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Twisted bilayer graphene (tBLG) has recently attracted growing interest due to its unique twist-angle-dependent electronic properties. The preparation of high-quality large-area bilayer graphene with rich rotation angles would be important for the investigation of angle-dependent physics and applications, which, however, is still challenging. Here, we demonstrate a chemical vapor deposition (CVD) approach for growing high-quality tBLG using a hetero-site nucleation strategy, which enables the nucleation of the second layer at a different site from that of the first layer. The fraction of tBLGs in bilayer graphene domains with twist angles ranging from 0° to 30° was found to be improved to 88%, which is significantly higher than those reported previously. The hetero-site nucleation behavior was carefully investigated using an isotope-labeling technique. Furthermore, the clear Moiré patterns and ultrahigh room-temperature carrier mobility of 68,000 cm 2  V −1  s −1 confirmed the high crystalline quality of our tBLG. Our study opens an avenue for the controllable growth of tBLGs for both fundamental research and practical applications. The synthesis of twisted bilayer graphene with controllable angles is challenging. Here, the authors devise a chemical vapor deposition approach using a hetero-site nucleation strategy that affords twist angles ranging from 0° to 30°.

Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response. Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.

PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18–75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0–1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1–14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5–23·5) months. 28 (54%; 95% CI 35–68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39–80) had a pathological complete response. 38 (73%; 95% CI 59–84) of 52 patients had a complete response. Grade 3–5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. For the Chinese translation of the abstract see Supplementary Materials section.

Topological semimetals in crystals with a chiral structure (which possess a handedness due to a lack of mirror and inversion symmetries) are expected to display numerous exotic physical phenomena, including fermionic excitations with large topological charge1, long Fermi arc surface states2,3, unusual magnetotransport4 and lattice dynamics5, as well as a quantized response to circularly polarized light6. So far, all experimentally confirmed topological semimetals exist in crystals that contain mirror operations, meaning that these properties do not appear. Here, we show that AlPt is a structurally chiral topological semimetal that hosts new four-fold and six-fold fermions, which can be viewed as a higher spin generalization of Weyl fermions without equivalence in elementary particle physics. These multifold fermions are located at high symmetry points and have Chern numbers larger than those in Weyl semimetals, thus resulting in multiple Fermi arcs that span the full diagonal of the surface Brillouin zone. By imaging these long Fermi arcs, we experimentally determine the magnitude and sign of their Chern number, allowing us to relate their dispersion to the handedness of their host crystal.AlPt is shown to be a chiral topological material with four-fold and six-fold degeneracies in the band structure. Fermi arc edge states span the whole Brillouin zone and their dispersion enables identification of the handedness of the chiral material.

Periodontitis, a chronic inflammatory disease affecting 20%-50% of adults worldwide, is driven by polymicrobial synergy and dysbiosis. Despite numerous studies on the oral microbiota in periodontitis, significant heterogeneity exists between findings, posing challenges for treatment strategies. To understand the sources of this variability and establish standardized protocols, we reviewed the literature to identify potential factors contributing to these discrepancies. We found most studies focus on microbial communities in periodontal pockets, with fewer investigating microbial composition within gingival tissue. Research indicates that bacterial communities in gingival tissue exist as biofilms, potentially serving as reservoirs for persistent infection. Therefore, further exploration of the microbiome within periodontal tissues is needed, which may offer new insights for treatment strategies. Metatranscriptomics provides valuable insights into gene expression patterns of the oral microbiota, enabling the exploration of microbial activity at a functional level. Previous studies revealed that most upregulated virulence factors in periodontitis originate from species not traditionally considered major periodontal pathogens. However, current studies have not fully identified or revealed the functional changes in key symbiotic microbes in periodontitis. We reviewed the analytical paradigms of metatranscriptomics and found that current analysis is largely limited to assessing functional changes in known periodontal pathogens, highlighting the need for a functional-driven approach. Beyond the limitations of current analytical paradigms, the metatranscriptomics also has inherent constraints. We suggested integrating emerging high-throughput microbial sequencing technologies with functional-driven analytical strategies to provide a more comprehensive and higher-resolution insight for microbiome reconstruction in periodontitis.

Periodontal disease (PD), as an age-related disease, prevalent in middle-aged and elderly population, is characterized as inflammatory periodontal tissue loss, including gingival inflammation and alveolar bone resorption. However, the definite mechanism of aging-related inflammation in PD pathology needs further investigation. Our study is aimed at exploring the effect of inflamm-aging-related cytokines of interleukin-17 (IL-17) and interferon-γ (IFN-γ) on osteoclastogenesis in vitro and periodontal destruction in vivo. For receptor activator of nuclear factor-κB ligand- (RANKL-) primed bone marrow macrophages (BMMs), IL-17 and IFN-γ enhanced osteoclastogenesis, with the expression of osteoclastogenic mRNA (TRAP, c-Fos, MMP-9, Ctsk, and NFATc1) and protein (c-Fos and MMP-9) upregulated. Ligament-induced rat models were established to investigate the role of IL-17 and IFN-γ on experimental periodontitis. Both IL-17 and IFN-γ could enhance the local inflammation in gingival tissues. Although there might be an antagonistic interaction between IL-17 and IFN-γ, IL-17 and IFN-γ could facilitate alveolar bone loss and osteoclast differentiation.

Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.

The incidence of young-onset colorectal cancer (yCRC) has been increasing in recent decades, but little is known about the gut microbiome of these patients. Most studies have focused on old-onset CRC (oCRC), and it remains unclear whether CRC signatures derived from old patients are valid in young patients. To address this, we assembled the largest yCRC gut metagenomes to date from two independent cohorts and found that the CRC microbiome had limited association with age across adulthood. Differential analysis revealed that well-known CRC-associated taxa, such as Clostridium symbiosum , Peptostreptococcus stomatis , Parvimonas micra and Hungatella hathewayi were significantly enriched (false discovery rate <0.05) in both old- and young-onset patients. Similar strain-level patterns of Fusobacterium nucleatum , Bacteroides fragilis and Escherichia coli were observed for oCRC and yCRC. Almost all oCRC-associated metagenomic pathways had directionally concordant changes in young patients. Importantly, CRC-associated virulence factors ( fadA , bft ) were enriched in both oCRC and yCRC compared to their respective controls. Moreover, the microbiome-based classification model had similar predication accuracy for CRC status in old- and young-onset patients, underscoring the consistency of microbial signatures across different age groups. The rising incidence of young-onset sporadic colorectal cancer (yCRC) is global concern. Here, leveraging a substantial number of deep sequencing metagenomes, the authors show striking similarities in gut microbial patterns at both the taxonomic and selected gene marker levels between yCRC and old-onset CRC.

Background At present, skeletal tuberculosis (TB) diagnosis is mostly by histopathology, but the positivity rate is low. There is a need to develop new methods for the molecular identification of this disorder. Therefore, we aimed to investigate the clinical utility of quantitative PCR (qPCR)-based diagnosis of skeletal TB from formalin-fixed paraffin-embedded (FFPE) tissues and its comparative evaluation with acid-fast bacillus staining (AFS). Methods We detected Mycobacterium tuberculosis ( M. tuberculosis/ MTB) DNA using qPCR and AFS in FFPE tissue samples from 129 patients suspected of having skeletal TB. The sensitivity, specificity as well as area under the curve (AUC) of qPCR and AFS were calculated. Meanwhile, some factors potentially affecting qPCR and AFS results were investigated. Results Overall, qPCR outperformed AFS in detecting M. tuberculosis . The AUC of qPCR was higher than that of AFS (0.744 vs.0.561, p  < 0.001). Furthermore, decalcification of bone tissues did not affect the sensitivity and specificity of qPCR tests. Whereas it impacted the performance of AFS, decalcification increased AFS's specificity and decreased its sensitivity (p < 0.05). Moreover, qPCR had a significantly larger AUC than AFS in decalcified and non-decalcified groups (0.735/0.756 vs. 0.582/0.534,  p  < 0.001) respectively. Similarly, the AUC of PCR was more extensive than that of AFS regardless of skeletal TB patients with concomitant pulmonary TB or not (0.929 vs. 0.762; 0.688 vs. 0.524, p  < 0.01). Conclusions Our data demonstrate that qPCR offers superior accuracy for the detection of mycobacteria in FFPE tissues compared to traditional AFS, indicating its clinical value in osteoarticular TB diagnosis.

Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.