Return to Work Within Four Months of Grade 3 Diffuse Axonal Injury

Neuroprognostication following diffuse axonal injury (DAI) has historically relied on neuroimaging techniques with lower spatial resolution and contrast than techniques currently available in clinical practice. Since the initial studies of DAI classification and prognosis in the 1980s and 1990s, advances in neuroimaging have improved detection of brainstem microbleeds, a hallmark feature of Grade 3 DAI that has traditionally been associated with poor neurologic outcome. Here, we report clinical and radiologic data from two patients with severe traumatic brain injury and grade 3 DAI who recovered functional independence and returned to work within 4 months of injury. Importantly, both patients were scanned using 3 Tesla MRI protocols that included susceptibility-weighted imaging (SWI), a technique that provides enhanced sensitivity for detecting brainstem microbleeds. These observations highlight the importance of developing approaches to DAI classification and prognosis that better align with contemporary neuroimaging capabilities.

Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion

Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least two weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.

In Vitro and In Vivo Approaches for Screening the Potential of Anti Cancer Agents: A Review

Background: Anticancer drug development is a tedious process, requiring several in vitro, in vivo, and clinical studies. To avoid chemical toxicity in animals during an experiment, it is necessary to envisage toxic doses of screened drugs in vivo at different concentrations. Several in vitro and in vivo studies have been reported to discover the management of cancer. Materials and Methods: This study has focused on bringing together a wide range of in vivo and in vitro assay methods, developed to evaluate each hallmark feature of cancer. Result: This review provides elaborated information about target-based and cell-based screening of new anticancer drugs in the molecular targeting period. This would help to incite an alteration from the preclinical screening of pragmatic compound-orientated to target-orientated drug selection. Conclusion: Selection methodologies for finding anticancer activity have importance for tumor-specific agents. In this study, advanced rationalization of the cell-based assay is explored along with broad applications of the cell-based methodologies considering other opportunities also.

Maintaining Energy: A Potential Transformative Power to Adapt to the Challenges of Older Age?

Reduced energy is a hallmark feature of aging. Maintaining higher energy late in life may be a key adaptive strategy to the challenges that accompany older age and ultimately promote resilience. Perceived lack of energy is often construed as synonymous with fatigue, and energy and fatigue are frequently considered opposite aspects of the same phenomenon. However, evidence suggests that energy and fatigue have distinct underlying neurobiology. Further exploration of the energy/fatigue dichotomy is needed in community-dwelling older adults free of neuropathologies and clinically overt conditions. This symposium will first present clinical and epidemiologic justifications for operationalizing energy as a separate construct from fatigue and then will provide evidence on the underlying neurobiological correlates. Taken together, our results suggest perceived energy: a) overlaps with but is distinct from lower fatigability (Katz); b) may signal resilience against age-related declining mood and gait speed despite self-reported tiredness (Ehrenkranz); c) appear negatively influenced by Alzheimer’s neuropathology (Dougherty); and d) may reflect a distinct spatial distribution of brain functional connectivity (Hengenius). Thus, this symposium will explore energy as a mechanism related to yet distinct from fatigue and its implications for both healthy aging and neuropathological processes.

The Flattening Metallicity Gradient in the Milky Way’s Thin Disk

We calculate the ages, orbits and phase-space coordinates for a sample of ∼4 million LAMOST and Gaia stars. The ages are cross-matched and compared with values from two other popular age catalogs, which derive the ages using different methods. Of these ∼4 million stars, we select a sample of 1.3 million stars and investigate their radial metallicity gradients (as determined by orbital radii) as a function of their ages. This analysis is performed on various subsets of the data split by chemistry and orbital parameters. We find that commonly used selections for “thin disk” stars (such as low-α chemistry or vertically thin orbits) yield radial metallicity gradients that generally grow shallower for the oldest stars. We interpret this as a hallmark feature of radial migration (churning). Constraining our sample to very small orbital Z max (the maximal height of a star’s integrated orbit) makes this trend most pronounced. A chemistry-based “thin disk” selection of α-poor stars displays the same trend, but to a lesser extent. Intriguingly, we find that “thick disk” selections in chemistry and Z max reveal slightly positive radial metallicity gradients, which seem similar in magnitude at all ages. This may imply that the thick disk population is well mixed in age, but not in radius. This finding could help constrain conditions during the early epochs of Milky Way formation and shed light on processes such as the accretion and reaccretion of gases of different metallicities.

Evidence for the Emergence of β-Trefoils by ‘Peptide Budding’ from an IgG-like β-Sandwich

As sequence and structure comparison algorithms gain sensitivity, the intrinsic interconnectedness of the protein universe has become increasingly apparent. Despite this general trend, β-trefoils have emerged as an uncommon counterexample: They are an isolated protein lineage for which few, if any, sequence or structure associations to other lineages have been identified. If β-trefoils are, in fact, remote islands in sequence-structure space, it implies that the oligomerizing peptide that founded the β-trefoil lineage itself arose de novo. To better understand β-trefoil evolution, and to probe the limits of fragment sharing across the protein universe, we identified both ‘β-trefoil bridging themes’ (evolutionarily-related sequence segments) and ‘β-trefoil-like motifs’ (structure motifs with a hallmark feature of the β-trefoil architecture) in multiple, ostensibly unrelated, protein lineages. The success of the present approach stems, in part, from considering β-trefoil sequence segments or structure motifs rather than the β-trefoil architecture as a whole, as has been done previously. The newly uncovered inter-lineage connections presented here suggest a novel hypothesis about the origins of the β-trefoil fold itself – namely, that it is a derived fold formed by ‘budding’ from an Immunoglobulin-like β-sandwich protein. These results demonstrate how the emergence of a folded domain from a peptide need not be a signature of antiquity and underpin an emerging truth: few protein lineages escape nature’s sewing table.

Body exposure, its forms of delivery and potentially associated working mechanisms: How to move the field forward

Background Body image disturbance (BID) is a hallmark feature of eating disorders (EDs) and has proven to be involved in their etiology and maintenance. Therefore, the targeting of BID in treatment is crucial, and has been incorporated in various treatment manuals. One of the most common techniques in the treatment of BID is body exposure (BE), the confrontation with one’s own body. BE has been found to be effective in individuals with EDs or high body dissatisfaction. However, BE is applied in a multitude of ways, most of which are based on one or a combination of the hypothesized underlying working mechanisms, with no differential effectiveness known so far. Method The aim of this paper is to selectively review the main hypothesized working mechanisms of BE and their translation into therapeutic approaches. Results and Conclusion Specifically, we underline that studies are needed to pinpoint the proposed mechanisms and to develop an empirically informed theoretical model of BE. We provide a framework for future studies in order to identify working mechanisms and increase effectiveness of BE.

Regulatory B Cells: Role in Type 1 Diabetes

Regulatory B cells (Bregs) have an anti-inflammatory role and can suppress autoimmunity, by employing both cytokine secretion and cell-contact mediated mechanisms. Numerous Breg subsets have been described and have overlapping phenotypes in terms of their immune expression markers or cytokine production. A hallmark feature of Bregs is the secretion of IL-10, although IL-35 and TGFβ−producing B cells have also been identified. To date, few reports have identified an impaired frequency or function of Bregs in individuals with type 1 diabetes; thus our understanding of the role played by these Breg subsets in the pathogenesis of this condition is limited. In this review we will focus on how regulatory B cells are altered in the development of type 1 diabetes, highlighting both frequency and function and discuss both human and animal studies.

JAK2V617F mutant megakaryocytes contribute to hematopoietic aging in a murine model of myeloproliferative neoplasm

Megakaryocytes (MKs) is an important component of the hematopoietic niche. Abnormal MK hyperplasia is a hallmark feature of myeloproliferative neoplasms (MPNs). The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs. Using a murine model of MPN in which the human JAK2V617F gene is expressed specifically in the MK lineage, we show that the JAK2V617F-bearing MKs promote hematopoietic stem cell (HSC) aging, manifesting as myeloid-skewed hematopoiesis with an expansion of CD41+ HSCs, a reduced engraftment and self-renewal capacity, and a reduced differentiation capacity. HSCs from 2yr old mice with JAK2V617F-bearing MKs were more proliferative and less quiescent than HSCs from age-matched control mice. Examination of the marrow hematopoietic niche reveals that the JAK2V617F-bearing MKs not only have decreased direct interactions with hematopoietic stem/progenitor cells during aging, but also suppress the vascular niche function during aging. Unbiased RNA expression profiling reveals that HSC aging has a profound effect on MK transcriptomic profiles, while targeted cytokine array shows that the JAK2V617F-bearing MKs can alter the hematopoietic niche through increased levels of pro-inflammatory and anti-angiogenic factors. Therefore, as a hematopoietic niche cell, MKs represent an important connection between the extrinsic and intrinsic mechanisms for HSC aging.

Prevention of Opioid Addiction

Opioid addiction is classified as a Substance Use Disorder (SUD), a complex and chronic health condition with physical, social, and psychological consequences. While there is no cure for it, we present a novel approach towards preventing a hallmark feature of addiction-- the opiate withdrawal syndrome. Opioids exert numerous effects, acutely and chronically, on the nervous system with physical dependence, tolerance, and withdrawal being the most adverse chronic features. The degree of opioid dependence can be quantified by the frequency and/or intensity of the behavioral expression of withdrawal seen after abrupt termination of opioid consumption or after treatment with an opioid antagonist such as naloxone. Although the Central Nervous System (CNS) is the primary area of opioid impact, the involvement of the immune system in modifying CNS phenomena was suggested nearly two centuries ago and proved by several groups within the last few decades. Through a series of studies with immunomodulators alpha interferon, cyclosporine A, and cortisol, preclinical experiments show that administration of these agents prior to chronic morphine exposure prevents the expression of opiate withdrawal a hallmark feature of addiction. This review provides updates on current developments in the management of the opioid epidemic and an overview of studies on preventative immunomodulation prior to repetitive opioid administration as a means of addressing one of the underlying symptomatology driving the epidemic.