Lipoproteins are important for bacterial growth and antibiotic resistance. These proteins use lipid acyl chains attached to the N-terminal cysteine residue to anchor on the outer surface of ...cytoplasmic membrane. In Gram-negative bacteria, many lipoproteins are transported to the outer membrane (OM), a process dependent on the ATP-binding cassette (ABC) transporter LolCDE which extracts the OM-targeted lipoproteins from the cytoplasmic membrane. Lipid-anchored proteins pose a unique challenge for transport machinery as they have both hydrophobic lipid moieties and soluble protein component, and the underlying mechanism is poorly understood. Here we determined the cryo-EM structures of nanodisc-embedded LolCDE in the nucleotide-free and nucleotide-bound states at 3.8-Å and 3.5-Å resolution, respectively. The structural analyses, together with biochemical and mutagenesis studies, uncover how LolCDE recognizes its substrate by interacting with the lipid and N-terminal peptide moieties of the lipoprotein, and identify the amide-linked acyl chain as the key element for LolCDE interaction. Upon nucleotide binding, the transmembrane helices and the periplasmic domains of LolCDE undergo large-scale, asymmetric movements, resulting in extrusion of the captured lipoprotein. Comparison of LolCDE and MacB reveals the conserved mechanism of type VII ABC transporters and emphasizes the unique properties of LolCDE as a molecule extruder of triacylated lipoproteins.
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have ...characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
Non-coding RNA (ncRNA) plays a regulatory role in a variety of cellular activities. And long non-coding RNA (lncRNA) is one of the important kinds of ncRNA. Previous studies have shown that various ...lncRNAs are involved in the progression of cancer. LncRNA plasmacytoma variant translocation 1 (PVT1) is a newly discovered oncogenic factor that has been confirmed to be overexpressed in many cancer cells. Moreover, the role of PVT1 in cancer development is closely linked to microRNAs (miRNAs). PVT1 can act as a "sponge" for miRNAs to inhibit their activities, thereby affecting proliferation, invasion, and angiogenesis of cancer. In addition, PVT1 itself can be spliced and processed into several miRNAs such as miR-1204 and miR-1207, which can also regulate the development of cancer. This review summarizes various pathways through which PVT1 regulates the progression of cancer via miRNAs. We also propose additional regulatory mechanisms of PVT1 and their potential clinical applications.
Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8
...immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8
immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8
immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.
Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane ...Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2
, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.
Purpose
Miliary pulmonary tuberculosis (TB) among pregnant women after
in vitro
fertilization embryo transfer (IVF-ET) causes poor outcomes but is rarely reported. This study analyzed the clinical ...characteristics and risk factors of these patients to provide hints for further studies.
Method
The demographic characteristics, clinical manifestations, radiologic features, treatment, and outcomes of six patients diagnosed from May 2012 to August 2021 in Xiangya Hospital and 69 patients that were reported in English or Chinese literature from January 1980 to August 2021 were retrospectively analyzed. Continuous variables were compared between groups by
t
-test or
Mann–Whitney U
test, and categorical variables were compared between groups by
chi-square
test or
Fisher exact
test.
Univariate and multiple logistic regression
analyses were used to determine the predictors of respiratory failure.
Results
A total of 75 patients were included. The average age of patients was about 30 years. All patients had tubal obstruction; 5 of them were diagnosed with pelvic TB before. Thirteen cases had a history of pulmonary or extrapulmonary TB, six out of them without any antituberculosis treatment history. All patients were in their first or second trimester during the onset of symptoms. The average interval between onset of symptoms and radiologic examination was about 21 days. The most common abnormalities on chest computed tomography scan were multiple nodules, pulmonary infiltrate, and consolidation. Merely 10 patients obtained bacteriological diagnosis by
Mycobacterium tuberculosis
culture or polymerase chain reaction test. The other patients were clinically diagnosed. All the patients received antituberculosis treatment. Although 44% of patients had fatal complications, all cases were cured or improved after antituberculosis treatment. Unfortunately, only eight fetuses survived (10.6%). The most frequent and severe complication was type I respiratory failure (20%). Patients with expectoration, dyspnea, coarse breath sounds, ground-glass opacity, and pulmonary infiltrate or consolidation were more likely to have respiratory failure (
P
< 0.05). Ground-glass opacity (OR = 48.545, 95% CI = 2.366–995.974,
P
= 0.012) and pulmonary infiltrate or consolidation (OR = 19.943, 95% CI = 2.159–184.213,
P
= 0.008) were independent predictors for respiratory failure.
Conclusion
Tube infertility with underscreened or untreated TB is a risk factor for miliary TB during pregnancy after IVF-ET. Ground-glass opacity and pulmonary infiltrate or consolidation are predictors of respiratory failure. We demonstrate risk factors for incidence and complications to supply clues for future intervention and improve patient prognosis.
Paeniclostridium sordellii lethal toxin (TcsL) is a potent exotoxin that causes lethal toxic shock syndrome associated with fulminant bacterial infections. TcsL belongs to the large clostridial toxin ...(LCT) family. Here, we report that TcsL with varied lengths of combined repetitive oligopeptides (CROPs) deleted show increased autoproteolysis as well as higher cytotoxicity. We next present cryo-EM structures of full-length TcsL, at neutral (pH 7.4) and acidic (pH 5.0) conditions. The TcsL at neutral pH exhibits in the open conformation, which resembles reported TcdB structures. Low pH induces the conformational change of partial TcsL to the closed form. Two intracellular interfaces are observed in the closed conformation, which possibly locks the cysteine protease domain and hinders the binding of the host receptor. Our findings provide insights into the structure and function of TcsL and reveal mechanisms for CROPs-mediated modulation of autoproteolysis and cytotoxicity, which could be common across the LCT family.
Since the 2008 financial crisis, it is an important issue to assess the systemic risk of banks, but there is a lack of research on the assessment of the systemic risk of Turkey’s financial system. In ...addition, geometric Brownian motion is used in most of the assessment frameworks of systemic risk under the normal financial market state, while the Turkish financial market has the situation of spike and thick tail. Therefore, this paper proposes a fractional Brownian motion measurement framework of systemic risk to study the systemic risk of the Turkish financial system. Firstly, this paper uses the data of 11 Turkish listed banks from 2014 to 2019 to conduct a normality test and demonstrate that its market has the characteristics of a fractal market; that is, there is a spike and thick tail distribution phenomenon in the stock price trend. Then, this paper proposes a fractional Brownian motion systemic risk measurement framework (fBSM). Based on the proposed theoretical framework and the actual data of Turkish listed banks from 2014 to 2019, a dynamically evolving Turkish banking network system is constructed to measure the systemic risk in the Turkish banking system. The research results find that the systemic risk is the highest in 2017, which then improved and gradually recovered. In addition, when analyzing the sensitivity of the Hurst index, it shows that with the increase in Hurst index, the Hurst index elasticity of Turkish banks’ asset value increases gradually and the asset value also increases continuously. Hence, the Hurst index has a greater impact on asset value. Therefore, the measurement framework of systemic risk based on the fBSM can better monitor the systemic risk than the traditional geometric Brownian motion in the Turkish banking system.
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