Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.

To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development.

Ten-Eleven Translocation (Tet) family of dioxygenases dynamically regulates DNA methylation and has been implicated in cell lineage differentiation and oncogenesis. Yet their functions and mechanisms of action in gene regulation and embryonic development are largely unknown. Here, we report that Xenopus Tet3 plays an essential role in early eye and neural development by directly regulating a set of key developmental genes. Tet3 is an active 5mC hydroxylase regulating the 5mC/5hmC status at target gene promoters. Biochemical and structural studies further demonstrate that the Tet3 CXXC domain is critical for specific Tet3 targeting. Finally, we show that the enzymatic activity and CXXC domain are both crucial for Tet3's biological function. Together, these findings define Tet3 as a transcription regulator and reveal a molecular mechanism by which the 5mC hydroxylase and DNA binding activities of Tet3 cooperate to control target gene expression and embryonic development.

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.

Antibody Profiling of Pan-Cancer Viral Proteome Reveals Biomarkers for Nasopharyngeal Carcinoma Diagnosis and Prognosis.

Diagnosing, predicting disease outcome, and identifying effective treatment targets for virus-related cancers are lacking. Protein biomarkers have the potential to bridge the gap between prevention and treatment for these types of cancers. While it has been shown that certain antibodies against EBV proteins could be used to detect nasopharyngeal carcinoma (NPC), antibodies targeting are solely a tiny part of the about 80 proteins expressed by the EBV genome. Furthermore, it remains unclear what role other viruses play in NPC since many diseases are the result of multiple viral infections. For the first time, this study measured both IgA and IgG antibody responses against 646 viral proteins from 23 viruses in patients with NPC and control subjects using nucleic acid programmable protein arrays. Candidate seromarkers were then validated by ELISA using 1665 serum samples from three clinical cohorts. We demonstrated that the levels of five candidate seromarkers (EBV-BLLF3-IgA, EBV-BLRF2-IgA, EBV-BLRF2-IgG, EBV-BDLF1-IgA, EBV-BDLF1-IgG) in NPC patients were significantly elevated than controls. Additional examination revealed that NPC could be successfully diagnosed by combining the clinical biomarker EBNA1-IgA with the five anti-EBV antibodies. The sensitivity of the six-antibody signature at 95% specificity to diagnose NPC was comparable to the current clinically-approved biomarker combination, VCA-IgA, and EBNA1-IgA. However, the recombinant antigens of the five antibodies are easier to produce and standardize compared to the native viral VCA proteins. This suggests the potential replacement of the traditional VCA-IgA assay with the 5-antibodies combination to screen and diagnose NPC. Additionally, we investigated the prognostic significance of these seromarkers titers in NPC. We showed that NPC patients with elevated BLLF3-IgA and BDLF1-IgA titers in their serum exhibited significantly poorer disease-free survival, suggesting the potential of these two seromarkers as prognostic indicators of NPC. These findings will help develop serological tests to detect and treat NPC in the future.

Proteomics Platform Reveals Broad-Spectrum Nanobodies for SARS-CoV-2 Variant Neutralization.

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of different variants of concerns with immune evasion that have been prevalent over the past three years. Nanobodies, the functional variable regions of camelid heavy-chain-only antibodies, have garnered interest in developing neutralizing antibodies due to their smaller size, structural stability, ease of production, high affinity, and low immunogenicity, among other characteristics. In this work, we describe an integrated proteomics platform for the high-throughput screening of nanobodies against different SARS-CoV-2 spike variants. To demonstrate this platform, we immunized a camel with subunit 1 (S1) of the wild-type spike protein and constructed a nanobody phage library. The binding and neutralizing activities of the nanobodies against 72 spike variants were then measured, resulting in the identification of two nanobodies (C-282 and C-39) with broad neutralizing activity against six non-Omicron variants (D614G, Alpha, Beta, Gamma, Delta, Kappa) and five Omicron variants (BA.1-5). Their neutralizing capability was validated using in vitro pseudovirus-based neutralization assays. All these results demonstrate the utility of our proteomics platform to identify new nanobodies with broad neutralizing capability and to develop a treatment for patients with SARS-CoV-2 variant infection in the future.

Decreased intranuclear cardiac troponin I impairs cardiac autophagy through FOS/ATG5 in ageing hearts.

In our previous study, intranuclear cardiac troponin I (cTnI) may function as a co-factor of Yin Yang 1(YY1). Here, we aimed to explore the role of intranuclear cTnI in ageing hearts. Nuclear translocation of cTnI was demonstrated using Western blot and immunofluorescence. The potential nuclear localization sequences (NLSs) of cTnI were predicted by a web server and then verified in 293T cells by putative NLS-eGFP-GST and NLS-mutant transfection. The ratio of Nuclear cTnI/ Total cTnI (Nu/T) decreased significantly in ageing hearts, accompanied with ATG5-decline-related impaired cardiac autophagy. RNA sequencing was performed in cTnI knockout hearts. The differential expressed genes (DEGs) were analysed by overlapping with YY1 ChIP-sequencing data. cTnI gain and loss experiments in vitro determined those filtered DEGs' expression levels. A strong correlation was found between expression patterns cTnI and FOS. Using ChIP-q-PCR, we demonstrated that specific binding DNA sequences of cTnI were enriched in the FOS promoter -299 to -157 region. It was further verified that pcDNA3.1 (-)-cTnI could increase the promoter activity of FOS by using luciferase report assay. At last, we found that FOS can regulate the ATG5 (autophagy-related gene 5) gene by using a luciferase report assay. Taken together, our results indicate that decreased intranuclear cTnI in ageing hearts may cause impaired cardiac autophagy through the FOS/ATG5 pathway.

Long-term immunogenicity and safety of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants who had received two or three doses of inactivated vaccine.

The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.

Ultrastable PLGA-Coated 177Lu-Microspheres for Radioembolization Therapy of Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) is a highly effective localized radionuclide therapy that has been successfully used to treat hepatocellular carcinoma (HCC). Extensive research has been conducted on the use of radioactive microspheres (MSs) in TARE, and the development of ideal radioactive MSs is crucial for clinical trials and patient treatment. This study presents the development of a radioactive MS for TARE of HCC. These MSs, referred to as 177Lu-MS@PLGA, consist of poly(lactic-co-glycolic acid) (PLGA) copolymer and radioactive silica MSs, labeled with 177Lu and then coated with PLGA. It has an extremely high level of radiostability. Cellular experiments have shown that it can cause DNA double-strand breaks, leading to cell death. In vivo radiostability of 177Lu-MS@PLGA is demonstrated by microSPECT/CT imaging. In addition, the antitumor study has shown that TARE of 177Lu-MS@PLGA can effectively restrain tumor growth without harmful side effects. Thus, 177Lu-MS@PLGA exhibits significant potential as a radioactive MS for the treatment of HCC.

Efficient Catalytic Elimination of Toxic Volatile Organic Compounds via Advanced Oxidation Process Wet Scrubbing with Bifunctional Cobalt Sulfide/Activated Carbon Catalysts.

Advanced oxidation process (AOP) wet scrubber is a powerful and clean technology for organic pollutant treatment but still presents great challenges in removing the highly toxic and hydrophobic volatile organic compounds (VOCs). Herein, we elaborately designed a bifunctional cobalt sulfide (CoS2)/activated carbon (AC) catalyst to activate peroxymonosulfate (PMS) for efficient toxic VOC removal in an AOP wet scrubber. By combining the excellent VOC adsorption capacity of AC with the highly efficient PMS activation activity of CoS2, CoS2/AC can rapidly capture VOCs from the gas phase to proceed with the SO4•- and HO• radical-induced oxidation reaction. More than 90% of aromatic VOCs were removed over a wide pH range (3-11) with low Co ion leaching (0.19 mg/L). The electron-rich sulfur vacancies and low-valence Co species were the main active sites for PMS activation. SO4•- was mainly responsible for the initial oxidation of VOCs, while HO• and O2 acted in the subsequent ring-opening and mineralization processes of intermediates. No gaseous intermediates from VOC oxidation were detected, and the highly toxic liquid intermediates like benzene were also greatly decreased, thus effectively reducing the health toxicity associated with byproduct emissions. This work provided a comprehensive understanding of the deep oxidation of VOCs via AOP wet scrubber, significantly accelerating its application in environmental remediation.

Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

How digital transformation facilitate synergy for pollution and carbon reduction: Evidence from China.

Frontier studies have neglected the impact of digital transformation (DT) on the synergy for pollution and carbon reduction (SPCR) from the perspective of micro enterprises. This paper explores the SPCR effect of DT, as well as its mechanism at micro-firm level. The study found that: (1) DT significantly facilitates corporate SPCR. For every 10% increase in the level of DT, the ranking of SPCR will rise by about 2.3 places. This effect is more obvious in high-tech firms and non-heavy polluters, firms in the eastern region in China, and non-SOE. (2) DT creates innovation-driven and structure-optimizing effects, which enhance the corporate green innovation ability, optimize the business structure and capital allocation structure of enterprises, and then drive the SPCR. (3) External public environmental concerns (PEC) and internal corporate ESG governance act as "accelerators" promoting the SPCR effect of DT. Based on these, policy implications are made to accelerate the pace of corporate DT, give full play to the first-mover advantage, and break the "pollution (carbon) lock-in" with a view to providing theoretical references for the listed enterprises' digitalized governance of SPCR, as well as the governmental departments' formulation of relevant guiding policies, and striving to achieve the high-quality development goal.

Using a DNA mini-barcode within the ITS region to identify toxic Amanita in mushroom poisoning cases.

Mushroom poisoning contributes significantly to global foodborne diseases and related fatalities. Amanita mushrooms frequently cause such poisonings; however, identifying these toxic species is challenging due to the unavailability of fresh and intact samples. It is often necessary to analyze residues, vomitus, or stomach extracts to obtain DNA sequences for the identification of species responsible for causing food poisoning. This usually proves challenging to obtain usable DNA sequences that can be analyzed using conventional molecular biology techniques. Therefore, this study aimed to develop a DNA mini-barcoding method for the identification of Amanita species. Following the evaluation and optimization of universal primers for DNA mini-barcoding in Amanita mushrooms, we found that the internal transcribed spacer (ITS) gene sequence primer ITS-a was the most suitable DNA barcode primer for identifying Amanita species. Forty-three Amanita samples were subsequently amplified and sequenced. The sequences obtained were analyzed for intra- and inter-species genetic distances, and a phylogenetic tree was constructed. The findings indicated that the designed primers had strong universality among the Amanita samples and could accurately identify the target gene fragment with a length of 290 bp. Notably, the DNA mini-barcode accurately identified the 43 Amanita samples, demonstrating high consistency with the conventional DNA barcode. Furthermore, it effectively identified DNA from digested samples. In summary, this DNA mini-barcode is a promising tool for detecting accidental ingestion of toxic Amanita mushrooms. It may be used as an optimal barcode for species identification and traceability in events of Amanita-induced mushroom poisoning. KEY POINTS: • Development of a DNA mini-barcoding method for Amanita species identification without fresh samples. • The ITS-a primer set was optimized for robust universality in Amanita samples. • The mini-barcode is suitable for screening toxic mushroom species in mushroom poisoning cases.

A Comparison of Patient Characteristics and Outcomes Between Patients Receiving Flexor Digitorum Superficialis Slip Excision or Isolated A1 Pulley Release for Trigger Finger.

PURPOSE: Resection of the radial or ulnar slip of the flexor digitorum superficialis (FDS) tendon is a known treatment option for persistent trigger finger. Risk factors for undergoing FDS slip excision are unclear. We hypothesized that patients who underwent A1 pulley release with FDS slip excision secondary to persistent triggering would have a higher comorbidity burden compared to those receiving A1 pulley release alone. METHODS: We identified all adult patients who underwent A1 pulley release with FDS slip excision because of persistent triggering either intraoperatively or postoperatively from 2018 to 2023. We selected a 3:1 age- and sex-matched control group who underwent isolated A1 pulley release. Charts were retrospectively reviewed for demographics, selected comorbidities, trigger finger history, and postoperative course. We performed multivariable logistic regression to assess the probability of FDS slip excision after adjusting for several variables that were significant in bivariate comparisons. RESULTS: We identified 48 patients who underwent A1 pulley release with FDS slip excision and 144 controls. Our multivariable model showed that patients with additional trigger fingers and a preoperative proximal interphalangeal (PIP) joint contracture were significantly more likely to undergo FDS slip excision. CONCLUSIONS: Patients who underwent A1 pulley release with FDS slip excision were significantly more likely to have multiple trigger fingers or a preoperative PIP joint contracture. Clinicians should counsel patients with these risk factors regarding the potential for FDS slip excision in addition to A1 pulley release to alleviate triggering of the affected digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Direct Photocatalytic Synthesis of Acetic Acid from Methane and CO at Ambient Temperature Using Water as Oxidant.

Direct functionalization of methane selectively to value-added chemicals is still one of the main challenges in modern science. Acetic acid is an important industrial chemical produced nowadays by expensive and environmentally unfriendly carbonylation of methanol using homogeneous catalysts. Here, we report a new photocatalytic reaction route to synthesize acetic acid from CH4 and CO at room temperature using water as the sole external oxygen source. The optimized photocatalyst consists of a TiO2 support and ammonium phosphotungstic polyoxometalate (NPW) clusters anchored with isolated Pt single atoms (Pt1). It enables a stable synthesis of 5.7 mmol·L-1 acetic acid solution in 60 h with the selectivity over 90% and 66% to acetic acid on liquid-phase and carbon basis, respectively, with the production of 99 mol of acetic acid per mol of Pt. Combined isotopic and in situ spectroscopy investigation suggests that synthesis of acetic acid proceeds via a photocatalytic oxidative carbonylation of methane over the Pt1 sites, with the methane activation facilitated by water-derived hydroxyl radicals.

Upregulation of mesencephalic astrocyte-derived neurotrophic factor (MANF) expression offers protection against alcohol neurotoxicity.

Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol-induced neuronal damages. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol-induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol-induced MANF upregulation, as pharmacological inhibition of ER stress by 4-PBA diminished alcohol-induced MANF expression. In addition, the presence of ER stress response element II (ERSE-II) was required for alcohol-stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol-regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol-induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol-induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno-associated viruses ameliorated alcohol-induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol-induced neurodegeneration.

Temperature-insensitive FDL-stabilized laser using a PMF-based dual interferometer.

We demonstrate a temperature-insensitive fiber-delay-line-stabilized (FDL-stabilized) laser based on a dual Mach-Zehnder interferometer (MZI) by using polarization maintaining fibers (PMFs). Two orthogonal polarization components of a beam are simultaneously transmitted in the interferometer. Each polarization component exhibits a unique phase shift in response to the changes in temperature, forming a dual MZI. One of the heterodyne signals is used to lock the laser frequency, while the other one is used to compensate the frequency change induced by the temperature fluctuation. The experiment shows that the laser frequency fluctuation has been suppressed at least 25 times. This is an effective method to reduce the laser frequency noise induced by the temperature fluctuation of the FDL. In this way, a compact system with less thermal shields can be realized, and the thermal equilibrium time could be decreased dramatically.

Biobased Biodegradable Copolyesters from 2,5-Thiophenedicarboxylic Acid: Effect of Aliphatic Diols on Barrier Properties and Degradation.

The demand for sustainable development has led to increasing attention in biobased polyesters due to their adjustable thermal and mechanical properties and biodegradability. In this study, we used a novel bioderived aromatic diacid, 2,5-thiophenedicarboxylic acid (TDCA) to synthesize a list of novel aromatic-aliphatic poly(alkylene adipate-co-thiophenedicarboxylate) (PAATh) copolyesters through a facile melt polycondensation method. PAAThs are random copolyesters with weight-average molecular weights of 58400 to 84200 g·mol-1 and intrinsic viscosities of 0.80 to 1.27 dL·g-1. All PAAThs exhibit sufficiently high thermal stability as well as the highest tensile strength of 6.2 MPa and the best gas barrier performances against CO2 and O2, 4.3- and 3.3-fold better than those of poly(butylene adipate-co-terephthalate) (PBAT). The biodegradability of PAAThs was fully evaluated through a degradation experiment and various experimental parameters, including residue weights, surface morphology, and molecular compositions. The state-of-the-art molecular dynamics (MD) simulations were applied to elucidate the different enzymatic degradation behaviors of PAAThs due to the effect of diols with different chain structures. The sterically hindered carbonyl carbon of the PHATh-enzyme complex was more susceptible to nucleophilic attack and exhibited a higher tendency to enter a prereaction state. This study has introduced a group of novel biobased copolyesters with their structure-property relationships investigated thoroughly, and the effect of diol components on the enzymatic degradation was revealed by computational analysis. These findings may lay the foundation for the development of promising substitutes for commercial biodegradable polyesters and shed light on their complicated degradation mechanisms.

PM2.5-Bound Organophosphate Flame Retardants in Hong Kong: Occurrence, Origins, and Source-Specific Health Risks.

Organophosphate flame retardants (OPFRs) are emerging organic pollutants in PM2.5, which have caused significant public health concerns in recent years, given their potential carcinogenic and neurotoxic effects. However, studies on the sources, occurrence, and health risk assessment of PM2.5-bound OPFRs in Hong Kong are lacking. To address this knowledge gap, we characterized 13 OPFRs in one-year PM2.5 samples using gas chromatography-atmospheric pressure chemical ionization tandem mass spectrometry. Our findings showed that OPFRs were present at a median concentration of 4978 pg m-3 (ranging from 1924 to 8481 pg m-3), with chlorinated OPFRs dominating and accounting for 82.7% of the total OPFRs. Using characteristic source markers and positive matrix factorization, we identified one secondary formation and five primary sources of OPFRs. Over 94.0% of PM2.5-bound OPFRs in Hong Kong were primarily emitted, with plastic processing and waste disposal being the leading source (61.0%), followed by marine vessels (14.1%). The contributions of these two sources to OPFRs were more pronounced on days influenced by local pollution emissions (91.9%) than on days affected by regional pollution (44.2%). Our assessment of health risks associated with human exposure to PM2.5-bound OPFRs indicated a low-risk level. However, further source-specific health risk assessment revealed relatively high noncarcinogenic and carcinogenic risks from chlorinated OPFRs emitted from plastic processing and waste disposal, suggesting a need for more stringent emission control of OPFRs from these sources in Hong Kong.

Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4.

In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms.

Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: For patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations. METHOD: Using PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis. RESULTS: One thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone. CONCLUSION: The combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.