-Lite),Advanced Peripheral Bus (APB) and Private Peripheral Bus, Serial Wire JTAG Debug port ). The robot controlled by the proposed algorithm was tested on wooden field while plying on curved paths.

This paper tries to model a four wheel holonomic drive with its design description. After deriving the kinematic model, the encoder and the gyroscope equations are used for position and orientation feedbacks respectively. Furthermore, it is controlled using deduced reckoning algorithm and a continuously running PID is applied to keep the errors in check. The equations used to implement PID helped to control the drive efficiently with minimal deviations. Moreover, the ideal velocity vs time curve is obtained for the actual system which is built using the selection criterion mentioned in this paper. This curve helped to traverse the drive on a predefined path in minimum possible time.

Background Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis. Methods We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction. Results LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment. Conclusions LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy.

Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD(+)) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD(+) derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD(+) synthesis depleted NAD(+), suppressed mitochondrial NAD(+)-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD(+) synthesis by limiting the conversion of downstream quinolinate to NAD(+), a profile recapitulated in aging macrophages. Increasing de novo NAD(+) generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD(+) operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD(+) synthesis may underlie declining NAD(+) levels and rising innate immune dysfunction in aging and age-associated diseases.

Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

Botticelli et al. proposed the activity of indoleamine-2,3-dioxygenase 1 (IDO) as a potential mechanism and predictive marker for primary resistance against anti-PD-1 treatment in the context of non-small cell lung cancer. However, there are a few points for the authors to address in order to strengthen their claims. First, there are many enzymes that modulate the kynurenine to tryptophan ratio, thereby calling into question their use of the ratio as a proxy for IDO activity. Second, the authors could compare IDO to other proposed markers in the literature, providing a better understanding of its predictive value.

How glycogen metabolism directly regulates macrophages in the acute inflammatory state is not well understood. In the recent issue of Nature Communications, Ma et al. provide new insight into this process, demonstrating that glycogenolysis-driven pentose phosphate pathway and UDP-glucose-driven P2Y14 receptor promote an inflammatory phenotype in macrophages. They show that in vivo blockade of glycogenolysis is sufficient to rescue survival in peritonitis, hepatitis, and sepsis. Their results hold implications for the treatment of acute inflammatory disorders at large.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

Development of therapeutic strategies to prevent Alzheimer's disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest that metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD., Highlights • Mild inhibition of complex I mitigates cognitive and behavioral decline in multiple transgenic animal models of AD. • Mechanism includes AMPK activation, reduction of Aβ, pTau and GSK3β activity, and restoration of axonal trafficking. • Metabolic adaptation induced by complex I inhibition augments neuronal bioenergetics and resistance to stress.

Background Although the proportion of ethnicities representing under-represented minorities in medicine (URM) in the general population has significantly increased, URM enrolment in medical schools within the USA has remained stagnant in recent years. Methods This study sought to examine the effect of an immersion in community medicine (ICM) programme on secondary school students' desire to enter the field of medicine and serve their communities. The authors asked all 69 ICM alumni to complete a 14-question survey consisting of six demographic, four programme and four career questions, rated on a Likert scale of 1 (completely disagree) to 5 (completely agree), coupled with optional free-text questions. Data were analysed using GraphPad prism and nvivo software. Results A total of 61 students responded, representing a response rate of 88.4 per cent, with a majority of respondents (73.7%) from URM backgrounds. An overwhelming majority of students agreed (with a Likert rating of 4 or 5) that the ICM programme increased their interest in becoming a physician (n = 56, 91.8%). Students reported shadowing patient-student-physician interactions to be the most useful (n = 60, 98.4%), and indicated that they felt that they would be more likely to lead to serving the local community as part of their future careers (n = 52, 85.3%). Of the students that were eligible to apply to medical school (n = 13), a majority (n = 11, 84.6%) have applied to medical school. URM enrolment in medical schools within the USA has remained stagnant in recent years DISCUSSION: Use of a community medicine immersion programme may help encourage secondary students from URM backgrounds to gain the confidence to pursue a career in medicine and serve their communities. Further examination of these programmes may yield novel insights into recruiting URM students to medicine.

The widely used reliable transport protocol TCP, is an end to end protocol designed for the wireline networks characterized by negligible random packet losses. This paper represents exploratory study of TCP congestion control principles and mechanisms. Modern implementations of TCP contain four intertwined algorithms: slow start, congestion avoidance, fast retransmit, and fast recovery. In addition to the standard algorithms used in common implementations of TCP, this paper also describes some of the more common proposals developed by researchers over the years. We also study, through extensive simulations, the performance characteristics of four representative TCP schemes, namely TCP Tahoe, New Reno and Vegas under the network conditions of bottleneck link capacities for wired network. Keywords - Congestion avoidance, Congestion control mechanisms, Newreno, Tahoe, TCP, Vegas.

Active learning is based on self-directed and autonomous teaching methods, whereas passive learning is grounded in instructor taught lectures. An animal physiology course was studied over a two-year period (Year 1, n = 42 students; Year 2, n = 30 students) to determine the effects of student-led seminar (andragogical) and lecture (pedagogical) teaching methods on students' retention of information and performance. For each year of the study, the course was divided into two time periods. The first half was dedicated to instructor-led lectures, followed by a control survey in which the students rated the efficiency of pedagogical learning on a five-point Likert scale from one (strongly disagree) to five (strongly agree). During the second period, students engaged in andragogical learning via peer-led seminars. An experimental survey was then administered to students using the same scale as above to determine students' preferred teaching method. Raw examination scores and survey results from both halves of the course were statistically analyzed by ANOVA with Newman-Keuls multiple comparison test. By the end of the study, student preference for peer-led seminars increased [mean ± SD: (2.47 ± 0.94)/(4.03 ± 1.36), P < 0.04], and examination scores significantly increased [mean ± SD: (73.91% ± 13.18)/(85.77 ± 5.22), P < 0.001]. A majority of students (68.8%) preferred a method that contained peer-led seminars and instructor-led lectures. These results may indicate that integration of active and passive learning into undergraduate courses may have greater benefit in terms of student preference and performance than either method alone.

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.

Hospitals are under increasing pressure to perform active surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. This study aimed to identify patients at low and high risk for positive admission surveillance cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in a neurocritical care unit using readily ascertainable historical factors.Before/after study with nested case/control study.Neurocritical care unit of an academic hospital.During the intervention period (July 2007 to June 2008), after implementation of an admission surveillance culture screening program for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, 2,059 patients were admitted to the neurocritical care unit for a total of 5,957 patient days.Cases had positive methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus admission surveillance cultures within 48 hrs of hospital admission. Controls had negative cultures.Admission surveillance cultures grew methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in 35 of 823 (4.3%) and 19 of 766 (2.5%) patients, respectively. Factors significantly associated with both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus colonization were intravenous antibiotics and hospitalization in the past year, immunocompromised health status, intravenous drug use, long-term hemodialysis, and known prior carrier status. Transfer from an outside hospital and residence in a long-term care facility in the past year were associated with vancomycin-resistant Enterococcus colonization. Classification and regression tree analysis was used to identify variables that best predicted positive methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus surveillance cultures. A classification and regression tree model with six of these variables yielded an overall cross-validated predictive accuracy of 87.12% to detect methicillin-resistant Staphylococcus aureus colonization. For vancomycin-resistant Enterococcus, a four-variable classification and regression tree model (intravenous antibiotics, hospitalization and long-term patient care in the past year, and not being "admitted same day of procedure") optimized the predictive accuracy (94.91%). There were no cases of vancomycin-resistant Enterococcus colonization in patients admitted same day of procedure.Colonization with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus in neurocritical care patients can be predicted with a high predictive accuracy using decision trees that include four to six readily attainable risk factors. In our setting, in the absence of these risk factors and in patients admitted from home for neurosurgical procedures, routine admission surveillance cultures to the intensive care unit may not be cost-effective.

During 2017, a total of 142 specimens of three cyprinid fish from the Sava River, Bosnia and Herzegovina, were sampled and the presence of the intestinal parasite Pomphorhynchus bosniacus was assessed.Morphological and molecular determination, the latter inferred by sequence analysis of the COI gene and the ITS region, were performed. In addition, the prevalence and intensity of the infection, as well as the pathogenic effect on the host were analysed. Observed morphological features of P. bosniacus were different from P. laevis, whereas COI and ITS sequence analyses revealed none or minimal genetic variability between P. bosniacus and P. laevis from the same geographic area. Histological analysis indicated that the greatest negative effect on the host intestinal tissues was the region by the neck close to the site of parasite penetration. Our results suggest the need for further species revision, as P. bosniacus, a recently evolved sister species of P. laevis complex, shows distinct morphology but limited sequence divergence.