Search

IntroductionAbnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer’s disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau deposits primarily affect neurons, but evidence indicates that glial cells may also be affected and contribute distinctively to disease progression. Cells can respond to toxic insults by orchestrating global changes in posttranslational modifications of their proteome. Previous studies suggest that SUMOylation, a posttranslational modification consisting of conjugation of SUMO (Small ubiquitin-like modifier) to target proteins, was decreased in the hippocampus of AD patients and in animal model of AD compared with controls. This decrease in SUMOylation was correlated with increased Tau pathology and cognitive decline. Other studies have reported increased levels of SUMO in AD brains. The goal of our study was to evaluate whether SUMO conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant TauP301L, in neurons and in glial cells.MethodsWe used viral approaches to express mutant TauP301L and SUMO2 in the hippocampus of wild-type mice. We assessed Tau distribution by immunostaining and Tau aggregation by insolubility assays followed by western blotting. We assessed neuronal toxicity and performed cell count and shape descriptor analyses on astrocytes and microglial cells.ResultsWe found that mutant TauP301L, when expressed exclusively in neurons, is toxic not only to neurons but also to glial cells, and that SUMO2 counteracts TauP301L toxicity in neurons as well as in glia.DiscussionOur results uncover an endogenous neuroprotective mechanism, whereby SUMO2 conjugation reduces Tau neuropathology and protects against toxic effects of Tau in glial cells.

Abstract High alpine regions are threatened but understudied ecosystems that harbor diverse endemic species, making them an important biome for testing the role of environmental factors in driving functional trait‐mediated community assembly processes. We tested the hypothesis that plant community assembly along a climatic and elevation gradient is influenced by shifts in habitat suitability, which drive plant functional, phylogenetic, and spectral diversity. In a high mountain system (2400–3500 m) Región Metropolitana in the central Chilean Andes (33°S, 70°W). We surveyed vegetation and spectroscopic reflectance (400–2400 nm) to quantify taxonomic, phylogenetic, functional, and spectral diversity at five sites from 2400 to 3500 m elevation. We characterized soil attributes and processes by measuring water content, carbon and nitrogen, and net nitrogen mineralization rates. At high elevation, colder temperatures reduced available soil nitrogen, while at warmer, lower elevations, soil moisture was lower. Metrics of taxonomic, functional, and spectral alpha diversity peaked at mid‐elevations, while phylogenetic species richness was highest at low elevation. Leaf nitrogen increased with elevation at the community level and within individual species, consistent with global patterns of increasing leaf nitrogen with colder temperatures. The increase in leaf nitrogen, coupled with shifts in taxonomic and functional diversity associated with turnover in lineages, indicate that the ability to acquire and retain nitrogen in colder temperatures may be important in plant community assembly in this range. Such environmental filters have important implications for forecasting shifts in alpine plant communities under a warming climate.

Neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

Abstract Alzheimer's disease and related dementias (ADRD) remain a major health‐care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration–approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real‐world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half‐life, and off‐target effects. HIGHLIGHTS Potent phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators. In animals PDE5 inhibitors enhance synaptic function and cognitive ability. In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease. Licensed PDE5 inhibitors have potential for repurposing in dementia. Prospective clinical trials of PDE5 inhibitors are warranted.

Background/Objectives: Brodalumab is a monoclonal antibody against the anti-IL-17 receptor A, approved for patients with moderate-to-severe psoriasis. This retrospective study investigated patients in clinical practice to assess the impact of body weight and previous treatments with biologics on the effectiveness of brodalumab. Methods: Patients were treated according to clinical practice, and assessed at baseline, 16, 36 and 52 weeks by means of the Psoriasis Area Severity Index (PASI) and DLQI score. Overall, 299 patients were included (147 naïve to biologics). Results: Mean PASI was significantly reduced compared with the baseline in the overall population by week 4 and continued to decrease at each study time point (15.9 ± 7.9 at baseline, 5.4 ± 5.3 at week 4, 1.9 ± 3.6 at week 6, 1.0 ± 2.1 at week 36, and 0.8 ± 2.1 at week 52; p < 0.001 at each control). PASI improved significantly both in bio-naïve and bio-experienced patients (p < 0.001). The proportions of patients achieving PASI 75, PASI 90, and PASI 100 were comparable between the bio-naïve and bio-experienced groups at all time points. The percentages of patients who achieved PASI 75 were similar in obese and non-obese subjects at all determinations except the visit performed after 36 weeks of treatment (94.3% non-obese vs. 83.1% obese, p = 0.005). PASI 90 was achieved more frequently among non-obese patients than obese patients after 36 weeks (80.7% vs. 64.4%, p = 0.008) and 52 weeks of treatment (84.1% vs. 71.7%, 0.027). The probability of achieving PASI 75 and PASI 100 was independent of nutritional status at any time during the study. Conclusions: In conclusion, our results confirm that brodalumab has both rapid and sustained effectiveness in patients with moderate-to-severe psoriasis; our results could be extended to patients with multiple risk factors impairing treatment response, such as multiple biological failure and obesity. [ABSTRACT FROM AUTHOR]

Mitochondrial and synaptic dysfunction are pathological features of brain ageing and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigated the mechanisms of advanced glycation end product (AGE)-mediated mitochondrial and synaptic stress and evaluated the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analysed alterations in accumulation/build-up of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrated for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGE-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in ageing brain. Importantly, clearance of AGE-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification of AGEs, reduces synaptic mitochondrial AGE accumulation and improves mitochondrial and cognitive function in ageing and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGE-induced synaptic plasticity and transmission by full recovery of decline in LTP or frequency of mEPSC. These studies explored crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain ageing and cognitive decline. Synaptic mitochondria are particularly susceptible to AGE-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGE accumulation and improve mitochondrial function and learning and memory. [ABSTRACT FROM AUTHOR]

Haematopoiesis is the process of blood cells' formation, with progenitor stem cells differentiating into mature forms such as white and red blood cells or platelets. While progenitor cells share regulatory pathways involving common nuclear factors, specific networks shape their fate towards particular lineages. This paper analyses the complex regulatory network that drives the formation of mature red blood cells and platelets from their common precursors. Using the latest reverse transcription quantitative real-time PCR genomic data, we develop a dedicated graphical model that incorporates the effect of external genomic data and allows inference of regulatory networks from the high-dimensional and partially observed data. [ABSTRACT FROM AUTHOR]

Abstract Statistical tests of differential expression usually suffer from two problems. Firstly, their statistical power is often limited when applied to small and skewed data sets. Secondly, gene expression data are usually discretized by applying arbitrary criteria to limit the number of false positives. In this work, a new statistical test obtained from a convolution of multivariate hypergeometric distributions, the Hy-test, is proposed to address these issues. Hy-test has been carried out on transcriptomic data from breast and kidney cancer tissues, and it has been compared with other differential expression analysis methods. Hy-test allows implicit discretization of the expression profiles and is more selective in retrieving both differential expressed genes and terms of Gene Ontology. Hy-test can be adopted together with other tests to retrieve information that would remain hidden otherwise, e.g., terms of (1) cell cycle deregulation for breast cancer and (2) “programmed cell death” for kidney cancer.

La desigualdad territorial asociada a la localización de población y actividades, al acceso a infraestructuras y servicios, al empleo y a las condiciones materiales de vida, es una realidad histórica en América Latina. Este fenómeno acompañó las demandas de los sucesivos modelos de desarrollo y desde mediados del siglo xx se comenzó a reconocer en su total complejidad a la par de la instalación de gobiernos desarrollistas. Consecuentemente, se adoptaron diversas políticas públicas que no lograron incidir significativamente sobre esas desigualdades ni aten­der a sus consecuencias sociales. Ante la necesidad de reformular enfoques, optimizar recur­sos y sortear obstáculos en la concreción de las políticas públicas, este trabajo busca analizar críticamente las políticas en agenda de gobierno en Argentina a partir del cambio de gestión concretado a fines de 2019, identificando las limitaciones, logros y potencialidades de las po­líticas propuestas en Argentina, Brasil y México y sus efectos sobre la desigualdad territorial.

Introduction: Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer's disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD). Tau deposits primarily affect neurons, but evidence indicates that glial cells may also be affected and contribute distinctively to disease progression. Cells can respond to toxic insults by orchestrating global changes in posttranslational modifications of their proteome. Previous studies suggest that SUMOylation, a posttranslational modification consisting of conjugation of SUMO (Small ubiquitin-like modifier) to target proteins, was decreased in the hippocampus of AD patients and in animal model of AD compared with controls. This decrease in SUMOylation was correlated with increased Tau pathology and cognitive decline. Other studies have reported increased levels of SUMO in AD brains. The goal of our study was to evaluate whether SUMO conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant TauP301L, in neurons and in glial cells. Methods: We used viral approaches to express mutant TauP301L and SUMO2 in the hippocampus of wild-type mice. We assessed Tau distribution by immunostaining and Tau aggregation by insolubility assays followed by western blotting. We assessed neuronal toxicity and performed cell count and shape descriptor analyses on astrocytes and microglial cells. Results: We found that mutant TauP301L, when expressed exclusively in neurons, is toxic not only to neurons but also to glial cells, and that SUMO2 counteracts TauP301L toxicity in neurons as well as in glia. Discussion: Our results uncover an endogenous neuroprotective mechanism, whereby SUMO2 conjugation reduces Tau neuropathology and protects against toxic effects of Tau in glial cells. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic, systemic, inflammatory disease affecting the skin, joints and other organs. Psoriasis negatively affects patients' quality of life, causing social anxiety and negative coping, thus determining a cumulative life course impairment (CLCI). The concept of CLCI in psoriasis is reinforced by the understanding that psoriasis-associated comorbidities and stigma accumulate over a patient's life course, resulting from an interaction between the burden of stigmatization, physical and psychological comorbidities, coping strategies and external factors. The concept may help identify more vulnerable patients and facilitate more appropriate treatment decisions or earlier referrals. Although some potential risk factors for CLCI have been clarified, no all-encompassing screening tools are available. Patients at risk for CLCI should be identified by applying clinical, personal and psychosocial indicators and predictors individually. Early intervention in psoriasis treatment could improve long-term patient outcomes and modify the disease course. However, more research is needed to clearly define what constitutes 'early' intervention and to identify the most effective strategies for implementation. From a preventive point of view, it is helpful to identify early interventions aimed at reducing the risk of CLCI and establishing a new life course trajectory in patients with psoriasis. This review summarizes the latest developments in CLCI and psoriasis, highlighting knowledge gaps and future directions to make control of CLCI a possible goal for therapies. [ABSTRACT FROM AUTHOR]

A growing number of studies link dysfunction of macroautophagy/autophagy to the pathogenesis of diseases such as Alzheimer disease (AD). Given the global importance of autophagy for homeostasis, how its dysfunction can lead to specific neurological changes is puzzling. To examine this further, we compared the global deactivation of autophagy in the adult mouse using the atg7iKO with the impact of AD-associated pathogenic changes in autophagic processing of synaptic proteins. Isolated forebrain synaptosomes, rather than total homogenates, from atg7iKO mice demonstrated accumulation of synaptic proteins, suggesting that the synapse might be a vulnerable site for protein homeostasis disruption. Moreover, the deactivation of autophagy resulted in impaired cognitive performance over time, whereas gross locomotor skills remained intact. Despite deactivation of autophagy for 6.5 weeks, changes in cognition were in the absence of cell death or synapse loss. In the symptomatic APP PSEN1 double-transgenic mouse model of AD, we found that the impairment in autophagosome maturation coupled with diminished presence of discrete synaptic proteins in autophagosomes isolated from these mice, leading to the accumulation of one of these proteins in the detergent insoluble protein fraction. This protein, SLC17A7/Vglut, also accumulated in atg7iKO mouse synaptosomes. Taken together, we conclude that synaptic autophagy plays a role in maintaining protein homeostasis, and that while decreasing autophagy interrupts normal cognitive function, the preservation of locomotion suggests that not all circuits are affected similarly. Our data suggest that the disruption of autophagic activity in AD may have relevance for the cognitive impairment in this adult-onset neurodegenerative disease. Abbreviations: 2dRAWM: 2-day radial arm water maze; AD: Alzheimer disease; Aβ: amyloid-beta; AIF1/Iba1: allograft inflammatory factor 1; APP: amyloid beta precursor protein; ATG7: autophagy related 7; AV: autophagic vacuole; CCV: cargo capture value; Ctrl: control; DLG4/PSD-95: discs large MAGUK scaffold protein 4; GFAP: glial fibrillary acidic protein; GRIN2B/NMDAR2b: glutamate ionotropic receptor NMDA type subunit 2B; LTD: long-term depression; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; m/o: months-old; PNS: post-nuclear supernatant; PSEN1/PS1: presenilin 1; SHB: sucrose homogenization buffer; SLC32A1/Vgat: solute carrier family 32 member 1; SLC17A7/Vglut1: solute carrier family 17 member 7; SNAP25: synaptosome associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYP: synaptophysin ; SYT1: synaptotagmin 1; Tam: tamoxifen; VAMP2: vesicle associated membrane protein 2; VCL: vinculin; wks: weeks. [ABSTRACT FROM AUTHOR]

Abstract Citrus limon (L.) Burm. F. is an important evergreen fruit crop whose rhizosphere and phyllosphere microbiota have been characterized, while seed microbiota is still unknown. Bacterial and fungal endophytes were isolated from C. limon surface-sterilized seeds. The isolated fungi—belonging to Aspergillus, Quambalaria and Bjerkandera genera—and bacteria—belonging to Staphylococcus genus—were characterized for indoleacetic acid production and phosphate solubilization. Next Generation Sequencing based approaches were then used to characterize the endophytic bacterial and fungal microbiota structures of surface-sterilized C. limon seeds and of shoots obtained under aseptic conditions from in vitro growing seedlings regenerated from surface-sterilized seeds. This analysis highlighted that Cutibacterium and Acinetobacter were the most abundant bacterial genera in both seeds and shoots, while Cladosporium and Debaryomyces were the most abundant fungal genera in seeds and shoots, respectively. The localization of bacterial endophytes in seed and shoot tissues was revealed by Fluorescence In Situ Hybridization coupled with Confocal Laser Scanning Microscopy revealing vascular bundle colonization. Thus, these results highlighted for the first time the structures of endophytic microbiota of C. limon seeds and the transmission to shoots, corroborating the idea of a vertical transmission of plant microbiota and suggesting its crucial role in seed germination and plant development.

Psoriasis is a chronic inflammatory disease which affects 29.5 million people worldwide and it can negatively impact quality of life, especially when it affects a special localization, such as nails, face, palms and soles, or intertriginous regions. Risankizumab is a humanized monoclonal antibody which targets the p19 subunit of interleukin-23 and it is currently licensed also as systemic therapy for moderate to severe plaque psoriasis. Here, we present eight cases of patients with moderate to severe psoriasis treated with risankizumab with a significant efficacy in the remission of the disease. Our cases represent a real-world clinical setting and provide a valuable adjunct to results obtained in the selected patients usually included in controlled clinical trials. In our cases, risankizumab rapidly improved clinical manifestations and relieved symptoms in patients with moderate to severe psoriasis, regardless of the presence of comorbidities or the location of the plaques in special sites, and without any safety concerns.

Introduction The amyloid cascade hypothesis dominates in the Alzheimer's disease (AD) field. It posits that amyloid-[beta] (A[beta]) and tau proteins are placed in a series with A[beta] upstream of tau, [...], The amyloid hypothesis posits that the amyloid-beta (A[beta]) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer's disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervention when A[beta] already activated tau. Here, using a multidisciplinary approach combining molecular biological, biochemical, histopathological, electrophysiological, and behavioral methods, we demonstrated that tau suppression did not protect against A[beta]-induced damage of long-term synaptic plasticity and memory, or from amyloid deposition. Tau suppression could even unravel a defect in basal synaptic transmission in a mouse model of amyloid deposition. Similarly, tau suppression did not protect against exogenous oligomeric tau-induced impairment of long-term synaptic plasticity and memory. The protective effect of tau suppression was, in turn, confined to short-term plasticity and memory. Taken together, our data suggest that therapies downstream of A[beta] and tau together are more suitable to combat AD than therapies against one or the other alone.

Abstract Introduction Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small‐molecule therapeutics for AD. Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon “self” neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis. Discussion Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.