Mechanisms and Impacts of Earth System Tipping Elements

Tipping elements are components of the Earth system which may respond nonlinearly to anthropogenic climate change by transitioning toward substantially different long-term states upon passing key thresholds or “tipping points.” In some cases, such changes could produce additional greenhouse gas emissions or radiative forcing that could compound global warming. Improved understanding of tipping elements is important for predicting future climate risks and their impacts. Here we review mechanisms, predictions, impacts, and knowledge gaps associated with 10 notable Earth system components proposed to be tipping elements. We evaluate which tipping elements are approaching critical thresholds and whether shifts may manifest rapidly or over longer timescales. Some tipping elements have a higher risk of crossing tipping points under middle-of-the-road emissions pathways and will possibly affect major ecosystems, climate patterns, and/or carbon cycling within the 21st century. However, literature assessing different emissions scenarios indicates a strong potential to reduce impacts associated with many tipping elements through climate change mitigation. The studies synthesized in our review suggest most tipping elements do not possess the potential for abrupt future change within years, and some proposed tipping elements may not exhibit tipping behavior, rather responding more predictably and directly to the magnitude of forcing. Nevertheless, uncertainties remain associated with many tipping elements, highlighting an acute need for further research and modeling to better constrain risks

Stepwise Maturation of Lytic Granules during Differentiation and Activation of Human CD8+ T Lymphocytes

During differentiation, cytotoxic T lymphocytes (CTL) acquire their killing potential through the biogenesis and maturation of lytic granules that are secreted upon target cell recognition. How lytic granule load in lytic molecules evolves during CTL differentiation and which subsets of lytic granules are secreted following activation remains to be investigated. We set up a flow cytometry approach to analyze single lytic granules isolated from primary human CTL according to their size and molecular content. During CTL in vitro differentiation, a relatively homogeneous population of lytic granules appeared through the progressive loading of Granzyme B, Perforin and Granzyme A within LAMP1+ lysosomes. PMA/ionomycin-induced lytic granule exocytosis was preceded by a rapid association of the docking molecule Rab27a to approximately half of the lytic granules. Activated CTL were found to limit exocytosis by sparing lytic granules including some associated to Rab27a. Our study provides a quantification of key steps of lytic granule biogenesis and highlights the potential of flow cytometry to study organelle composition and dynamics

Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages

This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments

HIV-Specific T-Cells Accumulate in the Liver in HCV/HIV Co-Infection

BACKGROUND AND AIMS: Hepatitis C Virus (HCV)-related liver disease progresses more rapidly in individuals co-infected with Human Immunodeficiency Virus-1 (HIV), although the underlying immunologic mechanisms are unknown. We examined whether HIV-specific T-cells are identified in the liver of HCV/HIV co-infected individuals and promote liver inflammation through bystander immune responses. METHODS: Ex-vivo intra-hepatic lymphocytes from HCV mono-infected and HCV/HIV co-infected individuals were assessed for immune responses to HIV and HCV antigens by polychromatic flow cytometry. RESULTS: HCV/HIV liver biopsies had similar frequencies of lymphocytes but lower percentages of CD4+ T-cells compared to HCV biopsies. In co-infection, intra-hepatic HIV-specific CD8+ and CD4+ T-cells producing IFN-gamma and TNF-alpha were detected and were comparable in frequency to those that were HCV-specific. In co-infected individuals, viral-specific CD8+ T-cells produced more of the fibrogenic cytokine, TNF-alpha. In both mono- and co-infected individuals, intra-hepatic HCV-specific T-cells were poorly functional compared to HIV-specific T-cells. In co-infection, HAART was not associated with a reconstitution of intra-hepatic CD4+ T-cells and was associated with reduction in both HIV and HCV-specific intra-hepatic cytokine responses. CONCLUSION: The accumulation of functional HIV-specific T-cells in the liver during HCV/HIV co-infection may represent a bystander role for HIV in inducing faster progression of liver disease

A two-step strategy for the complementation of M. tuberculosis mutants

The sequence of Mycobacterium tuberculosis, completed in 1998, facilitated both the development of genomic tools, and the creation of a number of mycobacterial mutants. These mutants have a wide range of phenotypes, from attenuated to hypervirulent strains. These phenotypes must be confirmed, to rule out possible secondary mutations that may arise during the generation of mutant strains. This may occur during the amplification of target genes or during the generation of the mutation, thus constructing a complementation strain, which expresses the wild-type copy of the gene in the mutant strain, becomes necessary. In this study we have introduced a two-step strategy to construct complementation strains using the Ag85 promoter. We have constitutively expressed dosR and have shown dosR expression is restored to wild-type level

Trivalent Adenovirus Type 5 HIV Recombinant Vaccine Primes for Modest Cytotoxic Capacity That Is Greatest in Humans with Protective HLA Class I Alleles

If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B*27, B*57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses

Physiotherapy scoliosis-specific exercises: a comprehensive review of seven major schools

In recent decades, there has been a call for change among all stakeholders involved in scoliosis management. Parents of children with scoliosis have complained about the so-called “wait and see” approach that far too many doctors use when evaluating children’s scoliosis curves between 10° and 25°. Observation, Physiotherapy Scoliosis Specific Exercises (PSSE) and bracing for idiopathic scoliosis during growth are all therapeutic interventions accepted by the 2011 International Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT). The standard features of these interventions are: 1) 3-dimension self-correction; 2) Training activities of daily living (ADL); and 3) Stabilization of the corrected posture. PSSE is part of a scoliosis care model that includes scoliosis specific education, scoliosis specific physical therapy exercises, observation or surveillance, psychological support and intervention, bracing and surgery. The model is oriented to the patient. Diagnosis and patient evaluation is essential in this model looking at a patient-oriented decision according to clinical experience, scientific evidence and patient’s preference. Thus, specific exercises are not considered as an alternative to bracing or surgery but as a therapeutic intervention, which can be used alone or in combination with bracing or surgery according to individual indication. In the PSSE model it is recommended that the physical therapist work as part of a multidisciplinary team including the orthopeadic doctor, the orthotist, and the mental health care provider - all are according to the SOSORT guidelines and Scoliosis Research Society (SRS) philosophy. From clinical experiences, PSSE can temporarily stabilize progressive scoliosis curves during the secondary period of progression, more than a year after passing the peak of growth. In non-progressive scoliosis, the regular practice of PSSE could produce a temporary and significant reduction of the Cobb angle. PSSE can also produce benefits in subjects with scoliosis other than reducing the Cobb angle, like improving back asymmetry, based on 3D self-correction and stabilization of a stable 3D corrected posture, as well as the secondary muscle imbalance and related pain. In more severe cases of thoracic scoliosis, it can also improve breathing function. This paper will discuss in detail seven major scoliosis schools and their approaches to PSSE, including their bracing techniques and scientific evidence. The aim of this paper is to understand and learn about the different international treatment methods so that physical therapists can incorporate the best from each into their own practices, and in that way attempt to improve the conservative management of patients with idiopathic scoliosis. These schools are presented in the historical order in which they were developed. They include the Lyon approach from France, the Katharina Schroth Asklepios approach from Germany, the Scientific Exercise Approach to Scoliosis (SEAS) from Italy, the Barcelona Scoliosis Physical Therapy School approach (BSPTS) from Spain, the Dobomed approach from Poland, the Side Shift approach from the United Kingdom, and the Functional Individual Therapy of Scoliosis approach (FITS) from Poland

First Precambrian palaeomagnetic data from the Mawson Craton (East Antarctica) and tectonic implications

A pilot palaeomagnetic study was conducted on the recently dated with in situ SHRIMP U-Pb method at 1134 ± 9 Ma (U-Pb, zircon and baddeleyite) Bunger Hills dykes of the Mawson Craton (East Antarctica). Of the six dykes sampled, three revealed meaningful results providing the first well-dated Mesoproterozoic palaeopole at 40.5°S, 150.1°E (A95 = 20°) for the Mawson Craton. Discordance between this new pole and two roughly coeval poles from Dronning Maud Land and Coats Land (East Antarctica) demonstrates that these two terranes were not rigidly connected to the Mawson Craton ca. 1134 Ma. Comparison between the new pole and that of the broadly coeval Lakeview dolerite from the North Australian Craton supports the putative ~40° late Neoproterozoic relative rotation between the North Australian Craton and the combined South and West Australian cratons. A mean ca. 1134 Ma pole for the Proto-Australia Craton is calculated by combining our new pole and that of the Lakeview dolerite after restoring the 40° intracontinental rotation. A comparison of this mean pole with the roughly coeval Abitibi dykes pole from Laurentia confirms that the SWEAT reconstruction of Australia and Laurentia was not viable for ca. 1134 Ma

Control of CydB and GltA1 Expression by the SenX3 RegX3 Two Component Regulatory System of Mycobacterium tuberculosis

Two component regulatory systems are used widely by bacteria to coordinate changes in global gene expression profiles in response to environmental signals. The SenX3-RegX3 two component system of Mycobacterium tuberculosis has previously been shown to play a role in virulence and phosphate-responsive control of gene expression. We demonstrate that expression of SenX3-RegX3 is controlled in response to growth conditions, although the absolute changes are small. Global gene expression profiling of a RegX3 deletion strain and wild-type strain in different culture conditions (static, microaerobic, anaerobic), as well as in an over-expressing strain identified a number of genes with changed expression patterns. Among those were genes previously identified as differentially regulated in aerobic culture, including ald (encoding alanine dehydrogenase) cyd,encoding a subunit of the cytochrome D ubiquinol oxidase, and gltA1, encoding a citrate synthase. Promoter activity in the upstream regions of both cydB and gltA1 was altered in the RegX3 deletion strain. DNA-binding assays confirmed that RegX3 binds to the promoter regions of ald, cydB and gltA1 in a phosphorylation-dependent manner. Taken together these data suggest a direct role for the SenX-RegX3 system in modulating expression of aerobic respiration, in addition to its role during phosphate limitation