Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with 'old' polymyxins often being the only available therapeutic ...option. Here, we systematically investigated the structure-activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membrane (OM) model of
and a series of chemically synthesized polymyxin analogs. By integrating chemical biology and all-atom molecular dynamics simulations, we deciphered how each residue of the polymyxin molecule modulated its conformational folding and specific interactions with the bacterial OM. Importantly, a novel designed polymyxin analog FADDI-287 with predicted stronger OM penetration showed improved
antibacterial activity. Collectively, our study provides a novel chemical biology and computational strategy to expedite the discovery of new-generation polymyxins against life-threatening Gram-negative 'superbugs'.
Background Google Flu Trends (GFT) claimed to generate real-time, valid predictions of population influenza-like illness (ILI) using search queries, heralding acclaim and replication across public ...health. However, recent studies have questioned the validity of GFT. Purpose To propose an alternative methodology that better realizes the potential of GFT, with collateral value for digital disease detection broadly. Methods Our alternative method automatically selects specific queries to monitor and autonomously updates the model each week as new information about CDC-reported ILI becomes available, as developed in 2013. Root mean squared errors (RMSEs) and Pearson correlations comparing predicted ILI (proportion of patient visits indicative of ILI) with subsequently observed ILI were used to judge model performance. Results During the height of the H1N1 pandemic (August 2 to December 22, 2009) and the 2012–2013 season (September 30, 2012, to April 12, 2013), GFT’s predictions had RMSEs of 0.023 and 0.022 (i.e., hypothetically, if GFT predicted 0.061 ILI one week, it is expected to err by 0.023) and correlations of r =0.916 and 0.927. Our alternative method had RMSEs of 0.006 and 0.009, and correlations of r =0.961 and 0.919 for the same periods. Critically, during these important periods, the alternative method yielded more accurate ILI predictions every week, and was typically more accurate during other influenza seasons. Conclusions GFT may be inaccurate, but improved methodologic underpinnings can yield accurate predictions. Applying similar methods elsewhere can improve digital disease detection, with broader transparency, improved accuracy, and real-world public health impacts.
Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with 'old' polymyxins often being the only available therapeutic ...option. Here, we systematically investigated the structure-activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membrane (OM) model of
Acinetobacter baumannii
and a series of chemically synthesized polymyxin analogs. By integrating chemical biology and all-atom molecular dynamics simulations, we deciphered how each residue of the polymyxin molecule modulated its conformational folding and specific interactions with the bacterial OM. Importantly, a novel designed polymyxin analog FADDI-287 with predicted stronger OM penetration showed improved
in vitro
antibacterial activity. Collectively, our study provides a novel chemical biology and computational strategy to expedite the discovery of new-generation polymyxins against life-threatening Gram-negative 'superbugs'.
Multidrug-resistant Gram-negative bacteria have been an urgent threat to global public health. Novel antibiotics are desperately needed to combat these 'superbugs'.
The energy-dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5'-AMP-activated protein kinase, a key nutrient sensor for ...maintaining cellular energy status, is a known therapeutic target in Type II diabetes. Despite its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Here we show that AMPKα1 deficiency in the intestine results in weight gain and impaired glucose tolerance under high fat diet feeding, while metformin administration fails to ameliorate these metabolic disorders in intestinal AMPKα1 knockout mice. Further, AMPKα1 in the intestine communicates with brown adipose tissue to promote thermogenesis. Mechanistically, we uncover a link between intestinal AMPKα1 activation and BAT thermogenic regulation through modulating anti-microbial peptide-controlled gut microbiota and the metabolites. Our findings identify AMPKα1-mediated mechanisms of intestine-BAT communication that may partially underlie the therapeutic effects of metformin.
Liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished. Bile acids are important liver products, and their levels are ...tightly regulated. Here, we identify a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. We propose that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.
Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream ...mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (
) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific
knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (
) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat absorption. These findings were verified in sterol 27-hydroxylase (
) knockout mice, which exhibited low intestinal BAs and fat absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and lipid absorption contribute to the metabolic benefits of VSG.
Acute pancreatitis (AP) is a common digestive disease without specific treatment, and its pathogenesis features multiple deleterious amplification loops dependent on translation, triggered by ...cytosolic Ca2+ (Ca2+i) overload; however, the underlying mechanisms in Ca2+ overload of AP remains incompletely understood. Here we show that microRNA-26a (miR-26a) inhibits pancreatic acinar cell (PAC) store-operated Ca2+ entry (SOCE) channel expression, Ca2+ overload, and AP. We find that major SOCE channels are post-transcriptionally induced in PACs during AP, whereas miR-26a expression is reduced in experimental and human AP and correlated with AP severity. Mechanistically, miR-26a simultaneously targets Trpc3 and Trpc6 SOCE channels and attenuates physiological oscillations and pathological elevations of Ca2+i in PACs. MiR-26a deficiency increases SOCE channel expression and Ca2+i overload, and significantly exacerbates AP. Conversely, global or PAC-specific overexpression of miR-26a in mice ameliorates pancreatic edema, neutrophil infiltration, acinar necrosis, and systemic inflammation, accompanied with remarkable improvements on pathological determinants related with Ca2+i overload. Moreover, pancreatic or systemic administration of an miR-26a mimic to mice significantly alleviates experimental AP. These findings reveal a previously unknown mechanism underlying AP pathogenesis, establish a critical role for miR-26a in Ca2+ signaling in the exocrine pancreas, and identify a potential target for the treatment of AP.
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Du and colleagues identified microRNA-26a as a crucial checkpoint for calcium overload in pancreatic acinar cells, the central event that induces acute pancreatitis, a common digestive disease without specific treatment, providing a previously unknown mechanism underlying acute pancreatitis pathogenesis and a novel therapeutic option for this disease.
•The etiological characteristics of different age groups should be considered for prevention.•The prehospital emergency burn care in China is relatively unsatisfactory at present.•BI can be a ...reliable prognostic factor in severely burned patients.•The BI of 29 in the 0–14 years, 43.5 in the 15–59 years and 35.5 in the ≧60 years group are the threshold for mortality.•A large BI, elderly age, delayed admission and inhalation injury are the main risk factors for death.
Epidemiological features of massively burned patients in China remains unclear. This study was designed to investigate the epidemiological characteristics and evaluate the burn index (BI) and other risk factors associated with the prognosis of massively burned patients.
Data of patients with ≥30% total body surface area burned admitted in 2014 were retrieved from 106 burn centers in the mainland of China. Information of epidemiological features and the outcome were collected for retrospective analysis.
A total of 2483 massively burned patients were included in this study, with a male-to-female ratio of 2.29:1, the mean age of 49.23±16.67 years, mean TBSA of 55.53±21.39% and the mean BI of 39.75±21.59. Scald accounted for 81.07% of the injuries in children, while flame accounted for 66.89% and 74.31% of the injuries in adults and seniors. Approximately 17.76% of the patients were admitted to the local burn center after 6h of injury, and the wound areas of 1154 (46.48%) patients were covered with folk remedies. The mortality was 9.79%, and the area under the receiver operating characteristic (ROC) curve for BI was 0.941 (95% CI, 0.929–0.954). When the value of BI was above a threshold of 29 in the 0–14 years age group, 43.5 in the 15–59 years age group and 35.5 in the 60 years or older age group, the mortality increased significantly. Multivariate logistic regression analyses showed that the odds ratio (OR) of death increased 6% with an increase in the BI of 1.0. Patients older than 60 years, the admission time longer than 6h after-injury (adjusted OR, 1.797; 95% CI, 1.179–2.740; adjusted p<0.001), and patients with a combined inhalation injury (adjusted OR, 6.649; 95% CI, 4.517–9.789; adjusted p<0.000), were at higher risk of death.
There are etiological characteristics of the different age groups that should be considered for prevention. BI can be a reliable index of prognosis in severely burned patients. The results of the study showed that a large BI, elderly age, delayed admission after injury and combined inhalation injury are the main risk factors for extensively burned patients.
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this ...study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ
mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuates the compensatory proliferation of hepatocytes in CAMK2γ
livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
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