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Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 10-20% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.

Background/Objectives: Protocadherin 7 (Pcdh7) belongs to the protocadherin family, the largest subgroup of cell adhesion molecules. Members of this family are highly expressed in the brain, where they serve fundamental roles in many neurodevelopmental processes, including axon guidance, dendrite self-avoidance, and synaptic formation. PCDH7 has been strongly associated with epilepsy in multiple genome-wide association studies (GWAS), as well as with schizophrenia, PTSD, and childhood aggression. Despite these associations, the specific contributions of PCDH7 to epileptogenesis and brain development remain largely unexplored. Most of the existing literature on PCDH7 focuses on its function during cancer progression, with only one study suggesting that PCDH7 regulates dendritic spine morphology and synaptic function via interaction with GluN1. Methods: Here, we generate, validate, and characterize a murine null Pcdh7 allele in which a large deletion was introduced by CRISPR. Results: Analysis of embryonic, postnatal, and adult brain datasets confirmed PCDH7 widespread expression. Pcdh7+/− and Pcdh7−/− mice present no gross morphological defects and normal cortical layer formation. However, a seizure susceptibility assay revealed increased latencies in Pcdh7+/− mice, but not in Pcdh7+/+ and Pcdh7−/− mice, potentially explaining the association of PCDH7 with epilepsy. Conclusions: This initial characterization of Pcdh7 null mice suggests that, despite its widespread expression in the CNS and involvement in human epilepsy, PCDH7 is not essential for murine brain development and thus is not a suitable animal model for understanding PCDH7 disruption in humans. However, further detailed analysis of this mouse model may reveal circuit or synaptic abnormalities in Pcdh7 null brains.

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to have functions in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1 (+/R203W) neural precursors, mature PACS1 (+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease. PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment.

Joseph Gleeson, David Silver and colleagues show that inactivating mutations in MFSD2A , which encodes an essential transporter of long-chain fatty acids in brain, cause a lethal microcephaly syndrome. These results establish a link between the activity of this transporter and human brain growth. Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease 1 , 2 . Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain–containing 2a (MFSD2A) protein 3 . MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa -morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

During phosphate starvation, Snf1-related kinase 1 (SnRK1) activity significantly decreases compared with plants growing under normal nutritional conditions. An analysis of the expression of the genes encoding for the catalytic subunits of SnRK1 showed that these subunits were not affected by phosphate starvation. Transgenic Arabidopsis (Arabidopsis thaliana) plants overexpressing the AKIN10 and AKIN11 catalytic subunits fused with green fluorescent protein (GFP) were produced, and their localizations were mainly chloroplastic with low but detectable signals in the cytoplasm. These data were corroborated with an immunocytochemistry analysis using leaf and root sections with an anti-AKIN10/AKIN11 antibody. The SnRK1 activity in transgenic plants overexpressing AKIN11-GFP was reduced by 35% to 40% in phosphate starvation, in contrast with the results observed in plants overexpressing AKIN10-GFP, which increased the activity by 100%. No differences in activity were observed in plants growing in phosphate-sufficient conditions. Biochemical analysis of the proteins indicated that AKIN11 is specifically degraded under these limited conditions and that the increase in AKIN10-GFP activity was not due to the phosphorylation of threonine-175. These results are consistent with an important role of AKIN10 in signaling during phosphate starvation. Moreover, akin10 mutant plants were deficient in starch mobilization at night during inorganic phosphate starvation, and under this condition several genes were up-regulated and down-regulated, indicating their important roles in the control of general transcription. This finding reveals novel roles for the different catalytic subunits during phosphate starvation.

The species of the genus Ceiba produces fruits with fibers with a high content of cellulose. The fiber is used for textiles, cushion filling and for industrial purposes and its characteristics have been studied in some species including Ceiba pentandra (kapok), C. speciosa and C. aesculifolia. The use of the trunk and seeds of Ceiba has also been described for different species. This article presents a review on the biological diversity of the genus Ceiba (Malvaceae). The genus Ceiba has 18 recognized species that are distributed naturally in America and Africa. However, some Ceiba trees have been introduced to various countries, especially in Asia, due to their ornamental interest and potential uses for their fiber. Ecophysiological studies of different Ceiba species have shown that resistance to adverse environmental conditions varies from species to species. Therefore, Ceiba species are considered potentially useful in restoring ecosystems impacted by human activity. The information related to the classification, morphological characteristics, phenology, ecophysiology and distribution of the different species will be extremely relevant for the sustainable production of kapok fiber. Finally, the recent genomic and transcriptomic studies also provide a valuable resource for further genetic improvement and effective use of Ceiba trees.

BackgroundThe tumor microenvironment (TME) is the complex milieu of cells and molecules surrounding the tumor. Single cell methods and systems biology have been used to identify cells with pro- or anti-tumor properties, and selectively modulating these has great therapeutic benefits in immunotherapy. However, there is limited information on how the spatial organization of the TME determines cells’ signaling and their therapeutic potential. Single cell resolved spatial computational analysis is needed to describe the complex interactions of the TME and their effect on patient outcomes. Hodgkin’s Lymphoma presents a unique spatial TME due to the sparse tumor distribution of Hodgkin’s Reed-Sternberg tumor cells. Hodgkin’s is highly receptive to checkpoint inhibitors and insights from the Hodgkin’s TME could better inform immunotherapies in general.MethodsHere we apply Imaging Mass Cytometry (IMC), a technology to perform ~40-plex protein analysis with 1 micron resolution in tissue (figure 1A), to study a cohort of 260 matched samples at diagnosis and after relapse from 91 patients with relapsed/refractory Hodgkin’s Lymphoma. We developed a computational pipeline to describe tumor architecture and propose putative biomarkers of Hodgkin’s clinical response and relapse. New methods are used to define biomarkers based on localized ligand receptor signaling driving tumor-immune clustering (rosetting) unique to Hodgkin’s.ResultsWe analyzed over 7 million cells with IMC to describe spatial features of the tumor – cell subtypes and their positioning – that correlate to clinical outcomes. In brief, we found signatures of spatial reorganization from diagnosis to the relapsed tumor. We validated existing biomarkers such as CD68+ macrophage proportion (p=0.018, likelihood ratio test). We used spatial metrics to perform ‘digital biopsies’ to derive novel, spatially-dependent biomarkers such as LAG3+Tregs (p=0.022 for all cells, p=0.66 near tumor) (figure 1B,C). We quantified cell rosetting, a recruitment of immune cells that is characteristic of Hodgkin’s (figure 1D), by defining ligand-receptor associations that are unique to different stages of disease severity. We proposed novel ligand-receptor biomarkers involving macrophages (TIM3/Galectin9, CD80, PDL1) and CD4 T cells (LAG3/HLAII, VISTA/Galectin9, PD1/PDL1) (p<0.05) (figure 1E).ConclusionsSpatial analysis of the HL microenvironment revealed composite features of the TME that predict clinical outcomes (figure 1F). These features cannot be described using single cell tools or low-plexed imaging, and represent a truer picture of HL biology. The pipeline developed here can be universally applied to other spatial protein data for biomarker discovery and analysis, and the novel spatial biomarkers proposed here have been validated with multi-color IHC in an independent cohort.Abstract 125 Figure 1IMC analysis of Hodgkin’s Lymphoma. (A) IMC generatesa 40-plex protein image that can be segmented into single cells. (B) (C) Single cell data can be processed to obtain immune phenotypes, shown by heatmap and UMAP. (D) Immune cells aggregate to form rosettes around tumor cells. We find specific ligand-receptor interactions associated with rosetting. (E) Tumor/Treg ICOSL/ICOS expression is highly correlated with Treg rosettes, while Tumor/CD4 LAG3/HLADPDQDR expression is negatively correlated with CD4 rosettes. (F) IMC-generated biomarkers predict overall survival.

Plant cell wall remodeling is an important process during plant responses to heat stress. Pectins, a group of cell wall polysaccharides with a great diversity of complex chemical structures, are also involved in heat stress responses. Enzymatic activity of the pectin methyl esterases, which remove methyl groups from pectins in the cell wall, is regulated by DUF642 proteins, as described in different plants, including Arabidopsis thaliana and Oryza sativa. Our results demonstrated that heat stress altered the expression of the DUF642 gene, BIIDXI. There was an important decrease in BIIDXI expression during the first hour of HS, followed by an increase at 24 h. bdx-1 seedlings had less tolerance to heat stress but presented a normal heat stress response; HSFA2 and HSP22 expressions were highly increased, as they were in WT seedlings. Thermopriming triggered changes in pectin methyl esterase activity in WT seedlings, while no increases in PME activity were detected in bdx-1 seedlings at the same conditions. Taken together, our results suggest that BIIDXI is involved in thermotolerance via PME activation.

Seed reserves play an essential role during germination and seedling establishment and are particularly important for species that grow in seasonal ecosystems with a short growing season. In this study, we examined (a) how and when the seedlings change their dependence from seed resources to external resources, (b) the lipid, nitrogen, and non-structural carbohydrate reserve translocation from seeds to seedlings over time, and (c) whether reserve translocation may be correlated to cotyledon and leaf lifespan of seedlings for eight tree species in a tropical deciduous forest in north-western Mexico. Our results showed that the cotyledon lifespan was not related to the cotyledon type (photosynthetic or reserve) and that the cotyledon biomass did not decrease significantly until germination. In six of the eight studied species, biomass allocation to the leaves was favored; lipids were the first reserve exhausted before the first leaves were totally expanded in seven of the eight study species. Species with the highest N concentration had expanded leaves and lost their cotyledons faster than species with a low N concentration. Our results suggest that tropical deciduous forest species employ different strategies to survive the dry season and resprout in the next growing season mediated by seed reserve concentrations, translocation patterns and subsequent biomass allocation.

Seeds constitute a key physiological stage in plants life cycle. During seed germination, there is a spatial-temporal imbibition pattern that correlates with described physiological processes. However, only the moment of testa rupture has been described as a critical, discrete stage. Could a specific relative water content (RWC) value reflect a physiological stage useful for comparisons between seed batches? We tracked seed-by-seed imbibition during germination to homogenize sampling and selected a transcriptomic approach to analyse the physiological transitions that occur in seed batches collected in different years and with contrasting phenotypic responses to a priming treatment. The seed RWC reflected the transcriptional transitions that occur during germination, regardless of imbibition time or collection year, and revealed a set of biological processes that occur in the dry seed and during early germination are associated with the phenotypic response to priming. As climate shifts, so do the timing of developmental events important for determining organismal fitness, and poses another challenge to the comprehension of molecular and physiological processes driving the interaction between organisms and environment. In this study, we demonstrate that the use of physiological traits, specific to a particular developmental stage, is a reliable time-independent approach.