Carbapenem-resistant Gram-negative bacteria (CR-GNB) in ICUs: resistance genes, therapeutics, and prevention - a comprehensive review.

Intensive care units (ICUs) are specialized environments dedicated to the management of critically ill patients, who are particularly susceptible to drug-resistant bacteria. Among these, carbapenem-resistant Gram-negative bacteria (CR-GNB) pose a significant threat endangering the lives of ICU patients. Carbapenemase production is a key resistance mechanism in CR-GNB, with the transfer of resistance genes contributing to the extensive emergence of antimicrobial resistance (AMR). CR-GNB infections are widespread in ICUs, highlighting an urgent need for prevention and control measures to reduce mortality rates associated with CR-GNB transmission or infection. This review provides an overview of key aspects surrounding CR-GNB within ICUs. We examine the mechanisms of bacterial drug resistance, the resistance genes that frequently occur with CR-GNB infections in ICU, and the therapeutic options against carbapenemase genotypes. Additionally, we highlight crucial preventive measures to impede the transmission and spread of CR-GNB within ICUs, along with reviewing the advances made in the field of clinical predictive modeling research, which hold excellent potential for practical application.

Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors.

Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.

CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation.

Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC.

Advances in Traditional Chinese Medicine research in diabetic kidney disease treatment.

CONTEXT: Diabetic kidney disease (DKD) is a prominent complication arising from diabetic microangiopathy, and its prevalence and renal impact have placed it as the primary cause of end-stage renal disease. Traditional Chinese Medicine (TCM) has the distinct advantage of multifaceted and multilevel therapeutic attributes that show efficacy in improving clinical symptoms, reducing proteinuria, protecting renal function, and slowing DKD progression. Over recent decades, extensive research has explored the mechanisms of TCM for preventing and managing DKD, with substantial studies that endorse the therapeutic benefits of TCM compounds and single agents in the medical intervention of DKD. OBJECTIVE: This review lays the foundation for future evidence-based research efforts and provide a reference point for DKD investigation. METHODS: The relevant literature published in Chinese and English up to 30 June 2023, was sourced from PubMed, Cochrane Library, VIP Database for Chinese Technical Periodicals (VIP), Wanfang Data, CNKI, and China Biology Medicine disc (CBM). The process involved examining and summarizing research on TCM laboratory tests and clinical randomized controlled trials for DKD treatment. RESULTS AND CONCLUSIONS: The TCM intervention has shown the potential to inhibit the expression of inflammatory cytokines and various growth factors, lower blood glucose levels, and significantly affect insulin resistance, lipid metabolism, and improved renal function. Furthermore, the efficacy of TCM can be optimized by tailoring personalized treatment regimens based on the unique profiles of individual patients. We anticipate further rigorous and comprehensive clinical and foundational investigations into the mechanisms underlying the role of TCM in treating DKD.

Construction of a Cu2+-Responsive NIR Fluorescent Probe and the Preliminary Evaluation of its Multifunctional Application.

Cu2+ was deemed as toxic and the most common heavy metal pollution in the water and food. Meanwhile, endogenous Cu2+ was deeply involved in plenty of physiological and pathological processes of human. Cu2+ imbalance was related to multiple diseases. Here we developed a Cu2+-responsive NIR probe HX, which not only demonstrated obvious color change when subjected to Cu2+, but also showed linear-dependent NIR fluorescence emission to Cu2+ concentration for Cu2+ detection and quantification both in vitro and in vivo. When HX was applied to imaging Cu2+ in the cell or living animals, intracellular Cu2+ fluctuation and Cu2+ accumulation in the liver could be visualized to indicate the copper level in the cell or organs with low background signals. Meanwhile, by applying HX to monitor Cu2+ uptake in the tumor, copper transporter function could be evaluated to screen the patient who are sensitivity to platinum drug.

Application of Mid-Pancreatectomy with End-to-End Anastomosis in Pancreatic Benign Tumors.

Mid-pancreatectomy combined with end-to-end anastomosis is a surgical procedure used to treat benign pancreatic tumors. It involves removing the tumor from the middle section of the pancreas and connecting the proximal and distal ends through an anastomosis. The traditional surgical approach for resecting the middle segment of the pancreas involves closing the proximal pancreas and creating a Roux-en-Y anastomosis with the jejunum. However, this approach carries a double risk of pancreatic stump fistula and pancreatico enteric anastomotic leak postoperatively. In this paper, a new procedure is described where stent tubes were placed into the proximal and distal sides of the pancreatic ducts after ensuring sufficient freedom from the proximal distal pancreas. The pancreatic parenchyma was then sutured continuously under direct vision to achieve pancreatic end-to-end anastomosis. This procedure helps preserve pancreatic function, reducing the risk of postoperative pancreatic insufficiency. However, due to the complexity and risks involved, thorough evaluation and preparation are necessary before surgery. We carefully assess the patient's history, serology, and imaging results to determine the feasibility and effectiveness of the procedure. During surgery, we consider the use of a suitable pancreatic duct stent to ensure the flow of pancreatic juice into the intestine through physiological pathways. Our goal is to remove the tumor while preserving as much normal pancreatic tissue as possible for the anastomosis. After the operation, it is crucial to monitor the patient's pancreatic function, paying close attention to blood glucose levels, drainage fluid volume, and amylase value of the pancreatic anastomosis. During the postoperative follow-up visit, the patient's pancreatic function was assessed, and there was no significant change in quality of life compared to before the surgery. This indicates that mid-pancreatectomy combined with end-to-end anastomosis is a safe and effective procedure for treating pancreatic benign neoplasms.

Laparoscopic Duodenum-Preserving Pancreatic Head Resection via Inferior Infracolic Approach: A Surgical Approach for Benign Lesions.

Minimally invasive pancreatic resections are gaining popularity despite being technically demanding. However, in contrast to laparoscopic pancreatoduodenectomy (LPD), laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) has not yet obtained wide acceptance. This could be attributed to the technical challenges involved in preserving the blood supply of the duodenum and bile duct. This study describes and demonstrates all the steps of LDPPHR. A 48-year-old woman was diagnosed with a 3.0 cm x 2.5 cm pancreatic head cystic mass, which was detected unexpectedly. The surgery was performed using the 3D laparoscopy via an inferior infracolic approach. The operation lasted approximately 310 min with 100 mL of blood loss. Postoperatively, the patient experienced no complications and was discharged 5 days later. Pathology revealed intraductal papillary mucinous neoplasms. LDPPHR via an inferior infracolic approach is feasible and safe when performed by experienced surgeons in selected patients with thin mesenteric fat layers. The described technique for LDPPHR via inferior infracolic approach should be well standardized and performed at high-volume centers with experienced surgeons in both open and laparoscopic pancreatology.

Enhanced cisplatin chemotherapy sensitivity by self-assembled nanoparticles with Olaparib.

Cisplatin (CDDP) is widely used as one kind of chemotherapy drugs in cancer treatment. It functions by interacting with DNA, leading to the DNA damage and subsequent cellular apoptosis. However, the presence of intracellular PARP1 diminishes the anticancer efficacy of CDDP by repairing DNA strands. Olaparib (OLA), a PARP inhibitor, enhances the accumulation of DNA damage by inhibiting its repair. Therefore, the combination of these two drugs enhances the sensitivity of CDDP chemotherapy, leading to improved therapeutic outcomes. Nevertheless, both drugs suffer from poor water solubility and limited tumor targeting capabilities. To address this challenge, we proposed the self-assembly of two drugs, CDDP and OLA, through hydrogen bonding to form stable and uniform nanoparticles. Self-assembled nanoparticles efficiently target tumor cells and selectively release CDDP and OLA within the acidic tumor microenvironment, capitalizing on their respective mechanisms of action for improved anticancer therapy. In vitro studies demonstrated that the CDDP-OLA NPs are significantly more effective than CDDP/OLA mixture and CDDP at penetrating cancer cells and suppressing their growth. In vivo studies revealed that the nanoparticles specifically accumulated at the tumor site and enhanced the therapeutic efficacy without obvious adverse effects. This approach holds great potential for enhancing the drugs' water solubility, tumor targeting, bioavailability, and synergistic anticancer effects while minimizing its toxic side effects.

Sertraline Promotes Health and Longevity in Caenorhabditis elegans.

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans. METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.

Extensive involvement of indolent T-cell lymphoma in a patient with ulcerative colitis.

Indolent T-cell lymphoma is a rare disease. Here we presented a 53-year-old male patient initially diagnosed as ulcerative colitis in 2000 that finally developed into extensive indolent T-cell lymphoma in 2022. We also described the differences between indolent T-cell lymphoma and inflammatory bowel disease, and the possible disease progression into lymphoma after biological therapy.

Fluoxetine Promotes Longevity via Reactive Oxygen Species in Caenorhabditis elegans.

Although several antidepressants have been identified as potential geroprotectors, the effect and mechanism of fluoxetine, a representative selective serotonin reuptake inhibitor, on longevity have not been fully elucidated. Here, we found that fluoxetine promoted longevity in Caenorhabditis elegans with a concomitant extension of a healthy life span as indicated by increasing mobility, reducing fertility and lipofuscin accumulation, and enhanced resistance to different abiotic stresses. Fluoxetine increased the level of reactive oxygen species (ROS), and antioxidant N-acetylcysteine abolished ROS elevation and the pro-longevity effect of fluoxetine. Additionally, fluoxetine extended life span through the daf-2-sod-3 pathway in daf-16-dependent and -independent manners, and fluoxetine-induced life-span extension was abolished in C. elegans sod-3, daf-2, and daf-16 mutants. In conclusion, these findings suggest that fluoxetine can promote health and longevity in C. elegans via the interaction of ROS and insulin signaling.

Extensive involvement of indolent T-cell lymphoma in a patient with ulcerative colitis

Indolent T-cell lymphoma is a rare disease. Here we presented a 53-year-old male patient initially diagnosed as ulcerative colitis in 2000 that finally developed into extensive indolent T-cell lymphoma in 2022. We also described the differences between indolent T-cell lymphoma and inflammatory bowel disease, and the possible disease progression into lymphoma after biological therapy. (AU)

A PCA Based Artifact Removal Algorithm for Neural Signal Acquisition with kS/s Sampling Rate.

The contamination of stimulus artifacts during Deep Brain Stimulation (DBS) brings challenges to the signal processing, especially when the ratio of the kS/s sampling rate to the stimulation frequency is not an integer. In this work we study to deal with this problem. A transfer function is built to describe the relationship between the stimulation signal and the artifact at the acquisition site. A principal component analysis (PCA) based linear regression algorithm for eliminating the artifact is proposed. The algorithm can be used for the artifact removal with low sampling rate of the neural signal. Higher than 60% correlation coefficient of the artifact-free signal and the predetermined self-generated signal is achieved when the artifact is 60dB larger than the predetermined signal. The numerical recipe for the critical algorithm is also proposed, lowering the complexity from cubic degree to square degree.

Biochar Enhances the Resistance of Legumes and Soil Microbes to Extreme Short-Term Drought.

Short-term drought events occur more frequently and more intensively under global climate change. Biochar amendment has been documented to ameliorate the negative effects of water deficits on plant performance. Moreover, biochar can alter the soil microbial community, soil properties and soil metabolome, resulting in changes in soil functioning. We aim to reveal the extent of biochar addition on soil nutrients and the soil microbial community structure and how this improves the tolerance of legume crops (peanuts) to short-term extreme drought. We measured plant performances under different contents of biochar, set as a gradient of 2%, 3% and 4%, after an extreme experimental drought. In addition, we investigated how soil bacteria and fungi respond to biochar additions and how the soil metabolome changes in response to biochar amendments, with combined growth experiments, high-throughput sequencing and soil omics. The results indicated that biochar increased nitrites and available phosphorus. Biochar was found to influence the soil bacterial community structure more intensively than the soil fungal community. Additionally, the fungal community showed a higher randomness under biochar addition when experiencing short-term extreme drought compared to the bacterial community. Soil bacteria may be more strongly related to soil nutrient cycling in peanut agricultural systems. Although the soil metabolome has been documented to be influenced by biochar addition independent of soil moisture, we found more differential metabolites with a higher biochar content. We suggest that biochar enhances the resistance of plants and soil microbes to short-term extreme drought by indirectly modifying soil functioning probably due to direct changes in soil moisture and soil pH.

The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals.

Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug's efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals' genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies' recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population.

Mid-infrared carbon isotope spectrum logging system combined with a thermostat of optical subsystem for high-precision detection of isotope ratio.

In the process of oil and gas exploration and development, carbon isotope ratio can reflect the maturity of oil and gas and predict the recovery factor, and the isotope ratio in the composition of shale gas is particularly important. Thus, a carbon isotope spectrum logging system was designed and exploited based on tunable diode laser absorption spectroscopy (TDLAS) technology under the fundamental frequency absorption band of 12CO2 and 13CO2 molecules, and a quantum cascade laser (QCL) with center wavelength of 4.35 µm was applied. For further detection sensitivity, wavelength modulation spectroscopy (WMS) technology was combined to suppress background noise through the modulation of QCL. A multi-pass gas cell (MPGC) with an optical path length of 41 m was utilized for lower limit of detection (LoD). In order to suppress the temperature dependence of the absorption spectrum, the optical subsystem was placed in a high-precision thermostat to maintain a stable temperature, so as to achieve high-precision and high-stability detection. Meanwhile, sparrow search algorithm-back propagation (SSA-BP) was applied for concentration prediction of 12CO2 and 13CO2. Taking advantage of the excellent optimization ability, fast convergence speed and high stability of SSA, the problem that BP neural network algorithm is highly dependent on initial value can be solved to some extent. Sensor performance was validated through calibration and stability experiments. The LoD of 12CO2 reached a minimum of 0.618 parts-per-billion (ppb) with an 88 s averaging time, and the LoD of 13CO2 reached 0.181 ppb when the averaging time was 96 s. Besides, the standard deviation of carbon isotope ratio obtained by this system was âˆ¼ 0.61 ‰. The results illustrate that this self-developed sensor has a bright prospect in the field of shale gas isotope detection.

The neutrophil-to-lymphocyte ratio and lactate dehydrogenase combined in predicting liver metastasis and prognosis of colorectal cancer.

Background: The neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level are inflammatory markers related to tumor growth and metabolism. This study investigated the value of preoperative NLR, LDH and the combination of NLR and LDH (NLR-LDH) for predicting colorectal cancer liver metastasis (CRLM) and tumor prognosis in the early stages of colorectal cancer (CRC). Materials and methods: Three hundred patients undergoing CRC resection were included. Logistic regression analysis was used to estimate the correlation between CRLM time and inflammatory markers, and Kaplan-Meier survival and Cox regression analyses were used to estimate overall survival (OS). Forest plots were prepared based on the multivariate Cox analysis model and evaluated by receiver operating characteristic (ROC) curve analysis. Results: The NLR cut-off value was 2.071 according to the ROC curve. The multivariate analysis showed that the elevated LDH level and a high NLR-LDH level were independent predictors of synchronous CRLM and OS (p < 0.05). The combination of a high NLR and elevated LDH and NLR-LDH levels suggested a poor prognosis and a significantly shorter median survival time than a low NLR and low levels of LDH and NLR-LDH. The ROC curve analysis results illustrated that the predictive value of the NLR-LDH score for synchronous CRLM [area under the curve (AUC) = 0.623, p < 0.001] and OS (AUC = 0.614, p = 0.001) was superior to that of the NLR or LDH score used alone. Conclusion: LDH and NLR-LDH are reliable, easy-to-use, independent biomarkers for predicting synchronous or metachronous CRLM and OS in CRC patients. The NLR is an important monitoring index for CRLM. Preoperative NLR, LDH and NLR-LDH may help to guide the use of therapeutic strategies and cancer surveillance.

Liver-targeting MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan.

Commercial gadolinium (Gd)-based contrast agents (GBCAs) play important role in clinical diagnostic of hepatocellular carcinoma, but their diagnostic efficacy remained improved. As small molecules, the imaging contrast and window of GBCAs is limited by low liver targeting and retention. Herein, we developed a liver-targeting gadolinium (Ⅲ) chelated macromolecular MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan, namely, CS-Ga-(Gd-DTPA)n, to improve hepatocyte uptake and liver retention. Compared to Gd-DTPA and non-specific macromolecular agent CS-(Gd-DTPA)n, CS-Ga-(Gd-DTPA)n showed higher hepatocyte uptake, excellent cell and blood biocompatibility in vitro. Furthermore, CS-Ga-(Gd-DTPA)n also exhibited higher relaxivity in vitro, prolonged retention and better T1-weighted signal enhancement in liver. At 10 days post-injection of CS-Ga-(Gd-DTPA)n at a dose of 0.03 mM Gd/Kg, Gd had a little accumulation in liver with no liver function damage. The good performance of CS-Ga-(Gd-DTPA)n gives great confidence in developing liver-specifc MRI contrast agents for clinical translation.

Ferroptosis and multi-organ complications in COVID-19: mechanisms and potential therapies.

COVID-19 is an infectious disease caused by SARS-CoV-2, with respiratory symptoms as primary manifestations. It can progress to severe illness, leading to respiratory failure and multiple organ dysfunction. Recovered patients may experience persistent neurological, respiratory, or cardiovascular symptoms. Mitigating the multi-organ complications of COVID-19 has been highlighted as a crucial part of fighting the epidemic. Ferroptosis is a type of cell death linked to altered iron metabolism, glutathione depletion, glutathione peroxidase 4 (GPX4) inactivation, and increased oxidative stress. Cell death can prevent virus replication, but uncontrolled cell death can also harm the body. COVID-19 patients with multi-organ complications often exhibit factors related to ferroptosis, suggesting a possible connection. Ferroptosis inhibitors can resist SARS-CoV-2 infection from damaging vital organs and potentially reduce COVID-19 complications. In this paper, we outline the molecular mechanisms of ferroptosis and, based on this, discuss multi-organ complications in COVID-19, then explore the potential of ferroptosis inhibitors as a supplementary intervention for COVID-19. This paper will provide a reference for the possible treatment of SARS-CoV-2 infected disease to reduce the severity of COVID-19 and its subsequent impact.

Mitochondria-Targeted Fluorescent Nanoparticles with Large Stokes Shift for Long-Term BioImaging.

Mitochondria (MITO) play a significant role in various physiological processes and are a key organelle associated with different human diseases including cancer, diabetes mellitus, atherosclerosis, Alzheimer's disease, etc. Thus, detecting the activity of MITO in real time is becoming more and more important. Herein, a novel class of amphiphilic aggregation-induced emission (AIE) active probe fluorescence (AC-QC nanoparticles) based on a quinoxalinone scaffold was developed for imaging MITO. AC-QC nanoparticles possess an excellent ability to monitor MITO in real-time. This probe demonstrated the following advantages: (1) lower cytotoxicity; (2) superior photostability; and (3) good performance in long-term imaging in vitro. Each result of these indicates that self-assembled AC-QC nanoparticles can be used as effective and promising MITO-targeted fluorescent probes.