Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis

Inflammatory illness is associated with depression. Preclinical work has shown that chemokines are linked with peripheral–central crosstalk and may be important in mediating depressive behaviours. We sought to establish what evidence exists that differences in blood or cerebrospinal fluid chemokine concentration discriminate between individuals with depression and those without. Following PRISMA guidelines, we systematically searched Embase, PsycINFO and Medline databases. We included participants with physical illness for subgroup analysis, and excluded participants with comorbid psychiatric diagnoses. Seventy-three studies met the inclusion criteria for the meta-analysis. Individuals with depression had higher levels of blood CXCL4 and CXCL7 and lower levels of blood CCL4. Sensitivity analysis of studies with only physically healthy participants identified higher blood levels of CCL2, CCL3, CCL11, CXCL7 and CXCL8 and lower blood levels of CCL4. All other chemokines examined did not reveal significant differences (blood CCL5, CCL7, CXCL9, CXCL10 and cerebrospinal fluid CXCL8 and CXCL10). Analysis of the clinical utility of the effect size of plasma CXCL8 in healthy individuals found a negative predictive value 93.5%, given the population prevalence of depression of 10%. Overall, our meta-analysis finds evidence linking abnormalities of blood chemokines with depression in humans. Furthermore, we have demonstrated the possibility of classifying individuals with depression based on their inflammatory biomarker profile. Future research should explore putative mechanisms underlying this association, attempt to replicate existing findings in larger populations and aim to develop new diagnostic and therapeutic strategies

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo

Introduction: Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour. Methods: Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6– 17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice. Results: CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm2 tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All CBZinduced effects were transient and rapidly lost following cessation of treatment. Conclusion: Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironmentin vivo highlighting a potential role in mediating treatment responses

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the serine/threonine kinase family is involved in apoptosis and serine/threonine kinase 3 (STK3) is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7, and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7, and -8 expression and activity vary significantly among the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or nonapoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration

Mineral abrasion experiments at Mars relevant temperatures

The aeolian transport of sand generates fine material through abrasion. On Mars this process occurs at lower temperatures than on Earth, however, there is minimal data on the effects of temperature on aeolian abrasion rates. Here, results are reported of laboratory experiments where a suite of single-phase, Mars relevant minerals (feldspar, olivine, pyroxene, quartz and opal) were exposed to conditions simulating aeolian abrasion at temperatures common to the Martian surface (193 to 293 K). Our results suggest that mineral specific differences in solid phase parameters result in non-similar changes in abrasion rates with temperature. We propose this will ultimately exert a control on the composition and reactivity of the Martian surface

Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD

Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein-protein interactions we performed a high throughput yeast-2-hybrid (Y2H) screen against ∼17,000 human proteins to gain further insight into the function of CASP6. We identified a high confidence list of 87 potential CASP6 interactors. From this list, 61% are predicted to contain a CASP6 recognition site. Of nine candidate substrates assessed, six are cleaved by CASP6. Proteins that did not contain a predicted CASP6 recognition site were assessed using a LUMIER assay approach and 51% were further validated as interactors by this method. Of note, 54% of the high-confidence interactors identified show alterations in human HD brain at the mRNA level, and there is a significant enrichment for previously validated huntingtin (HTT) interactors. One protein of interest, STK3, a proapoptotic kinase, was validated biochemically to be a CASP6 substrate. Furthermore, our results demonstrate that in striatal cells expressing mutant huntingtin (mHTT) an increase in full length and fragment levels of STK3 are observed. We further show that caspase-3 is not essential for the endogenous cleavage of STK3. Characterization of the interaction network provides important new information regarding key pathways of interactors of CASP6 and highlights potential novel therapeutic targets for HD, AD and cerebral ischemia

Demonstration of sub-luminal propagation of single-cycle terahertz pulses for particle acceleration

The sub-luminal phase velocity of electromagnetic waves in free space is generally unobtainable, being closely linked to forbidden faster than light group velocities. The requirement of sub-luminal phase-velocity in laser-driven particle acceleration schemes imposes a limit on the total acceleration achievable in free space, and necessitates the use of dispersive structures or waveguides for extending the field-particle interaction. We demonstrate a travelling source approach that overcomes the sub-luminal propagation limits. The approach exploits ultrafast optical sources with slow group velocity propagation, and a group-to-phase front conversion through nonlinear optical interaction. The concept is demonstrated with two terahertz generation processes, nonlinear optical rectification and current-surge rectification. We report measurements of longitudinally polarised single-cycle electric fields with phase and group velocity between 0.77c and 1.75c. The ability to scale to multi-megavolt-per-metre field strengths is demonstrated. Our approach paves the way towards the realisation of cheap and compact particle accelerators with femtosecond scale control of particles

Ancient Gondwana break-up explains the distribution of the mycoheterotrophic family Corsiaceae (Liliales)

Plant science

Phenomenology of flavor-mediated supersymmetry breaking

The phenomenology of a new economical SUSY model that utilizes dynamical SUSY breaking and gauge-mediation (GM) for the generation of the sparticle spectrum and the hierarchy of fermion masses is discussed. Similarities between the communication of SUSY breaking through a messenger sector, and the generation of flavor using the Froggatt-Nielsen (FN) mechanism are exploited, leading to the identification of vector-like messenger fields with FN fields, and the messenger U(1) as a flavor symmetry. An immediate consequence is that the first and second generation scalars acquire flavor-dependent masses, but do not violate FCNC bounds since their mass scale, consistent with effective SUSY, is of order 10 TeV. We define and advocate a minimal flavor-mediated model (MFMM), recently introduced in the literature, that successfully accommodates the small flavor-breaking parameters of the standard model using order one couplings and ratios of flavon field vevs. The mediation of SUSY breaking occurs via two-loop log-enhanced GM contributions, as well as several one-loop and two-loop Yukawa-mediated contributions for which we provide analytical expressions. The MFMM is parameterized by a small set of masses and couplings, with values restricted by several model constraints and experimental data. The next-to-lightest sparticle (NLSP) always has a decay length that is larger than the scale of a detector, and is either the lightest stau or the lightest neutralino. Similar to ordinary GM models, the best collider search strategies are, respectively, inclusive production of at least one highly ionizing track, or events with many taus plus missing energy. In addition, D^0 - \bar{D}^0 mixing is also a generic low energy signal. Finally, the dynamical generation of the neutrino masses is briefly discussed.Comment: 54 pages, LaTeX, 8 figure

A systematic review and qualitative synthesis of weight management interventions for people with spinal cord injury

People with spinal cord injury (SCI) are at greater risk of developing obesity and related co-morbidities than those without SCI. The objectives of this systematic review were to examine the effectiveness of weight management interventions for people with SCI and to synthesize the experiences of people involved with SCI weight management (e.g., SCI healthcare professionals and caregivers). Five databases were searched (up to July 31, 2023) and 5,491 potentially eligible articles were identified. Following screening, 22 articles were included, comprising 562 adults. There was considerable heterogeneity in study design and weight loss interventions included behavioral nutritional and exercise education sessions, recalling food diaries, exercise interventions, and pharmaceuticals. The mean percentage change of the pooled body mass data equated to −4.0 ± 2.3%, with a range from −0.5 to −7.6%. In addition, 38% of the individuals with SCI who completed a weight loss intervention (N = 262) had a ≥5% reduction in body weight. Collectively, although on average the included interventions led to moderate weight loss, the finding that just over a third of individuals achieved clinically meaningful 5% weight loss suggests that available interventions for this population may need to be improved