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AIM: Climate is widely recognized as a major predictor of species richness patterns along large‐scale environmental gradients. Nevertheless, the mechanisms by which climate influences species richness are still a matter of debate. We disentangle whether climate influences species richness of birds directly via physiological limitations or indirectly via vegetation structure or the availability of food resources. LOCATION: Mount Kilimanjaro, Tanzania. METHODS: We recorded bird species richness along an elevational gradient from 870 to 4550 m a.s.l. We quantified local climatic conditions, vegetation structure and the availability of food resources, and applied path analysis to disentangle their direct and indirect effects on species richness of all birds, frugivores and insectivores. RESULTS: Overall, we recorded 2945 individuals from 114 bird species. Species richness of all birds was closely correlated with temperature, vegetation structure and invertebrate biomass and both direct and indirect (via vegetation structure and availability of food resources) climatic effects were important for the diversity of the whole, trophically heterogeneous bird community. The species richness of insectivorous birds was linked to vegetation structure and invertebrate biomass, while the richness of frugivores was strongly associated with fruit abundance. Climatic factors influenced bird species richness of both avian feeding guilds exclusively indirectly via vegetation structure and availability of food resources. MAIN CONCLUSIONS: We reveal the importance of trophic interactions for generating species richness patterns along large‐scale environmental gradients. Our results challenge the general assumption that temperature and water availability influence species richness mostly directly, and underscore the importance of vegetation structure and the availability of food resources as principal mediators of climatic effects on species richness patterns on macroecological scales.

Dry eye disease (DED) is one of the most prevalent and distressing ocular conditions worldwide; it primarily results from alterations in the natural tear film that covers the ocular surface and is often due to enhanced evaporation of its aqueous component. This process is frequently associated with dysfunction of the meibomian glands (MGs), which are embedded within the tarsal plate of our eyelids and secrete the meibum, an oily mixture of proteins and lipids. Meibum forms the outermost layer of the tear film, playing a critical role in controlling water evaporation and stabilizing the tear film by lowering surface tension. Meibomian gland dysfunction (MGD) may result from structural abnormalities in the MGs, such as tortuosity, which impair normal delivery of meibum. Increased laxity of the eyelid is also associated with development of MGD and DED, likely due to insufficient mechanical support for the glands, and causing morphological changes. We designed and initiated the development of a noninvasive method to strengthen and stiffen the tarsal collagen containing the embedded MGs. By reducing tissue laxity, our aim is to halt further morphological deterioration of the glands and promote uniform and smooth delivery of meibum to the ocular surface. Our previous studies showed that both mechanical tensile strength and rigidity (Young's modulus) of tarsal collagen in animal and human eyelids were significantly enhanced by exposure to ultraviolet-A (UV-A) radiation with a wavelength of 365 nm in the presence of riboflavin as a photosensitizer. We propose that performing this procedure at the initial manifestations of MGD and DED may prevent disease progression by restoring and preserving the normal morphology of the glands through reduced laxity, thereby ensuring proper secretion of the meibum into the tear film. The underlying principles and safety of the procedure were discussed in detail, and further pre-clinical evaluation steps were proposed and justified. Based on the proposed concept and the results of previous ex-vivo studies, in-vivo animal experiments and human clinical trials are currently in preparation.

Tumor microenvironment infiltration by cells of the T helper cell type 1 (TH1) system, including TH1 cells, M1 macrophages, natural killer cells, and CD8+ T cells, is associated with better cancer prognosis. In contrast, tumor microenvironment infiltration by cells of the TH2 system, including TH2 cells, M2 macrophages, and innate lymphoid cells type 2, as well as immune suppressive myeloid-derived suppressor cells and regulatory T cells, is associated with poorer cancer prognosis. Beyond the tumor itself and a myriad of other modifying factors, such as genetic and epigenetic influences on tumorigenesis, the overall immune state of the patient, termed the macroenvironment, has also been shown to significantly influence cancer outcomes. Alterations in the tricarboxylic acid (TCA) cycle (TCA cycle breaks) involving loss of function of succinate dehydrogenase, isocitrate dehydrogenase, and fumarate hydratase have been shown to be associated with an intracellular metabolic shift away from oxidative phosphorylation and into glycolysis in cells that are transforming into cancer cells. The same loss of function of succinate dehydrogenase and isocitrate dehydrogenase has also been identified as inducing a shift in macrophages toward glycolysis that is associated with M1 macrophage polarization. M1 macrophages make interleukin 12, which stimulates TH1 cells and natural killer cells to produce interferon gamma (IFN-γ), which in turn stimulates M1 macrophage activity, forming an activation loop. IFN-γ also drives activation of CD8+ T cells. Thus, M1 macrophage activation initiates and sustains activation of the TH1 system of cells. In this fashion, TCA cycle breaks at succinate dehydrogenase and isocitrate dehydrogenase that promote cellular transformation into cancer cells are also associated with upregulation of the TH1 system that provides anti-cancer immune surveillance. The TH1 and TH2 systems are known to inhibit each other's activation. It is this author's hypothesis that, in patients whose macroenvironment is sufficiently TH2-dominant, the metabolic shift toward glycolysis induced by TCA cycle breaks that gives rise to mutagenic changes in tissue parenchymal cells is not counterbalanced by adequate activation of M1 macrophages, thus giving rise to cancer cell development. For instance, the atopic TH2-high asthma phenotype, a TH2 dominance-based comorbidity, is associated with a more than doubled incidence of colon, breast, lung, and prostate cancer, compared with non-asthmatics. Failure of TCA cycle breaks to induce M1 polarization of tissue-resident macrophages yields a tissue environment in which the tissue-resident macrophages fail to routinely perform M1-associated functions such as phagocytizing newly developing cancer cells. Failure of M1 phenotypic expression in both tissue-resident macrophages and monocyte-derived macrophages recruited to the tumor microenvironment yields both a loss of direct antitumor M1 macrophage actions and failure of TH1 system activation in general, including failure of CD8+ T cell activation, yielding a cancer-permissive tumor microenvironment and a poorer prognosis in patients with existing cancers. This paper proposes a conceptual framework that connects established elements in the existing research and points to the utility of a patient profiling process, aimed at personalization of treatment through identification and targeting of elements in each patient's tumor microenvironment and macroenvironment that contribute to unfavorable prognosis.Tumor microenvironment infiltration by cells of the T helper cell type 1 (TH1) system, including TH1 cells, M1 macrophages, natural killer cells, and CD8+ T cells, is associated with better cancer prognosis. In contrast, tumor microenvironment infiltration by cells of the TH2 system, including TH2 cells, M2 macrophages, and innate lymphoid cells type 2, as well as immune suppressive myeloid-derived suppressor cells and regulatory T cells, is associated with poorer cancer prognosis. Beyond the tumor itself and a myriad of other modifying factors, such as genetic and epigenetic influences on tumorigenesis, the overall immune state of the patient, termed the macroenvironment, has also been shown to significantly influence cancer outcomes. Alterations in the tricarboxylic acid (TCA) cycle (TCA cycle breaks) involving loss of function of succinate dehydrogenase, isocitrate dehydrogenase, and fumarate hydratase have been shown to be associated with an intracellular metabolic shift away from oxidative phosphorylation and into glycolysis in cells that are transforming into cancer cells. The same loss of function of succinate dehydrogenase and isocitrate dehydrogenase has also been identified as inducing a shift in macrophages toward glycolysis that is associated with M1 macrophage polarization. M1 macrophages make interleukin 12, which stimulates TH1 cells and natural killer cells to produce interferon gamma (IFN-γ), which in turn stimulates M1 macrophage activity, forming an activation loop. IFN-γ also drives activation of CD8+ T cells. Thus, M1 macrophage activation initiates and sustains activation of the TH1 system of cells. In this fashion, TCA cycle breaks at succinate dehydrogenase and isocitrate dehydrogenase that promote cellular transformation into cancer cells are also associated with upregulation of the TH1 system that provides anti-cancer immune surveillance. The TH1 and TH2 systems are known to inhibit each other's activation. It is this author's hypothesis that, in patients whose macroenvironment is sufficiently TH2-dominant, the metabolic shift toward glycolysis induced by TCA cycle breaks that gives rise to mutagenic changes in tissue parenchymal cells is not counterbalanced by adequate activation of M1 macrophages, thus giving rise to cancer cell development. For instance, the atopic TH2-high asthma phenotype, a TH2 dominance-based comorbidity, is associated with a more than doubled incidence of colon, breast, lung, and prostate cancer, compared with non-asthmatics. Failure of TCA cycle breaks to induce M1 polarization of tissue-resident macrophages yields a tissue environment in which the tissue-resident macrophages fail to routinely perform M1-associated functions such as phagocytizing newly developing cancer cells. Failure of M1 phenotypic expression in both tissue-resident macrophages and monocyte-derived macrophages recruited to the tumor microenvironment yields both a loss of direct antitumor M1 macrophage actions and failure of TH1 system activation in general, including failure of CD8+ T cell activation, yielding a cancer-permissive tumor microenvironment and a poorer prognosis in patients with existing cancers. This paper proposes a conceptual framework that connects established elements in the existing research and points to the utility of a patient profiling process, aimed at personalization of treatment through identification and targeting of elements in each patient's tumor microenvironment and macroenvironment that contribute to unfavorable prognosis.

A The author's comprehensive evaluation of the biochemical metabolomic literature over more than 40 years discusses multiple studies documenting abnormal elevations of the neurotransmitter dopamine and its metabolites as well as inhibitors of dopamine beta hydroxylase (DBH) from Clostridia bacteria in urine samples and cerebrospinal fluid samples of children with autism. The evaluation intends to elucidate the reasons for the elevation of dopamine and its metabolites in urine and their relationship to increased Clostridia colonization of the gastrointestinal tract in children with autism. In addition, to the evaluation of Clostridia metabolism and its effects on abnormal dopamine metabolism in autism, a secondary aim intends to demonstrate as a hypothesis that one particular metabolite of Clostridia bacteria-3-hydroxy-(3-hydroxyphenyl)- 3-hydroxypropionic acid (HPHPA)-may cause even more severe effects on in autism than other metabolites by leading to depletion of free coenzyme A (CoASH). This depletion of free Coenzyme A leads to a deficiency of cholesterol and activated palmitic acid needed for activation of the key brain developmental protein sonic hedgehog, which has recently been research has shown to be severely abnormal in severe autism. Laboratories throughout the world have consistently found high quantities of HPHPA and 4-cresol in high percentages of urine samples of children with autism. Those inhibitors, which intestinal Clostridia bacteria produce, cause an elevation in dopamine and its metabolites, which affect the brain's and the sympathetic nervous system's key enzyme dopamine-beta-hydroxylase (DBH). Excessive dopamine and its toxic metabolites due to these DBH inhibitors may cause brain damage due to excessive unstable dopamine quinones, toxic adducts of dopamine disrupting brain mitochondrial energy production, and oxygen superoxide. HPHPA, a short chain phenyl compound, may have additional biochemical effects on the brain in autism, causing a reduction in free CoASH needed to produce the CoA palmitic acid derivative necessary to activate the key brain developmental protein sonic hedgehog. The depletion of CoASH appears to be a new therapeutic target to reverse the adverse effects of the HPHPA metabolite on the beta oxidation of fatty acids and cholesterol synthesis that are prevalent in autism. Variations in the severity of autism could be based on the types and concentrations of the Clostridia markers produced and the extent to which these markers, such as HPHPA, have depleted critical lipids, such as cholesterol and CoA palmitic acid derivative. Patients need those lipids for the activation of the developmental protein sonic hedgehog. In addition, the sequestration of coenzyme A by short chain adducts of Clostridia leads to the depletion of critical free CoASH, needed throughout intermediary metabolism, and creates a biochemical storm that especially affects brain function.