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IScience Jun 2024Plasticity during the critical period is important for the functional maturation of cortical neurons. While characteristics of plasticity are diverse among cortical...
Plasticity during the critical period is important for the functional maturation of cortical neurons. While characteristics of plasticity are diverse among cortical layers, it is unknown whether critical period timing is controlled by a common or unique molecular mechanism among them. We here clarified layer-specific regulation of the critical period timing of ocular dominance plasticity in the primary visual cortex. Mice lacking the endocannabinoid synthesis enzyme diacylglycerol lipase-α exhibited precocious critical period timing, earlier maturation of inhibitory synaptic function in layers 2/3 and 4, and impaired development of the binocular matching of orientation selectivity exclusively in layer 2/3. Activation of cannabinoid receptor restored ocular dominance plasticity at the normal critical period in layer 2/3. Suppression of GABA receptor rescued precocious ocular dominance plasticity in layer 4. Therefore, endocannabinoids regulate critical period timing and maturation of visual function partly through the development of inhibitory synaptic functions in a layer-dependent manner.
PubMed: 38952682
DOI: 10.1016/j.isci.2024.110145 -
IScience Jun 2024The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite...
The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of the midgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessing , a recently identified regulator of Wnt signaling pathways, as a mechanistic tool. We find that Wnt signaling within Prospero-positive cells supports ISC proliferation and that regulates Wnt signaling in this context by antagonizing , a Cullin-3 E3 ligase adaptor that mediates Dishevelled polyubiquitination. This work establishes as a physiological regulator of Wnt/β-catenin signaling and suggests enteroendocrine cells as a new cell type that regulates ISC proliferation via Wnt/β-catenin signaling.
PubMed: 38952681
DOI: 10.1016/j.isci.2024.110113 -
IScience Jun 2024is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate...
is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, subsp. was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that subsp. RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by subsp. RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.
PubMed: 38952680
DOI: 10.1016/j.isci.2024.110157 -
Frontiers in Oncology 2024Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly...
BACKGROUND
Breast cancer is the leading cause of cancer death among women worldwide. Studies about the genomic landscape of metastatic breast cancer (MBC) have predominantly originated from developed nations. There are still limited data on the molecular epidemiology of MBC in low- and middle-income countries. This study aims to evaluate the prevalence of mutations in the PI3K-AKT pathway and other actionable drivers in estrogen receptor (ER)+/HER2- MBC among Brazilian patients treated at a large institution representative of the nation's demographic diversity.
METHODS
We conducted a retrospective observational study using laboratory data (OC Precision Medicine). Our study included tumor samples from patients with ER+/HER2- MBC who underwent routine tumor testing from 2020 to 2023 and originated from several Brazilian centers within the Oncoclinicas network. Two distinct next-generation sequencing (NGS) assays were used: GS Focus (23 genes, covering , , , , , , , , but not ) or GS 180 (180 genes, including PTEN, tumor mutation burden [TMB] and microsatellite instability [MSI]).
RESULTS
Evaluation of tumor samples from 328 patients was undertaken, mostly (75.6%) with GS Focus. Of these, 69% were primary tumors, while 31% were metastatic lesions. The prevalence of mutations in the PI3K-AKT pathway was 39.3% (95% confidence interval, 33% to 43%), distributed as 37.5% in and 1.8% in . Stratification by age revealed a higher incidence of mutations in this pathway among patients over 50 (44.5% vs 29.1%, p=0.01). Among the mutations, 78% were canonical (included in the alpelisib companion diagnostic non-NGS test), while the remaining 22% were characterized as non-canonical mutations (identifiable only by NGS test). mutations were detected in 6.1%, exhibiting a higher frequency in metastatic samples (15.1% vs 1.3%, p=0.003). Additionally, mutations in , or were identified in 3.9% of cases, while mutations in were found in 2.1%. No mutations were detected, nor were TMB high or MSI cases.
CONCLUSION
We describe the genomic landscape of Brazilian patients with ER+/HER2- MBC, in which the somatic mutation profile is comparable to what is described in the literature globally. These data are important for developing precision medicine strategies in this scenario, as well as for health systems management and research initiatives.
PubMed: 38952553
DOI: 10.3389/fonc.2024.1372947 -
Frontiers in Oncology 2024The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors,... (Review)
Review
The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.
PubMed: 38952548
DOI: 10.3389/fonc.2024.1373821 -
Frontiers in Neurology 2024Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female...
24-h continuous non-invasive multiparameter home monitoring of vitals in patients with Rett syndrome by an innovative wearable technology: evidence of an overlooked chronic fatigue status.
BACKGROUND
Sleep is disturbed in Rett syndrome (RTT), a rare and progressive neurodevelopmental disorder primarily affecting female patients (prevalence 7.1/100,000 female patients) linked to pathogenic variations in the X-linked methyl-CpG-binding protein 2 () gene. Autonomic nervous system dysfunction with a predominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PSNS) is reported in RTT, along with exercise fatigue and increased sudden death risk. The aim of the present study was to test the feasibility of a continuous 24 h non-invasive home monitoring of the biological vitals (biovitals) by an innovative wearable sensor device in pediatric and adolescent/adult RTT patients.
METHODS
A total of 10 female patients (mean age 18.3 ± 9.4 years, range 4.7-35.5 years) with typical RTT and pathogenic variations were enrolled. Clinical severity was assessed by validated scales. Heart rate (HR), respiratory rate (RR), and skin temperature (SkT) were monitored by the YouCare Wearable Medical Device (Accyourate Group SpA, L'Aquila, Italy). The average percentage of maximum HR (HRmax%) was calculated. Heart rate variability (HRV) was expressed by consolidated time-domain and frequency-domain parameters. The HR/LF (low frequency) ratio, indicating SNS activation under dynamic exercise, was calculated. Simultaneous continuous measurement of indoor air quality variables was performed and the patients' contributions to the surrounding water vapor partial pressure [P (pt)] and carbon dioxide [P (pt)] were indirectly estimated.
RESULTS
Of the 6,559.79 h of biovital recordings, 5051.03 h (77%) were valid for data interpretation. Sleep and wake hours were 9.0 ± 1.1 h and 14.9 ± 1.1 h, respectively. HRmax % [median: 71.86% (interquartile range 61.03-82%)] and HR/LF [median: 3.75 (interquartile range 3.19-5.05)] were elevated, independent from the wake-sleep cycle. The majority of HRV time- and frequency-domain parameters were significantly higher in the pediatric patients ( ≤ 0.031). The HRV HR/LF ratio was associated with phenotype severity, disease progression, clinical sleep disorder, subclinical hypoxia, and electroencephalographic observations of multifocal epileptic activity and general background slowing.
CONCLUSION
Our findings indicate the feasibility of a continuous 24-h non-invasive home monitoring of biovital parameters in RTT. Moreover, for the first time, HRmax% and the HR/LF ratio were identified as potential objective markers of fatigue, illness severity, and disease progression.
PubMed: 38952469
DOI: 10.3389/fneur.2024.1388506 -
Frontiers in Microbiology 2024Porcine circovirus 2 (PCV-2) is a key pathogen for the swine industry at a global level. Nine genotypes, differing in epidemiology and potentially virulence, emerged...
INTRODUCTION
Porcine circovirus 2 (PCV-2) is a key pathogen for the swine industry at a global level. Nine genotypes, differing in epidemiology and potentially virulence, emerged over time, with PCV-2a, -2b, and -2d being the most widespread and clinically relevant. Conversely, the distribution of minor genotypes appears geographically and temporally restricted, suggesting lower virulence and different epidemiological drivers. In 2022, PCV-2e, the most genetically and phenotypically divergent genotype, was identified in multiple rural farms in North-eastern Italy. Since rural pigs often have access to outdoor environment, the introduction from wild boars was investigated.
METHODS
Through a molecular and spatial approach, this study investigated the epidemiology and genetic diversity of PCV-2 in 122 wild boars across different provinces of North-eastern Italy.
RESULTS
Molecular analysis revealed a high PCV-2 frequency (81.1%, 99/122), and classified the majority of strains as PCV-2d (96.3%, 78/81), with sporadic occurrences of PCV-2a (1.2%, 1/81) and PCV-2b (2.5%, 2/81) genotypes. A viral flow directed primarily from domestic pigs to wild boars was estimated by phylogenetic and phylodynamic analyses.
DISCUSSION
These findings attested that the genotype replacement so far described only in the Italian domestic swine sector occurred also in wild boars. and suggested that the current heterogeneity of PCV-2d strains in Italian wild boars likely depends more on different introduction events from the domestic population rather than the presence of independent evolutionary pressures. While this might suggest PCV-2 circulation in wild boars having a marginal impact in the industrial sector, the sharing of PCV-2d strains across distinct wild populations, in absence of a consistent geographical pattern, suggests a complex interplay between domestic and wild pig populations, emphasizing the importance of improved biosecurity measures to mitigate the risk of pathogen transmission.
PubMed: 38952451
DOI: 10.3389/fmicb.2024.1412615 -
Frontiers in Microbiology 2024Biotic stresses, such as plant viruses, e.g., cotton leaf curl virus (CLCuV), can alter root-associated and leaf-associated microbial diversities in plants. There are...
Biotic stresses, such as plant viruses, e.g., cotton leaf curl virus (CLCuV), can alter root-associated and leaf-associated microbial diversities in plants. There are complex ecological dynamics at play, with each microbe contributing to a multitude of biotic and abiotic interactions, thus deciding the stability of the plant's ecosystem in response to the disease. Deciphering these networks of interactions is a challenging task. The inferential research in microbiome is also at a nascent stage, often constrained by the underlying analytical assumptions and the limitations with respect to the depth of sequencing. There is also no real consensus on network-wide statistics to identify the influential microbial players in a network. Guided by the latest developments in network science, including recently published metrics such as Integrated View of Influence (IVI) and some other centrality measures, this study provides an exposé of the most influential nodes in the rhizospheric and phyllospheric microbial networks of the cotton leaf curl disease (CLCuD) susceptible, partially tolerant, and resistant cotton varieties. It is evident from our results that the CLCuD-resistant possesses an equal share of keystone species, which helps it to withstand ecological pressures. In the resistant variety, the phyllosphere harbors the most influential nodes, whereas in the susceptible variety, they are present in the rhizosphere. Based on hubness score, spreading score, and IVI, the top 10 occurring keystone species in the FDH-228 (resistant) variety include and and were identified as the most influential nodes in the PFV-1 (partially tolerant) variety. In the PFV-2 (susceptible) variety, the keystone species were identified as and . This concept deciphers the diseased and healthy plant's response to viral disease, which may be microbially mediated.
PubMed: 38952448
DOI: 10.3389/fmicb.2024.1381883 -
Molecular Therapy. Nucleic Acids Sep 2024p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in...
p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in defective NADPH oxidase function in phagocytes. Due to its complex genomic context, the locus is not suited for safe gene editing with current genome editing technologies. Therefore, we developed a targeted coding sequence knock-in by CRISPR-Cas9 ribonucleoprotein and viral vector template delivery, to restore p47 expression under the control of the endogenous locus. encodes for p67 , an NADPH oxidase subunit that closely interacts with p47 and is predominantly expressed in myeloid cells. This approach restored p47 expression and NADPH oxidase function in p47-CGD patient hematopoietic stem and progenitor cells (HSPCs) and in p47 -deficient mouse HSPCs, with the transgene expression following a myeloid differentiation pattern. Adeno-associated viral vectors performed favorably over integration-deficient lentiviral vectors for template delivery, with fewer off-target integrations and higher correction efficacy in HSPCs. Such myeloid-directed gene editing is promising for clinical CGD gene therapy, as it leads to the co-expression of p47 and p67 , ensuring spatiotemporal and near-physiological transgene expression in myeloid cells.
PubMed: 38952440
DOI: 10.1016/j.omtn.2024.102229 -
Frontiers in Molecular Neuroscience 2024Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly... (Review)
Review
Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the discovery of targets and therapies against NDDs.
PubMed: 38952421
DOI: 10.3389/fnmol.2024.1414886