The efficacy and safety of neoadjuvant immunochemotherapy in resectable stage I-III non-small cell lung cancer: a systematic review and network meta-analysis.

BACKGROUND: Neoadjuvant immunochemotherapy (NICT) is a new treatment method for resectable non-small-cell lung cancer (NSCLC). Network meta-analysis assessed efficacy, safety, and optimal treatment. METHODS: We searched for randomized controlled trials (RCTs) comparing NICT with neoadjuvant chemotherapy (NCT) in PubMed, Embase, Web of Science, Cochrane Library, and international conferences. Outcomes were surgical resection rate, pathological complete response(pCR),event-free survival (EFS), and Grade 3-5 treatment-related adverse events (TRAEs). RESULTS: RCTs of 3,387 patients, six treatment combinations, and two modalities were included. Meta-analysis showed that NICT yielded higher pCR and EFS rates than NCT. The toripalimab-chemotherapy combination had the highest surgical resection rate (OR = 1.68, 95% CI: 1.05-2.73), pCR (OR = 38.84, 95% CI: 11.05-268.19) and EFS (HR = 0.40, 95% CI: 0.28-0.58).This regimen worked well for patients with low programmed death-ligand 1 (PD-L1) expression or squamous cell pathology. For high PD-L1 expression and patients with NSCLC, neoadjuvant nivolumab with chemotherapy had the most efficacy. The incidence of treatment-related adverse events increased with longer treatment cycles, with perioperative nivolumab combined with chemotherapy showing the worst safety profile (RR = 1.32, 95% CI: 1.00-1.76), while neoadjuvant nivolumab combined with chemotherapy alone had the best safety profile (RR = 0.91, 95% CI: 0.68-1.21). Indirect comparison showed no survival benefit for neoadjuvant-adjuvant immunotherapy (HR = 0.93, 95% CI: 0.65-1.35). In the indirect comparison between the two immune checkpoint inhibitors(ICIs), although there was no significant difference in EFS (HR = 0.81, 95% CI: 0.61-1.08), PD-1 inhibitors may still be the most effective treatment option. CONCLUSIONS: NICT effectively and safely treats resectable NSCLC. The optimal treatment combination is typically toripalimab and chemotherapy. Treatment based on PD-L1 expression and pathological type is recommended.

Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination.

The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors1. DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1-BARD1 (ref. 2). Specifically, three distinct nuclease entities-the 5'-3' exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase-act in synergy to execute the end resection process3. A major question concerns whether BRCA1-BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1-BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1-BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1-BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1-BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells.

Protocol for evaluating the E3 ligase activity of BRCA1-BARD1 and its variants by nucleosomal histone ubiquitylation.

The tumor suppressor breast cancer 1 (BRCA1) complexed with BRCA1-associated RING domain 1 (BARD1), a RING-type E3 ligase, facilitates the attachment of ubiquitin onto the substrate protein. Here, we present a protocol for evaluating the E3 ligase activity of BRCA1-BARD1 and its variants by nucleosomal histone ubiquitylation. We describe steps for isolating 147 bp Widom 601 DNA and assembling nucleosome core particles (NCPs). We then detail procedures for the in vitro ubiquitylation of nucleosome histone H2A by BRCA1-BARD1 and its variants. For complete details on the use and execution of this protocol, please refer to Wang et al.1.

Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis.

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.

Achromatic and Coma-Corrected Hybrid Meta-Optics for High-Performance Thermal Imaging.

Long-wave infrared (LWIR) imaging, or thermal imaging, is widely applied in night vision and security monitoring. However, the widespread use of LWIR imagers is impeded by their bulky size, considerable weight, and high cost. While flat meta-optics present a potential solution to these limitations, existing pure LWIR meta-optics face constraints such as severe chromatic or coma aberrations. Here, we introduce an approach utilizing large-scale hybrid meta-optics to address these challenges and demonstrate the achromatic, coma-corrected, and polarization-insensitive thermal imaging. The hybrid metalens doublet is composed of a metasurface corrector and a refractive lens, featuring a full field-of-view angle surpassing 20° within the 8-12 µm wavelength range. Employing this hybrid metalens doublet, we showcase high-performance thermal imaging capabilities both indoors and outdoors, effectively capturing ambient thermal radiation. The proposed hybrid metalens doublet holds considerable promise for advancing miniaturized, lightweight, and cost-effective LWIR optical imaging systems.

Brain development of a school-aged boy with autism spectrum condition talented in arithmetic: a case report.

Whereas autism spectrum condition is known for its social and communicative challenges, some autistic children demonstrate unusual islets of abilities including those related to mathematics, the neurobiological underpinnings of which are increasingly becoming the focus of research. Here we describe an 8-year-old autistic boy with intellectual and language challenges, yet exceptional arithmetic ability. He can perform verbal-based multiplication of three- and even four-digit numbers within 20 seconds. To gain insights into the neural basis of his talent, we investigated the gray matter in the child's brain in comparison to typical development, applying voxel-based morphometry to magnetic resonance imaging data. The case exhibited reduced gray matter volume in regions associated with arithmetic, which may suggest an accelerated development of brain regions with arithmetic compared to typically developing individuals: potentially a key factor contributing to his exceptional talent. Taken together, this case report describes an example of the neurodiversity of autism. Our research provides valuable insights into the potential neural basis of exceptional arithmetic abilities in individuals with the autism spectrum and its potential contribution to depicting the diversity and complexity of autism.

Evolved histone tail regulates 53BP1 recruitment at damaged chromatin.

The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin.

Impacts and Risk Assessments of Climate Change for the Yields of the Major Grain Crops in China, Japan, and Korea.

Climate change poses a high risk to grain yields. Maize, rice, and wheat are the three major grain crops in China, Japan, and Korea. Assessing the impacts and risks of climate on the yields of these grain cops is crucial. An economy-climate model (C-D-C model) was established to assess the impacts of climate factors on the grain yields in different crop areas. The peaks over threshold model based on the generalized Pareto distribution was used to calculate the value at risk and the expected shortfall, which can evaluate the yield risk of different crops. The impact ratio of climate change was employed to estimate the impacts of climate change under different climate scenarios. The main conclusions can be summarized as follows: the impacts of climate factors on grain yields and the risk vary widely across the different regions and crops. Compared to 1991-2020, climate change from 2021 to 2050 exerts positive impacts on rice and wheat, while the negative impacts on maize in the crop areas are significantly affected by climate factors. The impact ratios of climate change are larger in the SSP1-2.6 and the SSP5-8.5 scenarios than under the SSP2-4.5 scenario. These findings are useful for targeting grain yields in smaller study areas.

Horizontally-oriented barium titanate@polydomine/polyimide nanocomposite films for high-temperature energy storage.

High-temperature ceramics polymer dielectric nanocomposite materials have broad application prospects in energy storage. The barium titanate (BT) plays an important role as one of outstanding representative ceramics in the dielectric nanocomposite materials. However, there is little known for the effects of two-dimensional (2D) BT morphology and layout on the properties of high-temperature nanocomposite materials. Hence, 2D scale-like BT ceramic fillers were prepared from layered K0.8Li0.27Ti1.73O4 crystals as precursors using a combined solid-state and hydrothermal process. 2D scale-like BT@polydopamine (PDA) core-shell nanocomposites were prepared via coating PDA on the BT. BT@PDA/polyimide(PI) nanocomposite films were fabricated by horizontally oriented distribution of BT@PDA in the PI matrix. The BT@PDA/PI nanocomposite films exhibit a high energy density (3.34 J/cm3) and high charge-discharge efficiency (83.68 %) at 150 °C. It is currently the highest energy storage performance in the BT/PI nanocomposite films at 150 °C. The excellent properties are due to preventing upward breakdown of electrical pathways and promoting dispersion and entanglement of the electrical pathway routes. Additionally, strong electrostatic interactions between the different polymer chains (PDA and PI) restricts the movement of space charges. This work demonstrates that introducing horizontally oriented, organically shell-modified and 2D small-sized BT nanoparticles into a PI matrix is an effective method for improving energy storage performance.

Structure, Properties, Preparation, and Application of Layered Titanates.

As a typical cation-exchangeable layered compound, layered titanate has a unique open layered structure. Its excellent physical and chemical properties allow its wide use in the energy, environmental protection, electronics, biology, and other fields. This paper reviews the recent progress in the research on the structure, synthesis, properties, and application of layered titanates. Various reactivities, as well as the advantages and disadvantages, of different synthetic methods are discussed. The reaction mechanism and influencing factors of the ion exchange reaction, intercalation reaction, and exfoliation reaction are analyzed. The latest research progress on layered titanates and their modified products in the fields of photocatalysis, adsorption, electrochemistry, and other applications is summarized. Finally, the future development of layered titanate and its exfoliated product two-dimensional nanosheets is proposed.

OBMeta: a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases.

MOTIVATION: Gut dysbiosis is closely associated with obesity and related metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). The gut microbial features and biomarkers have been increasingly investigated in many studies, which require further validation due to the limited sample size and various confounding factors that may affect microbial compositions in a single study. So far, it lacks a comprehensive bioinformatics pipeline providing automated statistical analysis and integrating multiple independent studies for cross-validation simultaneously. RESULTS: OBMeta aims to streamline the standard metagenomics data analysis from diversity analysis, comparative analysis, and functional analysis to co-abundance network analysis. In addition, a curated database has been established with a total of 90 public research projects, covering three different phenotypes (Obesity, T2D, and NAFLD) and more than five different intervention strategies (exercise, diet, probiotics, medication, and surgery). With OBMeta, users can not only analyze their research projects but also search and match public datasets for cross-validation. Moreover, OBMeta provides cross-phenotype and cross-intervention-based advanced validation that maximally supports preliminary findings from an individual study. To summarize, OBMeta is a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases. AVAILABILITY AND IMPLEMENTATION: OBMeta is freely available at: http://obmeta.met-bioinformatics.cn/.

Developmental prediction modeling based on diffusion tensor imaging uncovering age-dependent heterogeneity in early childhood autistic brain.

OBJECTIVE: There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people in early childhood is clouded by the concurrently rapid brain growth, which might lead to the inconsistent findings of atypical WM microstructure in autism. Here, we aimed to reveal the developmental nature of autistic children and delineate atypical WM microstructure throughout early childhood while taking developmental considerations into account. METHOD: In this study, diffusion tensor imaging was acquired from two independent cohorts, containing 91 autistic children and 100 typically developing children (TDC), aged 4-7 years. Developmental prediction modeling using support vector regression based on TDC participants was conducted to estimate the WM atypical development index of autistic children. Then, subgroups of autistic children were identified by using the k-means clustering method and were compared to each other on the basis of demographic information, WM atypical development index, and autistic trait by using two-sample t-test. Relationship of the WM atypical development index with age was estimated by using partial correlation. Furthermore, we performed threshold-free cluster enhancement-based two-sample t-test for the group comparison in WM microstructures of each subgroup of autistic children with the rematched subsets of TDC. RESULTS: We clustered autistic children into two subgroups according to WM atypical development index. The two subgroups exhibited distinct developmental stages and age-dependent diversity. WM atypical development index was found negatively associated with age. Moreover, an inverse pattern of atypical WM microstructures and different clinical manifestations in the two stages, with subgroup 1 showing overgrowth with low level of autistic traits and subgroup 2 exhibiting delayed maturation with high level of autistic traits, were revealed. CONCLUSION: This study illustrated age-dependent heterogeneity in early childhood autistic children and delineated developmental stage-specific difference that ranged from an overgrowth pattern to a delayed pattern. Trial registration This study has been registered at ClinicalTrials.gov (Identifier: NCT02807766) on June 21, 2016 ( https://clinicaltrials.gov/ct2/show/NCT02807766 ).

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones. Cells expressing either of these BRCA1-BARD1 separation-of-function alleles are hypersensitive to DNA-damaging agents. Furthermore, we demonstrate that BRCA1-BARD1 ligase is not only required for DNA resection during homology-directed repair (HDR) but also contributes to later stages for HDR completion. Altogether, our findings reveal crucial, previously unrecognized roles of BRCA1-BARD1 ligase activity in genome repair via HDR, settle prior controversies regarding BRCA1-BARD1 ligase functions, and catalyze new efforts to uncover substrates related to tumor suppression.

Meet the authors: Meiling Wang, Wenjing Li, and Weixing Zhao.

Molecular Cell talks to co-first authors Meiling Wang and Wenjing Li with co-corresponding author Weixing Zhao about their paper, "Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair" (in this issue of Molecular Cell) and what motivates their scientific pursuits.

BRCA1/BARD1 intrinsically disordered regions facilitate chromatin recruitment and ubiquitylation.

BRCA1/BARD1 is a tumor suppressor E3 ubiquitin (Ub) ligase with roles in DNA damage repair and in transcriptional regulation. BRCA1/BARD1 RING domains interact with nucleosomes to facilitate mono-ubiquitylation of distinct residues on the C-terminal tail of histone H2A. These enzymatic domains constitute a small fraction of the heterodimer, raising the possibility of functional chromatin interactions involving other regions such as the BARD1 C-terminal domains that bind nucleosomes containing the DNA damage signal H2A K15-Ub and H4 K20me0, or portions of the expansive intrinsically disordered regions found in both subunits. Herein, we reveal novel interactions that support robust H2A ubiquitylation activity mediated through a high-affinity, intrinsically disordered DNA-binding region of BARD1. These interactions support BRCA1/BARD1 recruitment to chromatin and sites of DNA damage in cells and contribute to their survival. We also reveal distinct BRCA1/BARD1 complexes that depend on the presence of H2A K15-Ub, including a complex where a single BARD1 subunit spans adjacent nucleosome units. Our findings identify an extensive network of multivalent BARD1-nucleosome interactions that serve as a platform for BRCA1/BARD1-associated functions on chromatin.

Oriented Plate-like KNbO3 Polycrystals: Topochemical Mesocrystal Conversion and Piezoelectric and Photocatalytic Responses.

KNbO3 (KN) with a perovskite structure is an outstanding representative of lead-free piezoelectric materials, and its mesocrystals have broad application prospects in the fields of catalysis, energy storage, and conversion. However, the formation conditions of KN mesocrystals reported so far are difficult owing to their high aspect ratio and excellent preferred orientation. In this study, the solvothermal process was used successfully to prepare the flake-like potassium salt of Lindquist hexaniobate (K8Nb6O19·10H2O). Subsequently, the precursor niobate was calcined to prepare two-dimensional (2D) plate-like KN mesocrystals. The formation mechanism of the plate-like KN mesocrystals is further revealed from a paired topochemical mesocrystal conversion of K8Nb6O19·10H2O niobate. Finally, the microscopic piezoelectric and photocatalytic responses of the obtained plate-like KN mesocrystals were investigated. The high piezoelectric coefficient of plate-like KN mesocrystals implies that excellent charge separation promotes the photocatalytic performance of rhodamine B (RhB). This study provides a strategy for the efficient application of 2D oriented materials in the field of piezoelectricity and photocatalysis.

Structural insights into BCDX2 complex function in homologous recombination.

Homologous recombination (HR) fulfils a pivotal role in the repair of DNA double-strand breaks and collapsed replication forks1. HR depends on the products of several paralogues of RAD51, including the tetrameric complex of RAD51B, RAD51C, RAD51D and XRCC2 (BCDX2)2. BCDX2 functions as a mediator of nucleoprotein filament assembly by RAD51 and single-stranded DNA (ssDNA) during HR, but its mechanism remains undefined. Here we report cryogenic electron microscopy reconstructions of human BCDX2 in apo and ssDNA-bound states. The structures reveal how the amino-terminal domains of RAD51B, RAD51C and RAD51D participate in inter-subunit interactions that underpin complex formation and ssDNA-binding specificity. Single-molecule DNA curtain analysis yields insights into how BCDX2 enhances RAD51-ssDNA nucleoprotein filament assembly. Moreover, our cryogenic electron microscopy and functional analyses explain how RAD51C alterations found in patients with cancer3-6 inactivate DNA binding and the HR mediator activity of BCDX2. Our findings shed light on the role of BCDX2 in HR and provide a foundation for understanding how pathogenic alterations in BCDX2 impact genome repair.

DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation.

The tumor suppressor BRCA2 participates in DNA double-strand break repair by RAD51-dependent homologous recombination and protects stressed DNA replication forks from nucleolytic attack. We demonstrate that the C-terminal Recombinase Binding (CTRB) region of BRCA2, encoded by gene exon 27, harbors a DNA binding activity. CTRB alone stimulates the DNA strand exchange activity of RAD51 and permits the utilization of RPA-coated ssDNA by RAD51 for strand exchange. Moreover, CTRB functionally synergizes with the Oligonucleotide Binding fold containing DNA binding domain and BRC4 repeat of BRCA2 in RPA-RAD51 exchange on ssDNA. Importantly, we show that the DNA binding and RAD51 interaction attributes of the CTRB are crucial for homologous recombination and protection of replication forks against MRE11-mediated attrition. Our findings shed light on the role of the CTRB region in genome repair, reveal remarkable functional plasticity of BRCA2, and help explain why deletion of Brca2 exon 27 impacts upon embryonic lethality.