The impact of global climate change on genetic diversity within populations and species

Genetic diversity provides the basic substrate for evolution, yet few studies assess the impacts of global climate change (GCC) on intraspecific genetic variation. In this review, we highlight the importance of incorporating neutral and non‐neutral genetic diversity when assessing the impacts of GCC, for example, in studies that aim to predict the future distribution and fate of a species or ecological community. Specifically, we address the following questions: Why study the effects of GCC on intraspecific genetic diversity? How does GCC affect genetic diversity? How is the effect of GCC on genetic diversity currently studied? Where is potential for future research? For each of these questions, we provide a general background and highlight case studies across the animal, plant and microbial kingdoms. We further discuss how cryptic diversity can affect GCC assessments, how genetic diversity can be integrated into studies that aim to predict species' responses on GCC and how conservation efforts related to GCC can incorporate and profit from inclusion of genetic diversity assessments. We argue that studying the fate of intraspecifc genetic diversity is an indispensable and logical venture if we are to fully understand the consequences of GCC on biodiversity on all levels.     

Delta-sleep-inducing peptide (DSIP): An update

The isolation and characterization of delta-sleep-inducing peptide (DSIP) achieved from 1963 to 1977 were reviewed in 1984. The first reports describing sleep as well as extra-sleep effects of DSIP also were included in that work. Only two years later, much additional literature concerning DSIP has accumulated. Besides further sleep-inducing and/or-supporting effects of DSIP in animals, considerable work has been carried out to evaluate the potential use of the peptide for therapeutic purposes such as treatment of insomnia, pain, and withdrawal. Immunohistochemical as well as radioimmunochemical studies provided further insights into the natural occurrence of the nonapeptide and the distribution of DSIP-like material in the body, suggesting possible relations of the peptide to certain diseases. Various physiological functions of DSIP and a possible mechanism of action involving the modulation of adrenergic transmission remain to be established.     

On justifying arguments of species membership

In the debate about the moral status of human beings at the margins of life, arguments of species membership are often considered to be the least plausible ones. Against this backdrop, this article explores two possible ways to formulate feasible arguments of species membership. The first is an (in the broadest sense of the word) Aristotelian or neo-Aristotelian argument; the second is an argument from the intrinsic logic of human rights, which Robert Spaemann refers toas a ‘transcendental-pragmatic’ argument. On these grounds, the article proposes a philosophical justification for an at least moderate speciesism.     

Classification of the Gut Microbiota of Patients in Intensive Care Units During Development of Sepsis and Septic Shock

The gut microbiota of intensive care unit (ICU) patients displays extreme dysbiosis associated with increased susceptibility to organ failure, sepsis, and septic shock. However, such dysbiosis is difficult to characterize owing to the high dimensional complexity of the gut microbiota. We tested whether the concept of enterotype can be applied to the gut microbiota of ICU patients to describe the dysbiosis. We collected 131 fecal samples from 64 ICU patients diagnosed with sepsis or septic shock and performed 16S rRNA gene sequencing to dissect their gut microbiota compositions. During the development of sepsis or septic shock and during various medical treatments, the ICU patients always exhibited two dysbiotic microbiota patterns, or ICU-enterotypes, which could not be explained by host properties such as age, sex, and body mass index, or external stressors such as infection site and antibiotic use. ICU-enterotype I (ICU E1) comprised predominantly Bacteroides and an unclassified genus of Enterobacteriaceae, while ICU-enterotype II (ICU E2) comprised predominantly Enterococcus. Among more critically ill patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores > 18, septic shock was more likely to occur with ICU E1 (P = 0.041). Additionally, ICU E1 was correlated with high serum lactate levels (P = 0.007). Therefore, different patterns of dysbiosis were correlated with different clinical outcomes, suggesting that ICU-enterotypes should be diagnosed as independent clinical indices. Thus, the microbial-based human index classifier we propose is precise and effective for timely monitoring of ICU-enterotypes of individual patients. This work is a first step toward precision medicine for septic patients based on their gut microbiota profiles.     

FDPS promotes glioma growth and macrophage recruitment by regulating CCL20 via Wnt/β‐catenin signalling pathway

Glioma is one of the most lethal tumours and common malignant in the central nervous system (CNS), which exhibits diffuse invasion and aggressive growth. Several studies have reported the association of FDPS to tumour development and progression. However, the role of FDPS in progression of glioma and macrophage recruitment is not well‐elucidated. In the current study, a remarkable enhancement in FDPS level was observed in glioma tissues and associated with poor prognosis, contributed to tumour growth. FDPS was correlated with macrophage infiltration in glioma and pharmacological deletion of macrophages largely abrogated the oncogenic functions of FDPS in glioma. Mechanistically, FDPS activated Wnt/β‐catenin signalling pathway and ultimately facilitates macrophage infiltration by inducing CCL20 expression. In conclusion, overexpressed FDPS exhibits an immunomodulatory role in glioma. Therefore, targeting FDPS may be an effective therapeutic strategy for glioma.     

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

Interleukin‐10 (IL‐10) displays well‐documented anti‐inflammatory effects, but its effects on osteoblast differentiation have not been investigated. In this study, we found IL‐10 negatively regulates microRNA‐7025‐5p (miR‐7025‐5p), the down‐regulation of which enhances osteoblast differentiation. Furthermore, through luciferase reporter assays, we found evidence that insulin‐like growth factor 1 receptor (IGF1R) is a miR‐7025‐5p target gene that positively regulates osteoblast differentiation. In vivo studies indicated that the pre‐injection of IL‐10 leads to increased bone formation, while agomiR‐7025‐5p injection delays fracture healing. Taken together, these results indicate that IL‐10 induces osteoblast differentiation via regulation of the miR‐7025‐5p/IGF1R axis. IL‐10 therefore represents a promising therapeutic strategy to promote fracture healing.     

Use of Tregs as a cell‐based therapy via CD39 for benign prostate hyperplasia with inflammation

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg‐associated cytokine production. Sorted CD39^+/? Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL‐10, IL‐35 and TGF‐β. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down‐regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39‐ Tregs in mice, however, CD39⁺Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL‐1β and PSA secretion, and increasing IL‐10 and TGF‐β secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.     

Protein Kinase D3 promotes the cell proliferation by activating the ERK1/c‐MYC axis in breast cancer

Breast cancer is the second leading death cause of cancer death for all women. Previous study suggested that Protein Kinase D3 (PRKD3) was involved in breast cancer progression. In addition, the protein level of PRKD3 in triple‐negative breast adenocarcinoma was higher than that in normal breast tissue. However, the oncogenic mechanisms of PRKD3 in breast cancer is not fully investigated. Multi‐omic data showed that ERK1/c‐MYC axis was identified as a major pivot in PRKD3‐mediated downstream pathways. Our study provided the evidence to support that the PRKD3/ERK1/c‐MYC pathway play an important role in breast cancer progression. We found that knocking out PRKD3 by performing CRISPR/Cas9 genome engineering technology suppressed phosphorylation of both ERK1 and c‐MYC but did not down‐regulate ERK1/2 expression or phosphorylation of ERK2. The inhibition of ERK1 and c‐MYC phosphorylation further led to the lower protein level of c‐MYC and then reduced the expression of the c‐MYC target genes in breast cancer cells. We also found that loss of PRKD3 reduced the rate of the cell proliferation in vitro and tumour growth in vivo, whereas ectopic (over)expression of PRKD3, ERK1 or c‐MYC in the PRKD3‐knockout breast cells reverse the suppression of the cell proliferation and tumour growth. Collectively, our data strongly suggested that PRKD3 likely promote the cell proliferation in the breast cancer cells by activating ERK1‐c‐MYC axis.     

Reduction of SOST gene promotes bone formation through the Wnt/β-catenin signalling pathway and compensates particle-induced osteolysis

The increase in bone resorption and/or the inhibition of bone regeneration caused by wear particles are the main causes of periprosthetic osteolysis. The SOST gene and Sclerostin, a protein synthesized by the SOST gene, are the characteristic marker of osteocytes and regulate bone formation and resorption. We aimed to verify whether the SOST gene was involved in osteolysis induced by titanium (Ti) particles and to investigate the effects of SOST reduction on osteolysis. The results showed osteolysis on the skull surface with an increase of sclerostin levels after treated with Ti particles. Similarly, sclerostin expression in MLO-Y4 osteocytes increased when treated with Ti particles in vitro. After reduction of SOST, local bone mineral density and bone volume increased, while number of lytic pores on the skull surface decreased and the erodibility of the skull surface was compensated. Histological analyses revealed that SOST reduction increased significantly alkaline phosphatase- (ALP) and osterix-positive expression on the skull surface which promoted bone formation. ALP activity and mineralization of MC3T3-E1 cells also increased in vitro when SOST was silenced, even if treated with Ti particles. In addition, Ti particles decreased β-catenin expression with an increase in sclerostin levels, in vivo and in vitro. Inversely, reduction of SOST expression increased β-catenin expression. In summary, our results suggested that reduction of SOST gene can activate the Wnt/β-catenin signalling pathway, promoting bone formation and compensated for bone loss induced by Ti particles. Thus, this study provided new perspectives in understanding the mechanisms of periprosthetic osteolysis.