Targeting co-stimulatory molecules in autoimmune disease Edner, Natalie M; Carlesso, Gianluca; Rush, James S ...
Nature reviews. Drug discover/Nature reviews. Drug discovery,
12/2020, Letnik:
19, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 ...(CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.
Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this ...comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.
Background
Early reports of COVID‐19 in pregnancy described management by caesarean, strict isolation of the neonate and formula feeding. Is this practice justified?
Objective
To estimate the risk of ...the neonate becoming infected with SARS‐CoV‐2 by mode of delivery, type of infant feeding and mother‐infant interaction.
Search strategy
Two biomedical databases were searched between September 2019 and June 2020.
Selection criteria
Case reports or case series of pregnant women with confirmed COVID‐19, where neonatal outcomes were reported.
Data collection and analysis
Data were extracted on mode of delivery, infant infection status, infant feeding and mother–infant interaction. For reported infant infection, a critical analysis was performed to evaluate the likelihood of vertical transmission.
Main results
Forty nine studies included information on mode of delivery and infant infection status for 655 women and 666 neonates. In all, 28/666 (4%) tested positive postnatally. Of babies born vaginally, 8/292 (2.7%) tested positivecompared with 20/374 (5.3%) born by Caesarean. Information on feeding and baby separation were often missing, but of reported breastfed babies 7/148 (4.7%) tested positive compared with 3/56 (5.3%) for reported formula fed ones. Of babies reported as nursed with their mother 4/107 (3.7%) tested positive, compared with 6/46 (13%) for those who were reported as isolated.
Conclusions
Neonatal COVID‐19 infection is uncommon, rarely symptomatic, and the rate of infection is no greater when the baby is born vaginally, breastfed or remains with the mother.
Tweetable
Risk of neonatal infection with COVID‐19 by delivery route, infant feeding and mother‐baby interaction.
Tweetable
Risk of neonatal infection with COVID‐19 by delivery route, infant feeding and mother‐baby interaction.
This article includes Author Insights, a video available at https://vimeo.com/rcog/authorinsights16362
Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles ...associated with Alzheimer’s disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer’s disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer’s disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer’s disease.
This paper is the first of a series attempting to apply my 57‐year experience with durability and damage tolerance of aerospace structures to answer the question; why, after 50 plus years, have we ...not reached agreement on the validity of current crack growth assumptions.
To address this question, new concepts are introduced and interpreted in terms of strain energy.
The tentative answer to the question is that when interpreted in terms these new concepts and strain energy, there are serious conceptual errors in the da/dn diagrams that make the data base very difficult to properly interpret.
The materials presented raise new questions and provide possible answers to old ones.
During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many ...of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated
models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.
A new composition of gelatin/bioactive-glass/silver nanoparticle was synthesized and employed to prepare antibacterial macroporous scaffolds with potential applications in bone tissue engineering. A ...set of macroporous nanocomposite scaffolds were developed from an aqueous solution of gelatin by freeze-drying and crosslinking using genipin at ambient temperature. Silver nanoparticles were successfully synthesized in situ in gelatin solution by heat treatment reduction as a simple and "green" method in which gelatin acted as a natural reducing and stabilizing agent. The effect of the incorporation of the bioactive-glass and the silver nanoparticle concentration on the physicochemical properties of the scaffolds, such as the gel fraction, porosity, in vitro enzyme degradation, morphology, and swelling behavior was studied. Furthermore, the in vitro viability of human mesenchymal stem cells (hMSC) and the antibacterial activity against gram-negative Escherichia coli and gram-positive Staphylococcus aureus were tested on the scaffolds. It was found that upon the addition of silver nanoparticles the porosity, pore size, swelling, and antibacterial properties were enhanced. The silver nanoparticles increased the in vitro enzyme degradation in samples without bioactive-glass; however, the degradation was remarkably reduced by addition of bioactive-glass. In addition, formation of apatite particles, the main inorganic constituent of the bone, on the surface of the bioactive-glass containing scaffolds were confirmed after immersion in simulated body fluid (SBF). The viability of hMSC on the scaffold suggested that gelatin/bioactive-glass/nanosilver scaffolds can be used as an antibacterial scaffolds.
We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in ...specific domains of development in the offspring.
Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children's diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother.
All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 95% confidence interval: 1.10-2.37; odds ratio: 2.35 95% confidence interval: 1.43-3.88, respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite).
Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.
In this article we present ultra-sensitive, silicon nanowire (SiNW)-based biosensor devices for the detection of disease biomarkers. An electrochemically induced functionalisation method has been ...employed to graft antibodies targeted against the prostate cancer risk biomarker 8-hydroxydeoxyguanosine (8-OHdG) to SiNW surfaces. The antibody-functionalised SiNW sensor has been used to detect binding of the 8-OHdG biomarker to the SiNW surface within seconds of exposure. Detection of 8-OHdG concentrations as low as 1ng/ml (3.5nM) has been demonstrated. The active device has been bonded to a disposable printed circuit which can be inserted into an electronic readout system as part of an integrated Point of Care (POC) diagnostic. The speed, sensitivity and ease of detection of biomarkers using SiNW sensors render them ideal for eventual POC diagnostics.
•We present an ultra-sensitive antibody-functionalised SiNW sensor chip integrated with a readout device for detection of the biomarker 8-OHdG.•Functionalisation of SiNW was achieved using an electrochemical diazotization method for nitro-phenyl attachment to silicon surfaces.•The reduction process, converting the nitro group to an amine was achieved rapidly, under production friendly conditions.•The advantage of this functionalisation method lies in its simplicity, avoidance of harsh oxidation chemistry and speed of reaction.•Rapid detection of 8-OHdG concentrations as low as 1ng/ml (3.5nM) has been demonstrated.
Titanium dioxide (TiO2) nanoparticles (NPs) are used as an additive (E171 or INS171) in foods such as gum, candy and puddings. To address concerns about the potential hazardous effects of ingested ...NPs, the toxicity of these food-grade NPs was investigated with a defined model intestinal bacterial community. Each titania preparation (food-grade TiO2 formulations, E171-1 and E171-6a) was tested at concentrations equivalent to those found in the human intestine after sampling 1–2 pieces of gum or candy (100–250 ppm). At the low concentrations used, neither the TiO2 food additives nor control TiO2 NPs had an impact on gas production and only a minor effect on fatty acids profiles (C16:00, C18:00, 15:1 w5c, 18:1 w9c and 18:1 w9c, p < 0.05). DNA profiles and phylogenetic distributions confirmed limited effects on the bacterial community, with a modest decrease in the relative abundance of the dominant Bacteroides ovatus in favor of Clostridium cocleatum (−13% and +14% respectively, p < 0.05). Such minor shifts in the treated consortia suggest that food grade and nano-TiO2 particles do not have a major effect on human gut microbiota when tested in vitro at relevant low concentrations. However, the cumulative effects of chronic TiO2 NP ingestion remain to be tested.
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•Titania food additives had a modest impact on individual bacterial abundance in a model intestinal ecosystem.•The gut environment likely attenuates the toxicity of nano-TiO2 to human gut microbiota.•Amylase supplementation confirmed the suitability of the test gut ecosystem.
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