The control of apoptosis in mammals has been historically associated with the activity of the BCL-2 family of proteins at the mitochondria. In the past years, a novel group of cell death regulators ...have emerged, known as the Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) protein family. This group of proteins is composed of at least six highly conserved members expressed in mammals, with homologs in insects, fish, plants, viruses and yeast. Different studies indicate that all TMBIM family members have inhibitory activities in different setting of apoptosis. Here, we overview and integrate possible mechanisms underlying the impact of the TMBIM protein family in the regulation of cell death, which include activities at diverse subcellular compartments, including death receptor regulation, modulation of endoplasmic reticulum (ER) calcium homeostasis, ER stress signaling, autophagy, reactive oxygen species production, among other effects. The possible intersection between the BCL-2 and TMBIM family in the control of cell death is also discussed, in addition to their implication in the progression of cancer.
Abstract
The Allele Frequency Net Database (AFND, www.allelefrequencies.net) provides the scientific community with a freely available repository for the storage of frequency data (alleles, genes, ...haplotypes and genotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex Class I chain related genes (MIC) and a number of cytokine gene polymorphisms in worldwide populations. In the last five years, AFND has become more popular in terms of clinical and scientific usage, with a recent increase in genotyping data as a necessary component of Short Population Report article submissions to another scientific journal. In addition, we have developed a user-friendly desktop application for HLA and KIR genotype/population data submissions. We have also focused on classification of existing and new data into ‘gold–silver–bronze’ criteria, allowing users to filter and query depending on their needs. Moreover, we have also continued to expand other features, for example focussed on HLA associations with adverse drug reactions. At present, AFND contains >1600 populations from >10 million healthy individuals, making AFND a valuable resource for the analysis of some of the most polymorphic regions in the human genome.
A baseline study on metal concentrations in sediments was initiated from the Sodwana Bay and St. Lucia, adjacent to marine protected areas (MPAs) of South Africa. They were analysed to identify the ...acid leachable metal (ALM) (Fe, Mg, Mn, Cr, Cu, Mo, Ni, Co, Pb, Cd, Zn and Hg) concentration pattern. Metal distribution in 65 sediment samples exhibits higher abundances of Cr, Mo, Cd and Hg compared to the Upper Continental Crust. We relate the enrichment of these metals to beach placer deposits and activities related to former gold mining. Geochemical indices affirmed that Cr and Hg caused contamination, and Hg posed ~90% harmful effect on the biological community. These beach sediments, however, host lower metal concentrations compared to many worldwide beaches and other beaches in South Africa. This study suggests that it is largely unaffected by human activities, however, the overabundance of Hg demands regular monitoring.
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•Acid leachable metals in beaches of Marine Protected Areas in South Africa•Transport and deposition of metals due to human activities•Presence of metals above permissible limit•Identification of enrichment of metals through geochemical indices
Thirty sediment samples from four different beaches along Bahia Solano and Nuquí (Department of Chocó) of eastern Colombia, with tourism and gold mining activities, were analysed to estimate the ...concentrations of fourteen different acid leachable metals. Metal distribution patterns showed elevated concentrations of Co, Cr, Cu, Pb and Zn compared with the upper continental crust values. Calculation of geochemical indices confirmed that the enrichment is due to periodic gold mining activities (severe to extremely severe enrichment of Cu, Zn, V, Co, Cr and Pb) along with natural (geological) contributions (minor and moderate enrichment of Ca, Mg, Fe, Ti, Mn and Li). Potential ecological risk index revealed that Pb posed the highest risk. Our results together with a global comparison suggest that the observed metal enrichments are mainly caused by mining and to a lesser extent by tourism in this region, thus instigating continuous monitoring of metal concentrations in this region.
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•Acid leachable metals in beaches of Bahia de Solano and Nuquí in Colombia•Transport and deposition of metals due to illegal mining activities•Presence of metals above permissible limit•Identification of enrichment of metals through geochemical indices
Intervertebral disc (IVD) degeneration includes changes in tissue biomechanics, physical attributes, biochemical composition, disc microstructure, and cellularity, which can all affect the normal ...function of the IVD, and ultimately may lead to pain. The purpose of this research was to develop an in-vitro model of degeneration that includes the evaluation of physical, biomechanical, and structural parameters, and that does so over several load/recovery periods. Hyperphysiological loading was used as the degenerative initiator with three experimental groups employed using bovine coccygeal IVD specimens: Control; Single-Overload; and Double-Overload. An equilibrium stage comprising a static load followed by two load/recovery periods was followed by six further load/recovery periods. In the Control group all load/recovery periods were the same, comprising physiological cyclic loading. The overload groups differed in that hyperphysiological loading was applied during the 4th loading period (Single-Overload), or the 4th and 5th loading period (Double-Overload). Overloading led to a significant reduction in disc height compared to the Control group, which was not recovered in subsequent physiological load/recovery periods. However, there were no significant changes in stiffness. Overloading also led to significantly more microstructural damage compared to the Control group. Taking all outcome measures into account, the overload groups were evaluated as replicating clinically relevant aspects of moderate IVD degeneration. Further research into a potential dose–effect, and how more severe degeneration can be replicated would provide a model with the potential to evaluate new treatments and interventions for different stages of IVD degeneration.
The intervertebral disc (IVD) provides flexibility, acts as a shock absorber, and transmits load. Degeneration of the IVD includes alterations in the biomechanics, extracellular matrix (ECM), and ...cellular activity. These changes are not always perceived, however, IVD degeneration can lead to severe health problems including long-term disability. To understand the pathogenesis of IVD degeneration and suitable testing methods for emerging treatments and therapies, this review documents in-vitro models of IVD degeneration including physical disruption, hyperphysiological loading, ECM degradation by enzyme digestion, or a combination of these methods. This paper reviews and critically analyses the models of degeneration published since the year 2000 in either in human or animal specimens. The results are categorised in terms of the IVD biomechanics, physical attributes, ECM composition, tissue damage and cellularity to evaluate the models with respect to natural human degeneration, and to provide recommendations for clinically relevant models for the various stages of degeneration. There is no one model that replicates the wide range of degenerative changes that occur as part of normal degeneration. However, cyclic overloading replicates many aspects of degeneration, with the advantage of a dose–response allowing the tuning of damage initiated. Models of severe degeneration are currently lacking, but there is potential that combining cyclic overloading and enzymatic digestion will provide model that closely resembles human IVD degeneration. This will provide an effective way to investigate the effects of severe degeneration, and the evaluation of treatments for the IVD, which would generally be indicated at this advanced stage of degeneration.
Body size is a key life-history trait influencing all aspects of an organism's biology. Ants provide an interesting model for examining body-size variation because of the high degree of worker ...polymorphism seen in many taxa. We review worker-size variation in ants from the perspective of factors internal and external to the colony that may influence body-size distributions. We also discuss proximate and ultimate causes of size variation and how variation in worker size can promote worker efficiency and colony fitness. Our review focuses on two questions: What is our current understanding of factors influencing worker-size variation? And how does variation in body size benefit the colony? We conclude with recommendations for future work aimed at addressing current limitations and ask, How can we better understand the contribution of worker body-size variation to colony success? And, what research is needed to address gaps in our knowledge?
Previous studies have found that red giants (RGs) in close binary systems undergoing spin-orbit resonance exhibit an enhanced level of magnetic activity with respect to single RGs rotating at the ...same rate, from measurements of photometric variability, S ph ′ , and the chromospheric emission S -index, S Ca II . Here, we consider a sample of 4465 RGs observed by the NASA Kepler mission, for which previous studies have measured S ph ′ and S Ca II , in order to measure additional activity indicators that probe different heights in the chromosphere: the near-ultraviolet (NUV) excess from NASA GALEX photometric data, and chromospheric indices based on the depth of H α , Mg I , and infared Ca II absorption lines from LAMOST spectroscopic data. Firstly, as for Ca II H&K, we observe that RGs belonging to close binaries in a state of spin-orbit resonance display larger chromospheric emission than the cohort of RGs, as is illustrated by an NUV excess and shallower H α and infrared Ca II lines. We report no excess of Mg I emission. This result reinforces previous claims that tidal locking leads to enhanced magnetic fields, and allows us to provide criteria to classify active RGs – single or binary – based on their rotation periods and magnetic activity indices. Secondly, we strikingly observe that the depths of the Mg I and H α lines are anticorrelated and correlated, respectively, with the amplitude of solar-like oscillations for a given surface gravity, log g , regardless of the presence of photometric rotational modulation. Such a correlation opens up future possibilities of estimating the value of magnetic fields at the surface of RG stars, whether quiet or active, by combining spectroscopic and asteroseismic measurements with three-dimensional atmospheric models that include radiative transfer.
Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial ...DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.
The genetically encoded calcium indicator GCaMP2 shows promise for neural network activity imaging, but is currently limited by low signal-to-noise ratio. We describe x-ray crystal structures as well ...as solution biophysical and spectroscopic characterization of GCaMP2 in the calcium-free dark state, and in two calcium-bound bright states: a monomeric form that dominates at intracellular concentrations observed during imaging experiments and an unexpected domain-swapped dimer with decreased fluorescence. This series of structures provides insight into the mechanism of Ca2+-induced fluorescence change. Upon calcium binding, the calmodulin (CaM) domain wraps around the M13 peptide, creating a new domain interface between CaM and the circularly permuted enhanced green fluorescent protein domain. Residues from CaM alter the chemical environment of the circularly permuted enhanced green fluorescent protein chromophore and, together with flexible inter-domain linkers, block solvent access to the chromophore. Guided by the crystal structures, we engineered a series of GCaMP2 point mutants to probe the mechanism of GCaMP2 function and characterized one mutant with significantly improved signal-to-noise. The mutation is located at a domain interface and its effect on sensor function could not have been predicted in the absence of structural data.
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