Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression
. Diagnostic applications have been proposed for ...inflammatory bowel disease diagnosis and prognosis
, colorectal cancer prescreening
and therapeutic choices in melanoma
. Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic
and cardiovascular diseases
. To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
Abstract
Catalytic reductive coupling of two electrophiles and one unsaturated bond represents an economic and efficient way to construct complex skeletons, which is dominated by transition-metal ...catalysis via two electron transfer. Herein, we report a strategy of visible-light photoredox-catalyzed successive single electron transfer, realizing dearomative arylcarboxylation of indoles with CO
2
. This strategy avoids common side reactions in transition-metal catalysis, including ipso-carboxylation of aryl halides and β-hydride elimination. This visible-light photoredox catalysis shows high chemoselectivity, low loading of photocatalyst, mild reaction conditions (room temperature, 1 atm) and good functional group tolerance, providing great potential for the synthesis of valuable but difficultly accessible indoline-3-carboxylic acids. Mechanistic studies indicate that the benzylic radicals and anions might be generated as the key intermediates, thus providing a direction for reductive couplings with other electrophiles, including D
2
O and aldehyde.
Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference ...phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer "core" genes, such as the ribosomal proteins. The robustness of the results was tested with respect to several variables, including taxon and site sampling, amino acid substitution heterogeneity and saturation, non-vertical evolution, and the impact of exclusion of candidate phyla radiation (CPR) taxa. Our results provide an updated view of domain-level relationships.
Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these ...cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N‐methyl‐D‐aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC‐dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole‐cell patch‐clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA‐mEPSCs and synaptic NMDA‐eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1‐silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP‐quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper‐repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients.
Read the Editorial Highlight for this article on page 264.
Glutamate hypofunction has been a prominent hypothesis in schizophrenia pathology; however, when and how NMDAR dysfunction occurs is unknown. We report that NMDAR hypofunction is a feature of early postnatal development. Epigenetic hyper‐repression of the Grin2b promoter and subsequent loss of NR2B protein and synaptic NMDAR hypofunction weakens plPFC function. This may underlie early cognitive impairments in schizophrenia.
Read the Editorial Highlight for this article on page 264.
Over the past decades, organometallic complexes with precious elements, such as ruthenium and iridium, are widely used as visible‐light photoredox catalysts. Recently, more and more complexes based ...on earth‐abundant and inexpensive elements have been used as sensitizers in photochemistry. Although the photoexcited state lifetimes of iron complexes are typically shorter than those of traditional photosensitizers, the utilization of iron catalysts in photochemistry has sprung up owing to their abundance, low price, nontoxicity, and novel properties, including exhibiting ligand to metal charge transfer states. This concept focuses on recent advances in light‐driven iron catalysis in organic transformations, including iron/photoredox dual catalysis, light‐induced iron photoredox catalysis and light‐induced generation of active iron catalysts. The prospect for the future of this field is also discussed.
Light runs across iron catalysts: This Concept summarizes the recent advances in iron/photoredox dual catalysis, photoactive iron catalysts in photochemistry, as well as light‐induced generation of active iron catalysts in organic transformations. Prospects for the future of the field are also discussed.
A novel mass spectrometric method for probing the flash chemistry of electrogenerated reactive intermediates was developed based on rapid collision mixing of electrosprayed microdroplets by using a ...theta‐glass capillary. The two individual microchannels of the theta‐glass capillary are asymmetrically or symmetrically fabricated with a carbon bipolar electrode to produce intermediates in situ. Microdroplets containing the newly formed intermediates collide with those of the invoked reactants at sub‐10 microsecond level, making it a powerful tool for exploring their ultrafast initial transformations. As a proof‐of‐concept, we present the identification of the key radical cation intermediate in the oxidative dimerization of 8‐methyl‐1,2,3,4‐tetrahydroquinoline and also the first disclosure of previously hidden nitrenium ion involved reaction pathway in the C−H/N−H cross‐coupling between N,N′‐dimethylaniline and phenothiazine.
Microreactor on the fly: A special microreactor that permits mass spectrometric probing the flash chemistry of electrogenerated reactive intermediates was demonstrated based on collision mixing of electrosprayed microdroplets, which employed a theta‐glass capillary integrated with carbon bipolar electrodes to produce short‐lived intermediates in situ.
Insect halteres, as specialised hind wings, play an important role during aerial manoeuvres. In Drosophila, halteres and wings are homologous appendages with different morphology. Previous studies ...have focused on the metamorphosis of halteres, while current knowledge about its cell lineage and regional compartmentalization is still limited. In this study, we performed cell-lineage tracing of canonical landmark signals in halteres and present a simple model for haltere development. Cell lineage tracing in wings was used as a reference. The nub showed wing-like expressions in halteres, whereas hth and pnr exhibited different expressions in adult wings and halteres. The lineage tracing revealed that the pouch region gives rise to end-bulb, and hinge cells contribute to proximal haltere formation. Moreover, we demonstrated that twi-expressing cells participate in the cell population of the distal end-bulb. Haematoxylin and eosin staining indicated that muscle cells were present at the distal end-bulb. These results indicated that adult halteres displayed unique cell lineage patterns and the muscle cells are important components of end-bulbs.
Spinal long-term potentiation (LTP) at C-fiber synapses is hypothesized to underlie chronic pain. However, a causal link between spinal LTP and chronic pain is still lacking. Here, we report that ...high-frequency stimulation (HFS; 100 Hz, 10 V) of the mouse sciatic nerve reliably induces spinal LTP without causing nerve injury. LTP-inducible stimulation triggers chronic pain lasting for more than 35 days and increases the number of calcitonin gene-related peptide (CGRP) terminals in the spinal dorsal horn. The behavioral and morphological changes can be prevented by blocking NMDA receptors, ablating spinal microglia, or conditionally deleting microglial brain-derived neurotrophic factor (BDNF). HFS-induced spinal LTP, microglial activation, and upregulation of BDNF are inhibited by antibodies against colony-stimulating factor 1 (CSF-1). Together, our results show that microglial CSF1 and BDNF signaling are indispensable for spinal LTP and chronic pain. The microglia-dependent transition of synaptic potentiation to structural alterations in pain pathways may underlie pain chronicity.
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•HFS triggers synaptic plasticity of CGRP afferents and chronic pain•LTP-inducible HFS activates spinal microglia through CSF1 signaling•Microglial BDNF is essential for HFS-induced spinal LTP and chronic pain
Zhou et al. characterize chronic pain behaviors triggered by LTP-inducible HFS without nerve injury. They identify that HFS-induced LTP is accompanied by an increase in CGRP terminals in the spinal dorsal horn. Activation of neuronal CSF1-microglial BDNF signaling is indispensable for the synaptic and structural plasticity underlying HFS-induced chronic pain.
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