Deciphering signaling mechanisms critical for the extended pluripotent stem cell (EPSC) state and primed pluripotency is necessary for understanding embryonic development. Here, a membrane protein, ...podocalyxin‐like protein 1 (PODXL) as being essential for extended and primed pluripotency, is identified. Alteration of PODXL expression levels affects self‐renewal, protein expression of c‐MYC and telomerase, and induced pluripotent stem cell (iPSC) and EPSC colony formation. PODXL is the first membrane protein reported to regulate de novo cholesterol biosynthesis, and human pluripotent stem cells (hPSCs) are more sensitive to cholesterol depletion than fibroblasts. The addition of exogenous cholesterol fully restores PODXL knockdown‐mediated loss of pluripotency. PODXL affects lipid raft dynamics via the regulation of cholesterol. PODXL recruits the RAC1/CDC42/actin network to regulate SREBP1 and SREBP2 maturation and lipid raft dynamics. Single‐cell RNA sequencing reveals PODXL overexpression enhanced chimerism between human cells in mouse host embryos (hEPSCs 57%). Interestingly, in the human–mouse chimeras, laminin and collagen signaling‐related pathways are dominant in PODXL overexpressing cells. It is concluded that cholesterol regulation via PODXL signaling is critical for ESC/EPSC.
Cholesterol is important for membrane composition and cell division. Chen et al. show that PODXL regulates de novo cholesterol biosynthesis and further sustains the primed and extended renewal states in hPSCs through c‐MYC, TERT, and ITGA2. PODXL overexpression facilitates the extended pluripotency state in vitro and in vivo. These data highlight that PODXL links cellular metabolism to stem cell self‐renewal.
Using mobile phones for communication in emergency departments is a common practice; however, several studies have demonstrated that they may act as vectors for bacteria and viruses. This study ...evaluated the effectiveness of plastic wrapping in decreasing bacterial contamination on mobile phone surfaces.
We used culture dishes and a luminometer to detect bacterial colonies and contamination on the phone surfaces.
Our experiment showed that bacterial colonies exist on mobile phones before and after work. We found that wiping with 75% alcohol sanitizers effectively reduces the number of colonies on either a mobile phone or a temporary plastic covering. In addition, we found that bacterial colonies do not contaminate or adhere to plastic wrap any easier than to mobile phones.
These results demonstrated the effectiveness of plastic wrap for protecting mobile phone surfaces against bacterial colonization. In addition, applying a layer of plastic wrap protects the phone from potential damage due to the alcohol.
•A toxin- and thermo-tolerant yeast KY3 was isolated.•KY3 can survive at pH2.5–9 and utilize a wide spectrum of substrates.•KY3 can produce value-added chemicals for biorefinery.•KY3 can be ...engineered to perform cellulosic ethanol conversion.•A Bacillus subtilis–KY3 co-culture system can produce cellulosic ethanol.
Although biorefinery has become a common concept to convert biomass into biofuels and value-added chemicals for better cost-performance, good microbial hosts that can be used to implement the concept are still wanting. In this study, a Kluyveromyces marxianus yeast, named KY3, was isolated from a Taiwanese kefir microbial consortium. We showed that KY3 could grow on a broad spectrum of substrates, including hexose and pentose sugars. It is heat and toxin tolerant, can grow under a wide range of pH values (pH 2.5–9), and shows a high ethanol production rate at elevated temperatures. It also can produce value-added aromatic chemicals, such as 2-phenylethylethanol and 2-phenylethyl acetate, during the fermentative process. A genetic transformation was achieved in KY3 to express a rumen fungal β-glucosidase gene, and the transgenic host (KY3–NpaBGS) could efficiently convert cellobiose to ethanol. Furthermore, it was shown that a novel dual-microbe co-culture system of Bacillus subtilis and KY3–NpaBGS can be employed for bioethanol production from cellulosic material. Thus, KY3 has a high potential to be a good host for biorefinery.
Protecting cardiac function in patients with advanced left-breast cancer receiving radiation therapy (RT) with regional nodal irradiation (RNI) is an important issue. Modern RT techniques can limit ...cardiac exposure. The aim of this study was to explore the association be-tween cardiac dose and cardiac function.
Between 2017 and 2020, we retrospectively reviewed left-breast cancer patients who received adjuvant RT, including RNI with either volumetric-modulated arc therapy (VMAT) or helical tomotherapy (HT). Left ventricular ejection fraction (LVEF) was assessed by echocardiography before RT and 1 year after RT to detect any early deterioration in cardiac systolic function.
A total of 30 eligible patients were enrolled. The median follow-up time from the initiation of RT was 3.9 years (range 0.6-5 years). Seventeen patients received VMAT, and the other 13 patients received HT. The median RT dose was 55 Gray (Gy), and the mean heart dose was 3.73 Gy (range 1.95-9.36 Gy). The median LVEF before and after RT was 68% and 68.5%, respectively. No obvious deterioration was found. There was no association between cardiac dose (mean heart dose, V5-V30) and LVEF (change in values or post-RT).
For left-breast cancer patients undergoing RT with RNI, VMAT, or HT can be used to limit cardiac exposure. Cardiac function as evaluated by LVEF revealed no obvious deterioration after RT in our patients, and no association was found between cardiac dose and LVEF in those treated with either VMAT or HT in early cardiac surveillance.
Oligodendrocytes are glial cells located in the central nervous system (CNS) that play essential roles in the transmission of nerve signals and in the neuroprotection of myelinated neurons. The ...dysfunction or loss of oligodendrocytes leads to demyelinating diseases such as multiple sclerosis (MS). To treat demyelinating diseases, the development of a therapy that promotes remyelination is required. In the present study, we established an in vitro method to convert human fibroblasts into induced oligodendrocyte-like cells (iOLCs) in 3 days. The induced cells displayed morphologies and molecular signatures similar to oligodendrocytes after treatment with valproic acid and exposure to the small molecules Y27632, SU9516, and forskolin (FSK). To pursue the development of a cell-free remyelination therapy in vivo, we used a cuprizone-induced demyelinated mouse model. The small molecules (Y27632, SU9516, and FSK) were directly injected into the demyelinated corpus callosum of the mouse brain. This combination of small molecules rescued the demyelination phenotype within two weeks as observed by light and electron microscopy. These results provide a foundation for exploring the development of a treatment for demyelinating diseases via regenerative medicine.
OBJECTIVEThe use of nonselective beta blockers in cirrhotic patients experiencing complications is controversial. We aimed to investigate the association between propranolol treatment and outcomes ...for cirrhotic patients with hepatic encephalopathy.
METHODSUsing data from the Taiwan National Health Insurance Research Database, we identified 4754 cirrhotic patients newly diagnosed with hepatic encephalopathy between 2001 and 2010. Among them, 519 patients received propranolol treatment and the other 519 patients without exposure to propranolol were enrolled into our study, both of which were matched by sex, age, and propensity score. The Kaplan–Meier method and time-dependent–modified Cox proportional hazards models were employed for survival and multivariate-stratified analyses.
RESULTSThe median overall survival (OS) was significantly longer in the propranolol-treated cohort than in the untreated cohort (3.46 versus 1.88 years, P < 0.001). A dose-dependent increase in survival was observed (median OS4.49, 3.29, and 2.46 years in patients treated with propranolol more than 30 , 20–30 , and less than 20 mg/day, respectively P < 0.001, P = 0.001, and P = 0.079 versus the untreated group). In addition to reduce the risk of mortality (adjusted hazard ratio, 0.58; P < 0.001), propranolol also diminished the risk of sepsis-related death (adjusted hazard ratio, 0.31; P = 0.006) according to the multivariate analysis. However, the risk of circulatory or hepatic failure was nonsignificantly altered by propranolol treatment.
CONCLUSIONLow dose of propranolol treatment was associated with a better OS in cirrhotic patients with hepatic encephalopathy and its effects were dose dependent.
The Omicron variant BA.2 is the dominant form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in many countries, including those that have already implemented the ...strictest quarantine mandates that effectively contained the spread of the previous variants. Although many individuals were partially or fully vaccinated, confirmed Omicron infections have far surpassed all other variants combined in just a couple of months since the Omicron variant emerged. The ChAdOx1-S (AstraZeneca), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) vaccines offer protection against the severe illness of SARS-CoV-2 infection; however, these currently available vaccines are less effective in terms of preventing Omicron infections. As a result, a booster dose of BNT162b2 or mRNA-1273 is recommended for individuals >12 years old who had received their second dose of the approved vaccines for >5 months. Herein, we review the studies that assessed the clinical benefits of the booster dose of vaccines against Omicron infections. We also analyzed public data to address whether early booster vaccination effectively prevented the surge of the Omicron infections. Finally, we discuss the consideration of a fourth dose of vaccine as a way to prevent possible upcoming infections.
Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear ...localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFR
or EGFR
, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.
The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in ...children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks.
We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (<70 mg/day) for at least 1 month. The treatment, switched from IR-MPH to OROS-MPH according to a conversion scheme, started with a 6-week forced-titration phase of OROS-MPH to achieve symptomatic remission (defined as a score of 0 or 1 for each of the first 18 ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV SNAP-IV), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed.
Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score < 40), no family history of ADHD, and an appropriate dosage of medication according to the patient's weight.
The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme.
BACKGROUND: Many microorganisms possess enzymes that can efficiently degrade lignocellulosic materials, but do not have the capability to produce a large amount of ethanol. Thus, attempts have been ...made to transform such enzymes into fermentative microbes to serve as hosts for ethanol production. However, an efficient host for a consolidated bioprocess (CBP) remains to be found. For this purpose, a synthetic biology technique that can transform multiple genes into a genome is instrumental. Moreover, a strategy to select cellulases that interact synergistically is needed. RESULTS: To engineer a yeast for CBP bio-ethanol production, a synthetic biology technique, called “promoter-based gene assembly and simultaneous overexpression” (PGASO), that can simultaneously transform and express multiple genes in a kefir yeast, Kluyveromyces marxianus KY3, was recently developed. To formulate an efficient cellulase cocktail, a filter-paper-activity assay for selecting heterologous cellulolytic enzymes was established in this study and used to select five cellulase genes, including two cellobiohydrolases, two endo-β-1,4-glucanases and one beta-glucosidase genes from different fungi. In addition, a fungal cellodextrin transporter gene was chosen to transport cellodextrin into the cytoplasm. These six genes plus a selection marker gene were one-step assembled into the KY3 genome using PGASO. Our experimental data showed that the recombinant strain KR7 could express the five heterologous cellulase genes and that KR7 could convert crystalline cellulose into ethanol. CONCLUSION: Seven heterologous genes, including five cellulases, a cellodextrin transporter and a selection marker, were simultaneously transformed into the KY3 genome to derive a new strain, KR7, which could directly convert cellulose to ethanol. The present study demonstrates the potential of our strategy of combining a cocktail formulation protocol and a synthetic biology technique to develop a designer yeast host.
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