MOF@platelet-rich plasma antimicrobial GelMA dressing: structural characterization, bio-compatibility, and effect on wound healing efficacy.

In this study, a metal-organic framework (MOF) antimicrobial gel loaded with platelet-rich plasma (PRP) was prepared to improve the biological properties of gelatin gels and enhance their wound healing efficiency. PRP, MOF particles, and PRP-loaded MOF particles were each integrated into gelatin gels. The performance of the gels was evaluated for micro-structure, mechanical strength, in vitro bio-compatibility and pro-wound healing effects. The results revealed that the integration of PRP created a multi-cross-linked structure, increasing the ductility of the gels by over 40%. The addition of MOF particles significantly increased the strength of the gel from 13 kPa to 43 kPa. The combination of MOF and PRP further improved the cell induction and migration capabilities of the composite gel, and the scratches in the PRP/MOF@GelMA group had completely healed within 48 h. Due to the presence of MOF and PRP, the gel dressing exhibited inhibitory effects of 45.7% against Staphylococcus aureus (S. aureus) and 50.2% against Escherichia coli (E. coli). Different gels promoted tissue regeneration and wound healing ability of bacterial-infected wounds in C57 rats, while PRP/MOF@GelMA showed the strongest wound repair ability with 100% healing. This study provides a new strategy for the development and clinical application of gel dressings.

The gap-free genome of Forsythia suspensa illuminates the intricate landscape of centromeres.

Forsythia suspensa, commonly known as weeping forsythia, holds significance in traditional medicine and horticulture. Despite its ecological and cultural importance, the existing reference genome presents challenges with duplications and gaps, hindering in-depth genomic analyses. Here, we present a Telomere-to-Telomere (T2T) assembly of the F. suspensa genome, integrating Oxford Nanopore Technologies (ONT) ultra-long, Hi-C datasets, and high-fidelity (HiFi) sequencing data. The T2T reference genome (Fsus-CHAU) consists of 14 chromosomes, totaling 688.79 Mb, and encompasses 33 932 predicted protein-coding genes. Additionally, we characterize functional centromeres in the F. suspensa genome by developing a specific CENH3 antibody. We demonstrate that centromeric regions in F. suspensa exhibit a diverse array of satellites, showcasing distinctive types with unconventional lengths across various chromosomes. This discovery offers implications for the adaptability of CENH3 and the potential influence on centromere dynamics. Furthermore, after assessing the insertion time of full-length LTRs within centromeric regions, we found that they are older compared to those across the entire genome, contrasting with observations in other species where centromeric retrotransposons are typically young. We hypothesize that asexual reproduction may impact retrotransposon dynamics, influencing centromere evolution. In conclusion, our T2T assembly of the F. suspensa genome, accompanied by detailed genomic annotations and centromere analysis, significantly enhances F. suspensa potential as a subject of study in fields ranging from ecology and horticulture to traditional medicine.

Designing a hollow MoSe2/CuS nanospheres type-II heterojunction photocatalyst with superior UV-vis-NIR absorption for photocatalytic degradation of organic pollutants.

In this work, a hollow MoSe2/CuS type-II heterojunction was fabricated using hollow MoSe2 nanospheres as the basis for structural design. UV-Vis-NIR diffuse absorption tests show that MoSe2/CuS has a broad spectral absorption to extend the optical response range from UV-Vis to NIR. The light source utilization rate and interfacial area are increased by the hollow MoSe2/CuS core-shell structure. The broad absorption ability of MoSe2/CuS can facilitate the photocatalysis process. As the electrochemical impedance of MoSe2/CuS is lower than that of the MoSe2, MoSe2/CuS has a good photogenerated carrier separation efficiency. Benefiting from the synergistic facilitation effect of the multi-level 3D hollow nanosphere and the significant space charge region in type-II heterojunction, the RhB degradation efficiency of MoSe2/CuS reached 96.0% in 120.0 min under Xe (350 W) broadband spectrum light irradiation. The photocatalysis mechanism of the hollow MoSe2/CuS core-shell structure was investigated. This work provides an insight into the application of broad spectrum semiconductor heterojunctions to solve environmental problems.

IC-ECG guided PICC tip location in a dextrocardia: A case report.

INTRODUCTION: Mirror people have difficulty with PICC placement due to inversion of organs. Intracavitary electrocardiography (IC-ECG) guided peripherally inserted central catheter (PICC) tip location technique has been widely applied in clinical practice. CASE DESCRIPTION: Herein, we admitted a 59-year-old man diagnosed with esophageal cancer (EC). Chest X-ray and computed tomography (CT) revealed that the patient was with a mirror-image dextrocardia and situs inversus totalis: the heart and stomach located in the right side of the body, whereas the liver located in the left side. Echocardiography suggested that the apex of the heart pointed toward the right, while the left and right chambers were inverted. The relationship of the heart chambers, structure, and function were normal: left ventricular ejection fraction was 0.67, left atrial diameter was 31 mm, and heart output was 4.7 L/min. Surface ECG showed typical features of a dextrocardia: P-wave inverted on lead I. Amplitude of the R-wave and S-wave decreased gradually on lead chest from V1 to V5. Compared with the normal ECG image, the waves completely exchanged on lead II and III, so as on aVR and aVL. METHODS: Column of saline technique can assist operator estimate the tip position in real-time according to P-wave changes. When the height of P-wave reaches to its highest, it means that the tip of catheter has advanced to the target position of cavo-atrial junction (CAJ). OUTCOMES: Patient was inserted catheter and no adverse events were reported. CONCLUSIONS: Measuring the predicted length of catheter is still an indispensible procedure to help precisely adjusting the tip position in IC-ECG guided PICC. Our work provides both supplement for clinical data to facilitate further research and better understanding of special types of PICC to clinicians.

Post-Transition State Bifurcation Controls Torsional Selectivity in Radical Addition of Allenes.

Post-transition state bifurcation (PTSB) has received wide attention in the field of reaction mechanism research due to its role in producing nonstatistical reaction selectivity, which cannot be solely explained by transition state theory. Particularly, even subtle molecular motions such as bond torsion can precipitate PTSB, thereby significantly complicating the quantitative understanding of dynamic selectivity. In this work, we found that the radical addition of allenes is an elementary transformation that generally exhibits PTSB stereoselectivity, where a single radical addition transition state can lead to both Z- and E-allylic radicals via the post-transition state allylic single bond torsion. Interestingly, dynamic Z/E-selectivity favors the Z-allylic radicals, which contrasts the thermodynamic preference. Based on the dynamics study of twenty-five radical additions of mono-substituted allenes with diverse electronic and steric effects, we have identified that this dynamic stereoselectivity is synergistically controlled by the transition state structure and the differential trends within specific dimensions of the bifurcating reaction coordinates, which also holds true for di-substituted allene substrates. This study refines the mechanism of radical addition of allenes and underscores the importance of the differential trend of the reaction coordinates in controlling dynamic selectivity, offering a deeper insight into PTSB selectivity factors.

Combining molecular transmission network analysis and spatial epidemiology to reveal HIV-1 transmission pattern among the older people in Nanjing, China.

BACKGROUND: In China, the problem of HIV infection among the older people has become increasingly prominent. This study aimed to analyze the pattern and influencing factors of HIV transmission based on a genomic and spatial epidemiological analysis among this population. METHODS: A total of 432 older people who were aged ≥ 50 years, newly diagnosed with HIV-1 between January 2018 and December 2021 and without a history of ART were enrolled. HIV-1 pol gene sequence was obtained by viral RNA extraction and nested PCR. The molecular transmission network was constructed using HIV-TRACE and the spatial distribution analyses were performed in ArcGIS. The multivariate logistic regression analysis was performed to analyze the factors associated with clustering. RESULTS: A total of 382 sequences were successfully sequenced, of which CRF07_BC (52.3%), CRF01_AE (32.5%), and CRF08_BC (6.8%) were the main HIV-1 strains. A total of 176 sequences entered the molecular network, with a clustering rate of 46.1%. Impressively, the clustering rate among older people infected through commercial heterosexual contact was as high as 61.7% and three female sex workers (FSWs) were observed in the network. The individuals who were aged ≥ 60 years and transmitted the virus by commercial heterosexual contact had a higher clustering rate, while those who were retirees or engaged other occupations and with higher education degree were less likely to cluster. There was a positive spatial correlation of clustering rate (Global Moran I = 0.206, P < 0.001) at the town level and the highly aggregated regions were mainly distributed in rural area. We determined three large clusters which mainly spread in the intra-region of certain towns in rural areas. Notably, 54.5% of cases in large clusters were transmitted through commercial heterosexual contact. CONCLUSIONS: Our joint analysis of molecular and spatial epidemiology effectively revealed the spatial aggregation of HIV transmission and highlighted that towns of high aggregation were mainly located in rural area. Also, we found vital role of commercial heterosexual contact in HIV transmission among older people. Therefore, health resources should be directed towards highly aggregated rural areas and prevention strategy should take critical persons as entry points.

Dipyridamole-Grafted Copolymer Electrospun Nanofiber Membranes for Suppression of Peritendinous Adhesions.

Post-traumatic tendon adhesions significantly affect patient prognosis and quality of life, primarily stemming from the absence of effective preventive and curative measures in clinical practice. Current treatment modalities, including surgical excision and non-steroidal anti-inflammatory drugs, frequently exhibit limited efficacy or result in severe side effects. Consequently, the use of anti-adhesive barriers for drug delivery and implantation at the injury site to address peritendinous adhesion (PA) has attracted considerable attention. Electrospun nanofiber membranes (ENMs) have been extensively employed as drug-delivery platforms. In this study, we fabricated a polylactic acid (PLA)-dipyridamole (DP)-graft copolymer ENM called PLC-DP. This membrane exhibits enzyme-sensitive features, allowing more controlled and sustained drug release compared with conventional drug-loaded ENMs. In experiments, PLC-DP implantation reduced tissue adhesion by 47% relative to the control group while not adversely affecting tendon healing. Mechanistically, PLC-DP effectively activates the FXYD domain containing ion-transport regulator 2 (FXYD2) protein, thereby downregulating the fibroblast-transforming growth factor beta (TGF-ß)/Smad3 signaling pathway. PLC-DP leverages the anti-adhesive properties of DP and the enzyme-sensitive characteristics of graft copolymers, providing a promising approach for the future clinical treatment and prevention of PA. STATEMENT OF SIGNIFICANCE: Peritendinous adhesions (PA) are a common and disabling condition that seriously affects the prognosis and quality of life of post-trauma patients. Current treatments often have limited efficacy or severe side effects, leaving a serious gap in clinical practice. We developed a significant biomaterial, poly(lactic acid)-dipyridamole graft copolymer electrospun nanofibrous membrane (PLC-DP), specifically for PA inhibition.In addition, this study uniquely combines dipyridamole, an anti-adhesive agent, and enzyme-sensitive copolymers in electrospun nanofibrous membrane. Unlike conventional drug-loaded electrospun nanofibrous membranes, PLC-DPs have enzyme-sensitive drug properties that allow for sustained drug release on demand. Our experiments showed that implantation of PLC-DP was effective in reducing tissue adhesions by 47% without affecting tendon healing. We elucidated the mechanism behind this phenomenon, suggesting that PCD activates FXYD2 to inhibit TGF-ß-induced expression of Col III, which is a key factor in PA development.

Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.

Spatial network analysis and driving forces of urban carbon emission performance: Insights from Guangdong Province.

As the primary contributor to carbon emissions, how cities enhance their carbon emission performance and mitigate emissions is crucial for achieving low-carbon urban environments in China. However, existing research often overlooks the spatial interconnectedness of carbon emission performance, neglecting reciprocal influences among cities. This study examines the network structure of carbon emission performance among Guangdong's cities from 1997 to 2019, using a super-efficient SBM model and social network analysis, and measures spatial impacts of network factors with the spatial Durbin model. Findings reveal that: (1) The overall network of carbon emission performance is relatively loose with minimal changes in connectivity and efficiency but shows significant local clustering. (2) Shenzhen, Guangzhou, and Zhuhai have high centrality, dominating carbon emission performance resources and acting as key transmission nodes, while most other regions have low centrality, indicating network polarization and potential vulnerabilities. (3) Enhancing a region's centrality, economic development, industrial structure, openness, and attraction of talent and technology can boost local carbon emission performance, but may also lead to the displacement of emissions to neighboring areas and outflow of low-carbon and innovative elements, negatively affecting surrounding regions through spatial spillover effects. This research advances regional carbon emission reduction strategies by highlighting the interplay between spatial networks and carbon emission performance, fostering synergies in reduction efforts.

ß-resorcylic acid released by Limosilactobacillus reuteri protects against cisplatin-induced ovarian toxicity and infertility.

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib.

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

Deep-learning radiomics based on ultrasound can objectively evaluate thyroid nodules and assist in improving the diagnostic level of ultrasound physicians.

Background: The incidence rate of thyroid nodules has reached 65%, but only 5-15% of these modules are malignant. Therefore, accurately determining the benign and malignant nature of thyroid nodules can prevent unnecessary treatment. We aimed to develop a deep-learning (DL) radiomics model based on ultrasound (US), explore its diagnostic efficacy for benign and malignant thyroid nodules, and verify whether it improved the diagnostic level of physicians. Methods: We retrospectively included 1,076 thyroid nodules from 817 patients at three institutions. The radiomics and DL features of the US images were extracted and used to construct radiomics signature (Rad_sig) and deep-learning signature (DL_sig). A Pearson correlation analysis and least absolute shrinkage and selection operator (LASSO) regression analysis were used for feature selection. Clinical US semantic signature (C_US_sig) was constructed based on clinical information and US semantic features. Next, a combined model was constructed based on the above three signatures in the form of a nomogram. The model was constructed using a development set (institution 1: 719 nodules), and the model was evaluated using two external validation sets (institution 2: 74 nodules, and institution 3: 283 nodules). The performance of the model was assessed using decision curve analysis (DCA) and calibration curves. Furthermore, the C_US_sigs of junior physicians, senior physicians, and expers were constructed. The DL radiomics model was used to assist the physicians with different levels of experience in the interpretation of thyroid nodules. Results: In the development and validation sets, the combined model showed the highest performance, with areas under the curve (AUCs) of 0.947, 0.917, and 0.929, respectively. The DCA results showed that the comprehensive nomogram had the best clinical utility. The calibration curves indicated good calibration for all models. The AUCs for distinguishing between benign and malignant thyroid nodules by junior physicians, senior physicians, and experts were 0.714-0.752, 0.740-0.824, and 0.891-0.908, respectively; however, with the assistance of DL radiomics, the AUCs reached 0.858-0.923, 0.888-0.944, and 0.912-0.919, respectively. Conclusions: The nomogram based on DL radiomics had high diagnostic efficacy for thyroid nodules, and DL radiomics could assist physicians with different levels of experience to improve their diagnostic level.

Prediction models for retinopathy of prematurity occurrence based on artificial neural network.

INTRODUCTION: Early prediction and timely treatment are essential for minimizing the risk of visual loss or blindness of retinopathy of prematurity, emphasizing the importance of ROP screening in clinical routine. OBJECTIVE: To establish predictive models for ROP occurrence based on the risk factors using artificial neural network. METHODS: A cohort of 591 infants was recruited in this retrospective study. The association between ROP and perinatal factors was analyzed by univariate analysis and multivariable logistic regression. We developed predictive models for ROP screening using back propagation neural network, which was further optimized by applying genetic algorithm method. To assess the predictive performance of the models, the areas under the curve, sensitivity, specificity, negative predictive value, positive predictive value and accuracy were used to show the performances of the prediction models. RESULTS: ROP of any stage was found in 193 (32.7%) infants. Twelve risk factors of ROP were selected. Based on these factors, predictive models were built using BP neural network and genetic algorithm-back propagation (GA-BP) neural network. The areas under the curve for prediction models were 0.857, and 0.908 in test, respectively. CONCLUSIONS: We developed predictive models for ROP using artificial neural network. GA-BP neural network exhibited superior predictive ability for ROP when dealing with its non-linear clinical data.

Self-folding RCA product into a parallel monolayer DNA nanoribbon and woven into a nano-fence structure by a short bridge strand.

The universal programmed construction of patterned periodic self-assembled nanostructures is a technical challenge in DNA origami nanotechnology but has numerous potential applications in biotechnology and biomedicine. In order to circumvent the dilemma that traditional DNA origami requires a long unusual single-stranded virus DNA as the scaffold and hundreds or even thousands of short strands as staples, we report a method for constructing periodically-self-folded rolling circle amplification products (RPs). The repeating unit is designed to have 3 intra-unit duplexes (inDP1,2,3) and 2 between-unit duplexes (buDP1,2). Based on the complementary pairing of bases, RPs each can self-fold into a periodic grid-patterned ribbon (GR) without the help of any auxiliary oligonucleotide staple. Moreover, by using only an oligonucleotide bridge strand, the GRs are connected together into the larger and denser planar nano-fence-shaped product (FP), which substantially reduces the number of DNA components compared with DNA origami and eliminates the obstacles in the practical application of DNA nanostructures. More interestingly, the FP-based DNA framework can be easily functionalized to offer spatial addressability for the precise positioning of nanoparticles and guest proteins with high spatial resolution, providing a new avenue for the future application of DNA assembled framework nanostructures in biology, material science, nanomedicine and computer science that often requires the ordered organization of functional moieties with nanometer-level and even molecular-level precision.

Intelligent medicine in focus: the 5 stages of evolution in robot-assisted surgery for prostate cancer in the past 20 years and future implications.

Robot-assisted surgery has evolved into a crucial treatment for prostate cancer (PCa). However, from its appearance to today, brain-computer interface, virtual reality, and metaverse have revolutionized the field of robot-assisted surgery for PCa, presenting both opportunities and challenges. Especially in the context of contemporary big data and precision medicine, facing the heterogeneity of PCa and the complexity of clinical problems, it still needs to be continuously upgraded and improved. Keeping this in mind, this article summarized the 5 stages of the historical development of robot-assisted surgery for PCa, encompassing the stages of emergence, promotion, development, maturity, and intelligence. Initially, safety concerns were paramount, but subsequent research and engineering advancements have focused on enhancing device efficacy, surgical technology, and achieving precise multi modal treatment. The dominance of da Vinci robot-assisted surgical system has seen this evolution intimately tied to its successive versions. In the future, robot-assisted surgery for PCa will move towards intelligence, promising improved patient outcomes and personalized therapy, alongside formidable challenges. To guide future development, we propose 10 significant prospects spanning clinical, research, engineering, materials, social, and economic domains, envisioning a future era of artificial intelligence in the surgical treatment of PCa.

Pathological RNA-protein inclusions and dysregulated A-to-I RNA editing in synucleinopathies.

Aggregation of RNA binding proteins and dysregulation of RNA metabolism drives pathogenesis of multiple neurodegenerative diseases. In this issue of Neuron, Belur et al.1 identified pathological NONO/SFPQ inclusions and aberrant A-to-I-edited RNAs accumulated in nucleus, leading to dysregulation of gene expression and neurodegeneration in synucleinopathy-associated diseases.

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial.

BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.

Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.

Novel thiomaleimide-based fluorescent probe with aggregation-induced emission for detecting H2S.

It has been well established that Hydrogen sulfide (H2S) is involved in various pathophysiological processes. Therefore, accurate monitoring H2S levels in vitro or vivo is of great significance in biological systems. Herein, we firstly developed a thiomaleimide-based compound MAL-1 bearing aggregation-induced emission characteristic for selective response toward H2S due to its nucleophilicity. The proposed sensor presented prominent sensitivity and selectivity with low detection limit of 75 nM and pseudo-first-order reaction rate constant of 9.65 × 10-2 s-1, as well as low cytotoxicity which works well in recognizing H2S in real samples and visualizing H2S in living cells. Thus, it could be concluded that the novel thiomaleimide-based probe would be a promising tool for assessing intracellular H2S levels.

Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS.

Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.