The Making of a Flight Feather: Bio-architectural Principles and Adaptation.

The evolution of flight in feathered dinosaurs and early birds over millions of years required flight feathers whose architecture features hierarchical branches. While barb-based feather forms were investigated, feather shafts and vanes are understudied. Here, we take a multi-disciplinary approach to study their molecular control and bio-architectural organizations. In rachidial ridges, epidermal progenitors generate cortex and medullary keratinocytes, guided by Bmp and transforming growth factor ß (TGF-ß) signaling that convert rachides into adaptable bilayer composite beams. In barb ridges, epidermal progenitors generate cylindrical, plate-, or hooklet-shaped barbule cells that form fluffy branches or pennaceous vanes, mediated by asymmetric cell junction and keratin expression. Transcriptome analyses and functional studies show anterior-posterior Wnt2b signaling within the dermal papilla controls barbule cell fates with spatiotemporal collinearity. Quantitative bio-physical analyses of feathers from birds with different flight characteristics and feathers in Burmese amber reveal how multi-dimensional functionality can be achieved and may inspire future composite material designs. VIDEO ABSTRACT.

Protein-Based Inheritance: Epigenetics beyond the Chromosome.

Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. This phenomenon has largely been studied in the context of chromatin modification. Yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. Most such proteins are prions (e.g., [PSI+], [URE3], [SWI+], [MOT3+], [MPH1+], [LSB+], and [GAR+]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. This allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis. In some circumstances, self-templating can fuel disease, but it also permits access to multiple activity states from the same polypeptide and transmission of that information across generations. Ensuing phenotypic changes allow genetically identical cells to express diverse and frequently adaptive phenotypes. Although long thought to be rare, protein-based epigenetic inheritance has now been uncovered in all domains of life.

Ubiquitous coexisting electron-mode couplings in high-temperature cuprate superconductors.

In conventional superconductors, electron-phonon coupling plays a dominant role in generating superconductivity. In high-temperature cuprate superconductors, the existence of electron coupling with phonons and other boson modes and its role in producing high-temperature superconductivity remain unclear. The evidence of electron-boson coupling mainly comes from angle-resolved photoemission (ARPES) observations of [Formula: see text]70-meV nodal dispersion kink and [Formula: see text]40-meV antinodal kink. However, the reported results are sporadic and the nature of the involved bosons is still under debate. Here we report findings of ubiquitous two coexisting electron-mode couplings in cuprate superconductors. By taking ultrahigh-resolution laser-based ARPES measurements, we found that the electrons are coupled simultaneously with two sharp modes at [Formula: see text]70meV and [Formula: see text]40meV in different superconductors with different dopings, over the entire momentum space and at different temperatures above and below the superconducting transition temperature. These observations favor phonons as the origin of the modes coupled with electrons and the observed electron-mode couplings are unusual because the associated energy scales do not exhibit an obvious energy shift across the superconducting transition. We further find that the well-known "peak-dip-hump" structure, which has long been considered a hallmark of superconductivity, is also omnipresent and consists of "peak-double dip-double hump" finer structures that originate from electron coupling with two sharp modes. These results provide a unified picture for the [Formula: see text]70-meV and [Formula: see text]40-meV energy scales and their evolutions with momentum, doping and temperature. They provide key information to understand the origin of these energy scales and their role in generating anomalous normal state and high-temperature superconductivity.

DNA methylation regulates biosynthesis of tanshinones and phenolic acids during growth of Salvia miltiorrhiza.

DNA methylation plays a crucial role in the regulation of plant growth and the biosynthesis of secondary metabolites. Danshen (Salvia miltiorrhiza) is a valuable Chinese herbal medicine commonly used to treat cardiovascular diseases; its active ingredients are tanshinones and phenolic acids, which primarily accumulate in roots. Here, we conducted a targeted metabolic analysis of S. miltiorrhiza roots at 3 distinct growth stages: 40 d old (r40), 60 d old (r60), and 90 d old (r90). The contents of tanshinones (cryptotanshinone, tanshinone I, tanshinone IIA, and rosmariquinone) and phenolic acids (rosmarinic acid and salvianolic acid B) gradually increased during plant development. Whole-genome bisulfite sequencing and transcriptome sequencing of roots at the 3 growth stages revealed an increased level of DNA methylation in the CHH context (H represents A, T, or C) context at r90 compared with r40 and r60. Increased DNA methylation levels were associated with elevated expression of various genes linked to epigenetic regulations, including CHROMOMETHYLASE2 (SmCMT2), Decrease in DNA Methylation 1 (SmDDM1), Argonaute 4 (SmAGO4), and DOMAINS REARRANGED METHYLTRANSFERASE 1 (SmDRM1). Moreover, expression levels of many genes involved in tanshinone and salvianolic acid biosynthesis, such as copalyldiphosphate synthase 5 (SmCPS5), cytochrome P450-related enzyme (SmCYP71D464), geranylgeranyl diphosphate synthase (SmGGPPS1), geranyl diphosphate synthase (SmGPPS), hydroxyphenylpyruvate reductase (SmHPPR), and hydroxyphenylpyruvate dioxygenase (SmHPPD), were altered owing to hyper-methylation, indicating that DNA methylation plays an important role in regulating tanshinone and phenolic acid accumulation. Our data shed light on the epigenetic regulation of root growth and the biosynthesis of active ingredients in S. miltiorrhiza, providing crucial clues for further improvement of active compound production via molecular breeding in S. miltiorrhiza.

Facioscapulohumeral Muscular Dystrophy is Associated With Altered Myoblast Proteome Dynamics.

Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D2O) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of "older" less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2'-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.

Guide-specific loss of efficiency and off-target reduction with Cas9 variants.

High-fidelity clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) variants have been developed to reduce the off-target effects of CRISPR systems at a cost of efficiency loss. To systematically evaluate the efficiency and off-target tolerance of Cas9 variants in complex with different single guide RNAs (sgRNAs), we applied high-throughput viability screens and a synthetic paired sgRNA-target system to assess thousands of sgRNAs in combination with two high-fidelity Cas9 variants HiFi and LZ3. Comparing these variants against wild-type SpCas9, we found that ∼20% of sgRNAs are associated with a significant loss of efficiency when complexed with either HiFi or LZ3. The loss of efficiency is dependent on the sequence context in the seed region of sgRNAs, as well as at positions 15-18 in the non-seed region that interacts with the REC3 domain of Cas9, suggesting that the variant-specific mutations in the REC3 domain account for the loss of efficiency. We also observed various degrees of sequence-dependent off-target reduction when different sgRNAs are used in combination with the variants. Given these observations, we developed GuideVar, a transfer learning-based computational framework for the prediction of on-target efficiency and off-target effects with high-fidelity variants. GuideVar facilitates the prioritization of sgRNAs in the applications with HiFi and LZ3, as demonstrated by the improvement of signal-to-noise ratios in high-throughput viability screens using these high-fidelity variants.

Aerobic glycolysis of bronchial epithelial cells rewires Mycoplasma pneumoniae pneumonia and promotes bacterial elimination.

The immune response to Mycoplasma pneumoniae infection plays a key role in clinical symptoms. Previous investigations focused on the pro-inflammatory effects of leukocytes and the pivotal role of epithelial cell metabolic status in finely modulating the inflammatory response have been neglected. Herein, we examined how glycolysis in airway epithelial cells is affected by M. pneumoniae infection in an in vitro model. Additionally, we investigated the contribution of ATP to pulmonary inflammation. Metabolic analysis revealed a marked metabolic shift in bronchial epithelial cells during M. pneumoniae infection, characterized by increased glucose uptake, enhanced aerobic glycolysis, and augmented ATP synthesis. Notably, these metabolic alterations are orchestrated by adaptor proteins, MyD88 and TRAM. The resulting synthesized ATP is released into the extracellular milieu via vesicular exocytosis and pannexin protein channels, leading to a substantial increase in extracellular ATP levels. The conditioned medium supernatant from M. pneumoniae-infected epithelial cells enhances the secretion of both interleukin (IL)-1ß and IL-18 by peripheral blood mononuclear cells, partially mediated by the P2X7 purine receptor (P2X7R). In vivo experiments confirm that addition of a conditioned medium exacerbates pulmonary inflammation, which can be attenuated by pre-treatment with a P2X7R inhibitor. Collectively, these findings highlight the significance of airway epithelial aerobic glycolysis in enhancing the pulmonary inflammatory response and aiding pathogen clearance.

Transformed pupil-function misalignment calibration strategy for Fourier ptychographic microscopy.

Fourier ptychographic microscopy (FPM) is an enabling quantitative phase imaging technique with both high-resolution (HR) and wide field-of-view (FOV), which can surpass the diffraction limit of the objective lens by employing an LED array to provide angular-varying illumination. The precise illumination angles are critical to ensure exact reconstruction, while it's difficult to separate actual positional parameters in conventional algorithmic self-calibration approaches due to the mixing of multiple systematic error sources. In this paper, we report a pupil-function-based strategy for independently calibrating the position of LED array. We first deduce the relationship between positional deviation and pupil function in the Fourier domain through a common iterative route. Then, we propose a judgment criterion to determine the misalignment situations, which is based on the arrangement of LED array in the spatial domain. By combining the mapping of complex domains, we can accurately solve the spatial positional parameters concerning the LED array through a boundary-finding scheme. Relevant simulations and experiments demonstrate the proposed method is accessible to precisely correct the positional misalignment of LED array. The approach based on the pupil function is expected to provide valuable insights for precise position correction in the field of microscopy.

Microbiome of periodontitis and peri-implantitis before and after therapy: Long-read 16S rRNA gene amplicon sequencing.

AIMS: The microbial profiles of peri-implantitis and periodontitis (PT) are inconclusive. The controversies mainly arise from the differences in sampling sites, targeted gene fragment, and microbiome analysis techniques. The objective of this study was to explore the microbiomes of peri-implantitis (PI), control implants (CI), PT and control teeth (CT), and the microbial change of PI after nonsurgical treatment (PIAT). METHODS: Twenty-two patients diagnosed with both PT and peri-implantitis were recruited. Clinical periodontal parameters and radiographic bone levels were recorded. In each patient, the subgingival and submucosal plaque samples were collected from sites with PI, CI, PT, CT, and PIAT. Microbiome diversity was analyzed by high-throughput amplicon sequencing using full-length of 16S rRNA gene by next generation sequencing. RESULTS: The 16S rRNA gene sequencing analysis revealed 512 OTUs in oral microbiome and 377 OTUs reached strain levels. The PI and PT groups possessed their own unique core microbiome. Treponema denticola was predominant in PI with probing depth of 8-10 mm. Interestingly, Thermovirga lienii DSM 17291 and Dialister invisus DSM 15470 were found to associate with PI. Nonsurgical treatment for peri-implantitis did not significantly alter the microbiome, except Rothia aeria. CONCLUSION: Our study suggests Treponemas species may play a pivotal role in peri-implantitis. Nonsurgical treatment did not exert a major influence on the peri-implantitis microbiome in short-term follow-up. PT and peri-implantitis possess the unique microbiome profiles, and different therapeutic strategies may be suggested in the future.

Anti-inflammatory effects of Olive (olea europaea L.) fruit extract in LPS-stimulated RAW264.7 cells via MAPK and NF-κB signal pathways.

BACKGROUND: Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are well-documented, there remains a dearth of in-depth researches on the immunosuppressive effects of olive fruit water extract. This study aimed to elucidate the dose-effect relationship and underlying molecular mechanisms of olive fruit extract in mediating anti-inflammatory responses. METHODS AND RESULTS: The impacts of olive fruit extract on the release of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukins-6 (IL-6) and reactive oxygen species (ROS) were assessed in RAW264.7 cells induced by lipopolysaccharide (LPS). For deeper understanding, the expression of genes encoding inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was quantitatively tested. Additionally, the expression patterns of MAPK and NF-κB pathways were further observed to analyze the action mechanisms. Results suggested that olive fruit extract (200, 500, 1000 µg/mL) markedly exhibited a dose-dependent reduction in the generation of NO, TNF-α, IL-6 and ROS, as well as the expression of correlative genes studied. The activation of ERK, JNK, p38, IκB-α and p65 were all suppressed when p65 nuclear translocation was further restricted by olive fruit extract in NF-κB and MAPK signal pathways. CONCLUSIONS: Olive fruit extract targeted imposing restrictions on the signal transduction of key proteins in NF-κB and MAPK pathways, and thereby lowered the level of inflammatory mediators, which put an enormous hindrance to inflammatory development. Accordingly, it is reasonable to consider olive fruit as a potent ingredient in immunomodulatory products.

Potential environmental and human health menace of spent graphite in lithium-ion batteries.

The growing demand for lithium-ion batteries for portable electronics and electric vehicles results in a booming lithium battery market, leading to a concomitant increase in spent graphite. This research investigated the potential impacts of spent graphite on environmental and human health using standardized toxicity extraction and Life Cycle Impact Assessment models. The spent graphite samples were classified as hazardous waste due to the average nickel content of 337.14 mg/L according to Chinese regulations. Besides, cadmium and fluorine were the other elements that exceeded the regulations threshold. Easily ignored aluminum and heavy metal cobalt are other harmful elements according to the results of Life Cycle Impact Assessments. All the metallic harmful elements mainly exist in a transferable state. Thermogravimetry infrared spectrometry coupled with mass spectrometry was employed to recognize the emitted gases and explore gas emission behavior. Inorganic gases of CO, H2S, SO2, SO3, oxynitride, HCl, and fluoride-containing gases were detected. Sulfur-containing gases released from spent graphite were contributed by the residual sulfuric acid after leaching. The correlation between the evolution of emitted gases and the heating schedule was established simultaneously. The research comprehensively illustrates the pollution of spent graphite and provides assistance for the design of green recycling schemes for spent graphite.

YouTube/ Bilibili/ TikTok videos as sources of medical information on laryngeal carcinoma: cross-sectional content analysis study.

BACKGROUND: YouTube, a widely recognized global video platform, is inaccessible in China, whereas Bilibili and TikTok are popular platforms for long and short videos, respectively. There are many videos related to laryngeal carcinoma on these platforms. This study aims to identify upload sources, contents, and feature information of these videos on YouTube, Bilibili, and TikTok, and further evaluate the video quality. METHODS: On January 1, 2024, we searched the top 100 videos by default sort order (300 videos in total) with the terms "laryngeal carcinoma" and "throat cancer" on YouTube, "" on Bilibili and TikTok. Videos were screened for relevance and similarity. Video characteristics were documented, and quality was assessed by using the Patient Education Materials Assessment Tool (PEMAT), Video Information and Quality Index (VIQI), Global Quality Score (GQS), and modified DISCERN (mDISCERN). RESULTS: The analysis included 99 YouTube videos, 76 from Bilibili, and 73 from TikTok. Median video lengths were 193 s (YouTube), 136 s (Bilibili), and 42 s (TikTok). TikTok videos demonstrated higher audience interaction. Bilibili had the lowest ratio of original contents (69.7%). Treatment was the most popular topic on YouTube and Bilibili, while that was the prognosis on TikTok. Solo narration was the most common video style across all platforms. Video uploaders were predominantly non-profit organizations (YouTube), self-media (Bilibili), and doctors (TikTok), with TikTok authors having the highest certification rate (83.3%). Video quality, assessed using PEMAT, VIQI, GQS, and mDISCERN, varied across platforms, with YouTube generally showing the highest scores. Videos from professional authors performed better than videos from non-professionals based on the GQS and mDISCERN scores. Spearman correlation analysis showed no strong relationships between the video quality and the audience interaction. CONCLUSIONS: Videos on social media platforms can help the public learn about the knowledge of laryngeal cancer to some extent. TikTok achieves the best flow, but videos on YouTube are of the best quality. However, the video quality across all platforms still needs enhancement. We need more professional uploaders to ameliorate the video quality related to laryngeal carcinoma. Content creators also should be aware of the certification, the originality, and the style of video shooting. As for the platforms, refining the algorithm will allow users to receive more high-quality videos.

Titanium Surfaces with a Laser-Produced Microchannel Structure Enhance Pre-Osteoblast Proliferation, Maturation, and Extracellular Mineralization In Vitro.

The clinical success of dental titanium implants is profoundly linked to implant stability and osseointegration, which comprises pre-osteoblast proliferation, osteogenic differentiation, and extracellular mineralization. Because of the bio-inert nature of titanium, surface processing using subtractive or additive methods enhances osseointegration ability but limits the benefit due to accompanying surface contamination. By contrast, laser processing methods increase the roughness of the implant surface without contamination. However, the effects of laser-mediated distinct surface structures on the osteointegration level of osteoblasts are controversial. The role of a titanium surface with a laser-mediated microchannel structure in pre-osteoblast maturation remains unclear. This study aimed to elucidate the effect of laser-produced microchannels on pre-osteoblast maturation. Pre-osteoblast human embryonic palatal mesenchymal cells were seeded on a titanium plate treated with grinding (G), sandblasting with large grit and acid etching (SLA), or laser irradiation (L) for 3-18 days. The proliferation and morphology of pre-osteoblasts were evaluated using a Trypan Blue dye exclusion test and fluorescence microscopy. The mRNA expression, protein expression, and protein secretion of osteogenic differentiation markers in pre-osteoblasts were evaluated using reverse transcriptase quantitative polymerase chain reaction, a Western blot assay, and a multiplex assay, respectively. The extracellular calcium precipitation of pre-osteoblast was measured using Alizarin red S staining. Compared to G- and SLA-treated titanium surfaces, the laser-produced microchannel surfaces enhanced pre-osteoblast proliferation, the expression/secretion of osteogenic differentiation markers, and extracellular calcium precipitation. Laser-treated titanium implants may enhance the pre-osteoblast maturation process and provide extra benefits in clinical application.

CsCuAO1 Associated with CsAMADH1 Confers Drought Tolerance by Modulating GABA Levels in Tea Plants.

Our previous study showed that COPPER-CONTAINING AMINE OXIDASE (CuAO) and AMINOALDEHYDE DEHYDROGENASE (AMADH) could regulate the accumulation of γ-aminobutyric acid (GABA) in tea through the polyamine degradation pathway. However, their biological function in drought tolerance has not been determined. In this study, Camellia sinensis (Cs) CsCuAO1 associated with CsAMADH1 conferred drought tolerance, which modulated GABA levels in tea plants. The results showed that exogenous GABA spraying effectively alleviated the drought-induced physical damage. Arabidopsis lines overexpressing CsCuAO1 and CsAMADH1 exhibited enhanced resistance to drought, which promoted the synthesis of GABA and putrescine by stimulating reactive oxygen species' scavenging capacity and stomatal movement. However, the suppression of CsCuAO1 or CsAMADH1 in tea plants resulted in increased sensitivity to drought treatment. Moreover, co-overexpressing plants increased GABA accumulation both in an Agrobacterium-mediated Nicotiana benthamiana transient assay and transgenic Arabidopsis plants. In addition, a GABA transporter gene, CsGAT1, was identified, whose expression was strongly correlated with GABA accumulation levels in different tissues under drought stress. Taken together, CsCuAO1 and CsAMADH1 were involved in the response to drought stress through a dynamic GABA-putrescine balance. Our data will contribute to the characterization of GABA's biological functions in response to environmental stresses in plants.

Decreased NOTCH1 signaling activated autophagy in the mid-secretory endometrium of patients with recurrent implantation failure†.

Recurrent implantation failure severely impairs fertility in females of childbearing age, which poses a great challenge to assisted reproductive technology, and its etiology is still unclear. Several studies have demonstrated that endometrial autophagy takes an important part in human endometrial receptivity, but its role in recurrent implantation failure remains largely unknown. Here, we collected mid-secretory endometrial tissue from recurrent implantation failure patients and fertile controls during menstruation and early pregnancy. Immunohistochemistry, western blotting, and quantitative real-time PCR were performed to compare the expression of microtubule-associated protein 1 light chain 3B, sequestosome 1, NOTCH1 signaling pathway members, and endometrial receptivity markers between recurrent implantation failure and control groups. In addition, to assess endometrial autophagy, transmission electron microscopy was used to observe autophagosomes. By RNA interference, we further investigated the effects of NOTCH1 on autophagy in Ishikawa cells. We found that endometrial autophagy was upregulated in the mid-secretory and decidual phases than in the early-proliferative phase. Compared to the control group, more autophagosomes were observed in the mid-secretory endometrium of recurrent implantation failure patients, which was accompanied by the downregulation of NOTCH1 signaling pathway members and endometrial receptivity markers. Moreover, knockdown of NOTCH1 impaired the receptivity of Ishikawa cells via protein kinase B/mammalian target of rapamycin pathway-mediated autophagy activation. Our data suggested that abnormally elevated autophagy and decreased NOTCH1 signaling pathway activity were observed in the mid-secretory endometrium of patients with recurrent implantation failure, perhaps due to decreased NOTCH1 pathway-mediated autophagy activation in endometrial cells impairing receptivity.

Enterovirus-71 utilizes small extracellular vesicles to cross the blood-brain barrier for infecting the central nervous system via transcytosis.

BACKGROUND: Central nervous system (CNS) infections caused by Enterovirus 71 (EV71) pose a serious threat to children, causing severe neurogenic complications and even fatality in some patients. However, the pathogenesis of EV71 infections in the CNS remains unclear. METHODS: An in vitro blood-brain barrier (BBB) model was constructed by coculturing brain microvascular endothelial cells (BMECs) and astrocytes in transwell inserts for simulating CNS infections. EV71 virions and small extracellular vesicles (sEVs) derived from EV71-infected cells (EV71-sEVs) were isolated from the cell culture supernatant by density gradient centrifugation. The BBB model was separately infected with EV71 virions and EV71-sEVs. The mechanism of crossing the BBB was determined by inhibiting the different endocytic modes. A murine model of EV71 infection was constructed for confirming the results of in vitro experiments. RESULTS: The EV71-sEVs containing viral components were endocytosed by BMECs and released on the abluminal side of the BBB model, where they infected the astrocytes without disrupting the BBB in the early stages of infection. The integrity of the tight junctions (TJs) between BMECs was breached via downregulation of PI3K/Akt signaling in the late stages of infection. CONCLUSIONS: EV71 utilized the circulating sEVs for infecting the CNS by crossing the BBB.

Sintilimab Plus Modified FOLFIRINOX in Metastatic or Recurrent Pancreatic Cancer: The Randomized Phase II CISPD3 Trial.

BACKGROUND: Folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or modified FOLFIRINOX (mFFX) is the first-line standard of care for metastatic pancreatic adenocarcinoma; effective and safe treatment strategies are needed as survival remains poor. Sintilimab, a human immunoglobulin G4 monoclonal antibody for programmed cell death-1, has shown efficacy in various cancers. We evaluated the efficacy and safety of sintilimab with mFFX for metastatic/recurrent pancreatic ductal adenocarcinoma in China. PATIENTS AND METHODS: This was a single-center, randomized, controlled, open-label phase II study. Patients were assigned 1:1 to sintilimab + mFFX or mFFX (n = 55, each). RESULTS: In the intention-to-treat population, median overall survivals (primary endpoint) were similar in the sintilimab + mFFX and mFFX groups: 10.9 and 10.8 months, respectively [hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.69-1.68]. The objective response rate was higher [50.0% (95% CI 34.6-65.4%) versus 23.9% (95% CI 11.1-36.7%)] in the sintilimab + mFFX group (P < 0.05). Median (HR, 95% CI) progression-free survival and disease control rates (95% CI) were also similar at 5.9 and 5.7 months (0.93, 0.62-1.40), and 84.1% (72.8-95.3%) and 71.7%, (58.2-85.3%), respectively. Incidences of grade ≥ 3 treatment-emergent adverse events were 84.9% (45/53) and 74.1% (40/54), and that of grade ≥ 3 immune-related adverse events were 5.7% (3/53) and 0 in each group, respectively. CONCLUSIONS: The study did not meet its primary endpoint, no clear survival benefit was observed, and the benefit of sintilimab + mFFX for advanced pancreatic cancer was not supported; however, the findings suggest that using this regimen for pancreatic cancer is feasible, has an acceptable safety profile, and leads to an objective response rate of 50%. Trial registration ClinicalTrials.Gov; NCT03977272.

Normalization of tumor markers and a clear resection margin affect progression-free survival of patients with unresectable pancreatic cancer who have undergone conversion surgery.

BACKGROUND: With the advent of intensive combination regimens, an increasing number of patients with unresectable pancreatic cancer (UPC) have regained the opportunity for surgery. We investigated the clinical benefits and prognostic factors of conversion surgery (CS) in UPC patients. METHODS: We retrospectively enrolled patients with UPC who had received CS following first-line systemic treatment in our center between 2014 to 2022. Treatment response, safety of the surgical procedure and clinicopathological data were collected. We analyzed the prognostic factors for postoperative survival among UPC patients who had CS. RESULTS: Sixty-seven patients with UPC were enrolled (53 with locally advanced pancreatic cancer (LAPC) and 14 with metastatic pancreatic cancer (MPC)). The duration of preoperative systemic treatment was 4.17 months for LAPC patients and 6.52 months for MPC patients. All patients experienced a partial response (PR) or had stable disease (SD) preoperatively according to imaging. Tumor resection was unsuccessful in four patients and, finally, R0 resection was obtained in 81% of cases. Downstaging was determined pathologically in 87% of cases; four patients achieved a complete pathological response. Median postoperative-progression-free survival (PO-PFS) was 9.77 months and postoperative overall survival (PO-OS) was 31.2 months. Multivariate logistic regression analyses revealed that the resection margin and postoperative changes in levels of tumor markers were significant prognostic factors for PO-PFS. No factors were associated significantly with PO-OS according to multivariate analyses. CONCLUSIONS: CS is a promising strategy for improving the prognosis of UPC patients. The resection margin and postoperative change in levels of tumor markers are the most important prognostic factors for prolonged PFS. Multidisciplinary treatment in high-volume centers is strongly recommended. Prospective studies must be undertaken to resolve the various problems regarding optimal regimens, the duration of treatment, and detailed criteria for CS.

Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex.

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.

Regiospecificity C(sp2)-C(sp3) Bond Construction between Purines and Alkenes to Synthesize C6-Alkylpurines and Purine Nucleosides Using O2 as the Oxidant.

A highly site-selective and Markovnikov-type radical C6-H alkylation of purines with alkenes is achieved, allowing fast construction of the C(sp2)-C(sp3) bond at the C-6-position of purines and purine nucleosides using O2 as a green oxidant and alkenes as cheap alkylation reagents. The route was also a radical route to synthesize C6-alkyl-N7-substituted purines with potential steric hindrance between C6-alkyl groups and N7-substituted groups. This reaction is easily scaled up and has excellent functional group compatibility and broad substrate scopes. Moreover, the unstable intermediate was also separated, which was the key evidence for the reaction mechanism.