Activity-dependent feedback regulation of thalamocortical axon development by Lhx2 in cortical layer 4 neurons.

Establishing neuronal circuits requires interactions between pre- and postsynaptic neurons. While presynaptic neurons were shown to play instructive roles for the postsynaptic neurons, how postsynaptic neurons provide feedback to regulate the presynaptic neuronal development remains elusive. To elucidate the mechanisms for circuit formation, we study the development of barrel cortex (the primary sensory cortex, S1), whose development is instructed by presynaptic thalamocortical axons (TCAs). In the first postnatal weeks, TCA terminals arborize in layer (L) 4 to fill in the barrel center, but it is unclear how TCA development is regulated. Here, we reported that the deletion of Lhx2 specifically in the cortical neurons in the conditional knockout (cKO) leads to TCA arborization defects, which is accompanied with deficits in sensory-evoked and spontaneous cortical activities and impaired lesion-induced plasticity following early whisker follicle ablation. Reintroducing Lhx2 back in L4 neurons in cKO ameliorated TCA arborization and plasticity defects. By manipulating L4 neuronal activity, we further demonstrated that Lhx2 induces TCA arborization via an activity-dependent mechanism. Additionally, we identified the extracellular signaling protein Sema7a as an activity-dependent downstream target of Lhx2 in regulating TCA branching. Thus, we discovered a bottom-up feedback mechanism for the L4 neurons to regulate TCA development.

The association between non­high­density lipoprotein cholesterol to high­density lipoprotein cholesterol ratio (NHHR) and low muscle mass in adults aged 20-59: a population-based study in the United States.

BACKGROUND: The ratio between non-high-density lipoprotein cholesterol and high-density lipoprotein cholesterol (NHHR) is a reliable marker for assessing the risk linked to lipid metabolism disorders. Sarcopenia, characterized by age-related loss of muscle mass and strength/function, includes the assessment of muscle mass, muscle strength, and muscle-specific strength. However, research into NHHR's relationship with low muscle mass risk remains unexplored. METHODS: Our study utilized a cross-sectional approach, examining data derived from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Through multivariable linear and logistic regression, we investigated the relationships of the NHHR with muscle mass and low muscle mass. We visualized the results using smoothing curves and assessed threshold effects. We also performed various subgroup and sensitivity analyses. RESULTS: This research encompassed 9,012 participants and demonstrated significant nonlinear associations between NHHR and ALMBMI or low muscle mass risk in a generalized additive model (GAM), pinpointing critical NHHR values (3.328 and 3.367) where changes in NHHR significantly impacted ALMBMI and low muscle mass risk. CONCLUSIONS: The NHHR demonstrates a significant association with an increased risk of low muscle mass among middle-aged Americans. This ratio has potential as a predictive marker for low muscle mass. Further exploration of NHHR is expected to aid in advancing preventive and therapeutic measures for this condition.

Overexpression of SHARPIN promotes tumor progression in ovarian cancer.

SHARPIN (Shank-associated RH domain interacting protein) plays an important role in tumorigenesis. However, its role in ovarian cancer remains largely unknown. To investigate this issue, we systematically analyzed the amplification and expression of the SHARPIN in the TCGA database. From the database, we found that SHARPIN was amplified in ovarian cancer compared to normal ovarian tissue, and the mRNA level of SHARPIN was significantly elevated in ovarian cancer compared to non-tumorigenic ovarian tissue. In addition, we observed similar results from ovarian cancer cell lines and clinical samples from ovarian cancer patients, which indicated that increased SHARPIN expression is associated with tumorigenesis in ovarian cancer. SHARPIN knockdown inhibited the migration and invasion of ovarian cancer cells, also inhibited cell cycle and promoted apoptosis, thereby suppressing cell proliferation. RNA-seq results showed that SHARPIN significantly increased the expression of P53 and P21 and decreased the expression of Cyclin D1 and c-Myc, all of which are involved in the regulation of cell proliferation. Subsequent mechanistic exploration revealed that SHARPIN knockdown increased the expression of caspases 3 and 9, leading to apoptosis of ovarian cancer cells. We also found that high expression of SHARPIN was associated with poor prognosis of ovarian cancer patients. Collectively, we demonstrated a positive correlation between SHARPIN and ovarian cancer progression and provide a basis for combined targeted therapy strategies for future ovarian cancer treatment.

miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aß1-42-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.

Single-nucleotide polymorphisms in genes related to oxidative stress and ion channels in chickens are associated with semen quality and hormonal responses to thermal stress.

Heat stress causes economic loss of livestock industry in tropical areas. Exploring genetic markers for selection of thermotolerance will benefit chicken production. Oxidative stress and fluid-salt balance are tightly associated with thermotolerance and productivity in domestic animals. The study aimed to identify single-nucleotide polymorphisms (SNPs) in genes related to oxidative stress and ion-channel regulation and their associations with semen quality and hormonal responses. In total, 28 SNPs within 11 candidate genes were identified to associate with hormonal changes and semen quality in both broiler- and layer-type Taiwan country chickens (TCCs) after exposure to acute heat stress at 38 °C for 4 h. Acute heat stress significantly affected plasma levels of triiodothyronine and corticosterone and reduced sperm motility, viability, and concentrations in both strains at Day 1 after exposure. In the B-strain TCCs, five SNPs within NDUFA8 and DAB2IP had significant effects on plasma adrenaline and corticosterone levels, and six SNPs within TRPC1, SLC9A9, and TRPC7 markedly affected plasma corticosterone and triiodothyronine levels. In the L2 strain, 15 SNPs within PSMA2, TPK1, MTF1, and CUL1 exerted effects on plasma corticosterone and triiodothyronine levels. Five SNPs within CUL3, TRPC1, and SLC9A9 in the B strain and two SNPs within MTF1 in the L2 strain were associated with sperm concentrations at Day 1 after exposure to heat stress. In conclusion, acute heat stress impaired semen quality and altered plasma corticosterone and triiodothyronine levels in TCCs. Some SNPs involved in oxidative stress and ion-channel regulation were identified to associate with the hormonal and semen alterations. These SNPs in conjunction with differential hormonal responses and semen quality serve as genetic markers for thermotolerance selection in sire lines of chickens.

Temporal Differences in Interneuron Invasion of Neocortex and Piriform Cortex during Mouse Cortical Development.

Establishing a balance between excitation and inhibition is critical for brain functions. However, how inhibitory interneurons (INs) generated in the ventral telencephalon integrate with the excitatory neurons generated in the dorsal telencephalon remains elusive. Previous studies showed that INs migrating tangentially to enter the neocortex (NCx), remain in the migratory stream for days before invading the cortical plate during late corticogenesis. Here we show that in developing mouse cortices, INs in the piriform cortex (PCx; the major olfactory cortex) distribute differently from those in the NCx. We provide evidence that during development INs invade and mature earlier in PCx than in NCx, likely owing to the lack of CXCR4 expression in INs from PCx compared to those in NCx. We analyzed IN distribution patterns in Lhx2 cKO mice, where projection neurons in the lateral NCx are re-fated to generate an ectopic PCx (ePCx). The PCx-specific IN distribution patterns found in ePCx suggest that properties of PCx projection neurons regulate IN distribution. Collectively, our results show that the timing of IN invasion in the developing PCx fundamentally differs from what is known in the NCx. Further, our results suggest that projection neurons instruct the PCx-specific pattern of IN distribution.

[Effect of C21 steroidal glycoside of Cynanchum auriculatum on liver and kidney fibrosis through TLR4 pathway].

The liver and kidney fibrosis model was established by thioacetamide(TAA) and unilateral ureteral obstruction(UUO) in SD rats. The rats were randomly divided into three groups: model group, low and high-dose groups of C21 steroidal glycosides of Cynanchum auriculatum. Another blank control group was set. Four weeks later, serum was taken to detect the biochemical indexes of liver and kidney function. Urine protein and urine creatinine were detected by kits. Liver and kidney tissue samples were stained with HE and Masson staining, and hydroxyproline content was detected. Western blot was used to detect expressions of fibrotic proteins, inflammatory factors and TLR4 signaling pathways, so as to observe the preventive and therapeutic effects of C21 steroidal glycosides from C. auriculatum on hepatic and renal fibrosis and explore its molecular mechanism. Four weeks later, serum biochemical results showed that liver and kidney functions were seriously damaged, and pathological sections showed that inflammatory cell infiltration, decrease of parenchymal cells, and increase of interstitial fibrosis in liver and kidney tissues. The results showed that low and high doses(150, 300 mg·kg~(-1)) of C21 steroidal glycosides could significantly reduce the collagen deposition and the pathological changes of liver and kidney fibrosis compared with the model group. At the same time, we found that the expression levels of TLR4 and MyD88 signaling pathway proteins were significantly increased in the liver and kidney tissues of the model group, and a large number of NF-κB signaling pathway proteins migrated into the nucleus. On the contrary, the expression levels of TLR4, MyD88 signaling pathway proteins and the nuclear migration of NF-κB were significantly inhibited in the low and high dose groups of C21 steroidal glycosides from C. auriculatum. Therefore, it was speculated that the mechanism of C21 steroidal glycoside for preventive and therapeutic effect on hepatic and renal fibrosis was related to inhibit TLR4/MYD88/NF-κB inflammatory pathway, thus preventing hepatic and renal fibrosis.

An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer cells.

The inhibitory signaling of natural killer (NK) cells is crucial in the regulation of innate immune responses. Here we show that the association of KIR2DL1, an inhibitory receptor of NK cells, with beta-arrestin 2 mediated recruitment of the tyrosine phosphatases SHP-1 and SHP-2 to KIR2DL1 and facilitated 'downstream' inhibitory signaling. Consequently, the cytotoxicity of NK cells was higher in beta-arrestin 2-deficient mice but was inhibited in beta-arrestin 2-transgenic mice. Moreover, beta-arrestin 2-deficient mice were less susceptible than wild-type mice to mouse cytomegalovirus infection, an effect that was abolished by depletion of NK cells. Our findings identify a previously unknown mechanism by which the inhibitory signaling in NK cells is regulated.

Genomic regions and pathways associated with thermotolerance in layer-type strain Taiwan indigenous chickens.

This study aimed to investigate genetic markers and candidate genes associated with thermotolerance in a layer-type strain Taiwan indigenous chickens exposed to acute heat stress. One hundred and ninety-two 30-week-old roosters were subjected to acute heat stress. Changes in body temperature (BT, ΔT) were calculated by measuring the difference between the initial BT and the highest BT during heat stress and the results were categorized into dead, susceptible, tolerant, and intermediate groups depending on their survival and ΔT values at the end of the experiment. A genome-wide association study on survival and ΔT values was conducted using the Cochran-Armitage trend test and Fisher's exact test. Association analyses identified 80 significant SNPs being annotated to 23 candidate genes, 440 SNPs to 71 candidate genes, 64 SNPs to 25 candidate genes, and 378 SNPs to 78 candidate genes in the dead versus survivor, tolerant versus susceptible, intermediate versus tolerant, and intermediate versus susceptible groups, respectively. The annotated genes were associated with apoptosis, cellular stress responses, DNA repair, and metabolic oxidative stress. In conclusion, the identified SNPs of candidate genes provide insights into the potential mechanisms underlying physiological responses to acute heat stress in chickens.

Effect of Seasonal Change on Testicular Protein Expression in White Roman Geese.

The purpose of this study was to investigate the change in protein expression in the testes of ganders at various breeding stages. A total of nine 3-year-old male White Roman ganders were used. The blood and testis samples were collected at the nonbreeding, sexual reactivation, and breeding stages for sex hormone analysis and proteomic analysis, respectively. The testicular weight and serum testosterone observed for ganders at the breeding stage were higher than those for ganders at nonbreeding and sexual reactivation stages (P < 0.05). There were 124 protein spots differentially expressed in the testes of ganders at various reproductive stages. A total of 107 protein spots of 74 proteins was identified through mass spectrometry. Most of the differentially expressed proteins were responsible for the molecular functions of protein binding (24%) and catalytic activity (16%). A functional pathway analysis suggested that proteins involved in steroidogenesis, metabolism, and spermatogenesis pathways changed in the White Roman geese at various reproductive stages. In conclusion, ganders at various reproductive stages exhibited different levels of testosterone and protein expression in the testes. The varied levels of the proteins might be essential and unique key factors in seasonal reproduction in ganders.

Genome-wide association study on the body temperature changes of a broiler-type strain Taiwan country chickens under acute heat stress.

Body temperature is the simplest parameter for evaluating the physiological conditions of animals under thermal stress. Genome-wide association studies (GWAS) have identified candidate genes related to economic traits in domestic animals. The present study conducted a GWAS on body temperature changes in a broiler-type strain Taiwan country chickens (TCCs) under acute heat stress. A total of two hundred 30-week-old roosters of a broiler-type strain TCCs were used. The roosters were subjected to acute heat stress at 38 °C for 4 h, and their body temperature was recorded before and during heat stress. The change in body temperature (ΔT) of each rooster was calculated according to the difference between the initial temperature and the highest body temperature during heat stress. The roosters were categorized according to survival and ΔT at the end into dead, susceptible, resistant, and intermediate groups. Collected red blood cells were genotyped using a 600 K chicken single-nucleotide polymorphism (SNP) array. A GWAS for ΔT was conducted using the Cochran-Armitage trend test. Significant SNPs were annotated as candidate genes according to the nearest genes. Results indicated that the ΔT of the heat-resistant group was significantly lower than that of the heat-susceptible group. A total of 17 SNPs belonging to 8 candidate genes, 352 SNPs for 78 candidate genes, and 174 significant SNPs for 63 candidate genes were identified in the association analyses in the dead vs. survival, resistant vs. susceptible, and intermediate vs. susceptible groups, respectively. The annotated candidate genes are associated with apoptosis, cellular response to external stimuli, and signal transduction pathways. In conclusion, the significant SNPs located in and proximal to genes in the GWAS analysis were related to apoptosis or responses to external stimuli which serve as potential candidates underlying physiological adaptation to heat stress or thermotolerance in chickens.

Mechanical force increases tooth movement and promotes remodeling of alveolar bone defects augmented with bovine bone mineral.

BACKGROUND: Orthodontic tooth movement (OTM) in a region containing alveolar bone defects with insufficient height and width is hard to achieve. Bovine bone mineral (Bio-Oss) is available to restore the alveolar defect; however, whether the region augmented with a bovine bone mineral graft (BG) is feasible for OTM, and the mechanisms by which macrophages remodel the BG material, is uncertain under the mechanical force induced by OTM. MATERIAL AND METHODS: Rats were divided into three groups: OTM (O), OTM + BG material (O + B), and Control (C). First molars were extracted to create bone defects in the O and O + B groups with bovine bone mineral grafting in the latter. Second molars received OTM towards the bone defects in both groups. After 28 days, maxillae were analyzed using microfocus-computed tomography (µCT) and scanning-electron-microscopy (SEM); and macrophages (M1/M2) were stained using immunofluorescence. THP-1 cell-induced macrophages were cultured under mechanical force (F), BG material (B), or both (F + B). Phagocytosis-related signaling molecules (cAMP/PKA/RAC1) were analyzed, and conditioned media was analyzed for MMP-9 and cytokines (IL-1ß, IL-4). RESULTS: Our study demonstrated that alveolar defects grafted with BG materials are feasible for OTM, with significantly increased OTM distance, bone volume, and trabecular thickness in this region. SEM observation revealed that the grafts served as a scaffold for cells to migrate and remodel the BG materials in the defect during OTM. Moreover, the population of M2 macrophages increased markedly both in vivo and in cell culture, with enhanced phagocytosis via the cAMP/PKA/RAC1 pathway in response to mechanical force in combination with BG particles. By contrast, M1 macrophage populations were decreased under the same circumstances. In addition, M2 macrophage polarization was also indicated by elevated IL-4 levels, reduced IL-1ß levels, and less active MMP-9 in cell culture. CONCLUSION: This study explored the mechanisms of mechanical force-induced alveolar bone remodeling with bovine bone mineral grafts during OTM. The results might provide molecular insights into the related clinical problems of whether we can move teeth into the grafted materials; and how these materials become biologically remodeled and degraded under mechanical force.

MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination.

Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury. Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter. However, milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a microglial phagocytosis-related protein, has not been well studied in hypoperfusion-related cognitive dysfunction. We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis (BCAS). MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests. In addition, we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy. Meanwhile, MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS. Moreover, in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via the αVß3/αVß5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes. Interestingly, we found that MFG-E8 was mainly derived from astrocytes, not microglia. Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.

Exploring the impact of protein intake on the association between oxidative balance score and lean mass in adults aged 20-59: NHANES 2011-2018.

BACKGROUND: Previous studies have established a correlation between the pathogenesis of oxidative stress and sarcopenia. The Oxidative Balance Score (OBS) is an integrated measure that reflects the overall balance of antioxidants and pro-oxidants in dietary components and lifestyle. However, there are limited reports on the association between OBS and lean mass and the impact of protein intake on the association between OBS and lean mass. METHODS: Using data from the National Health and Nutrition Examination Survey from 2011 to 2018, multivariate linear and logistic regression analyses were conducted to explore the associations between OBS and outcomes. The findings were then illustrated through fitted smoothing curves and threshold effect analyses. RESULTS: This study included 2,441 participants, demonstrating that higher OBS is significantly associated with an increased ratio of appendicular lean mass to body mass index. Key inflection points at OBS 31 mark pronounced changes in these associations, with age and protein intake notably affecting the association. The effect of OBS on lean mass varies among populations with high and low protein intake. CONCLUSIONS: Our findings suggest that OBS is significantly and positively associated with lean mass. A high protein intake of more than 84.5 g/day may enhance the role of OBS in influencing muscle health to improve muscle outcomes.

Performance of ChatGPT on Chinese Master's Degree Entrance Examination in Clinical Medicine.

BACKGROUND: ChatGPT is a large language model designed to generate responses based on a contextual understanding of user queries and requests. This study utilised the entrance examination for the Master of Clinical Medicine in Traditional Chinese Medicine to assesses the reliability and practicality of ChatGPT within the domain of medical education. METHODS: We selected 330 single and multiple-choice questions from the 2021 and 2022 Chinese Master of Clinical Medicine comprehensive examinations, which did not include any images or tables. To ensure the test's accuracy and authenticity, we preserved the original format of the query and alternative test texts, without any modifications or explanations. RESULTS: Both ChatGPT3.5 and GPT-4 attained average scores surpassing the admission threshold. Noteworthy is that ChatGPT achieved the highest score in the Medical Humanities section, boasting a correct rate of 93.75%. However, it is worth noting that ChatGPT3.5 exhibited the lowest accuracy percentage of 37.5% in the Pathology division, while GPT-4 also displayed a relatively lower correctness percentage of 60.23% in the Biochemistry section. An analysis of sub-questions revealed that ChatGPT demonstrates superior performance in handling single-choice questions but performs poorly in multiple-choice questions. CONCLUSION: ChatGPT exhibits a degree of medical knowledge and the capacity to aid in diagnosing and treating diseases. Nevertheless, enhancements are warranted to address its accuracy and reliability limitations. Imperatively, rigorous evaluation and oversight must accompany its utilization, accompanied by proactive measures to surmount prevailing constraints.

Metagenomic survey of viral diversity obtained from feces of piglets with diarrhea.

Pigs are natural host to various zoonotic pathogens including viruses. In this study, we analyzed the viral communities in the feces of 89 piglets with diarrhea under one month old which were collected from six farms in Jiangsu Province of the Eastern China, using the unbiased virus metagenomic method. A total of 89 libraries were constructed, and 46937894 unique sequence reads were generated by Illumina sequencing. Overall, the family Picornaviridae accounted for the majority of the total reads of putative mammalian viruses. Ten novel virus genomes from different family members were discovered, including Parvoviridae (n = 2), Picobirnaviridae (n = 4) and CRESS DNA viruses (n = 4). A large number of phages were identified, which mainly belonged to the order Caudovirales and the family Microviridae. Moreover, some identified viruses were closely related to viruses found in non-porcine hosts, highlighting the potential for cross-species virus dissemination. This study increased our understanding of the fecal virus communities of diarrhea piglets and provided valuable information for virus monitoring and preventing.

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity.

Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism.

Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.

The adhesin RadD enhances Fusobacterium nucleatum tumour colonization and colorectal carcinogenesis.

Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.

A Flexible Bivalent Approach to Comprehensively Improve the Performances of Stilbazolium Dyes as Amyloid-ß Fluorescent Probes.

Exploring new ways to reconstruct the structure and function of inappropriate organic fluorophores for improving amyloid-ß (Aß) fluorescent imaging performance is desired for precise detection and early diagnosis of Alzheimer's disease (AD). With stilbazolium dyes as examples, here, we present a multipronged approach to comprehensively improved the Aß fluorescent imaging performance through a flexible bivalent method, where a flexible carbon chain was introduced to link two monomers to form a homodimer. Our results reveal a mechanism wherein the flexible linker creates a well-defined probe with specific orientations and distinct photophysical properties. Applying this approach in combination with theoretical simulation, the homodimers exhibited a comprehensive improvement of the Aß fluorescent imaging performance of the dye monomers, including better photostability and higher signal-to-noise (S/N) ratio, higher "off-on" near-infrared fluorescence (NIRF) response sensitivity, higher specificity and affinity to Aß deposits, and more reasonable lipophilicity for blood-brain barrier (BBB) penetrability. The results demonstrate that flexible homodimers offer a multipronged approach to obtaining high-performance NIRF imaging reagents for the detection of Aß deposits both in vitro and in vivo.