Biology subjects

Hou, X.

Publications and source records attributed to Hou, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Formation process of the twinning β-form anhydrous guanine platelets in the scallop eyes

Square shaped twinning guanine microplates with high symmetry are assembled into highly ordered layered patterns and function as image-forming mirrors in the scallop eyes. However, the formation process and biomineralization mechanism of twinning guanine microplatelets are still unclear. Herein, the eyes of juvenile Yesso scallops were investigated to understand the formation mechanism of the twinning {beta}-form anhydrous guanine ({beta}-AG) microplatelets exposing (100) plane. We find form anhydrous guanine (-AG) and single-crystal {beta}-AG nanoplatelets in the very early stage of the eyes of the juvenile scallops, while the -AG was supposed to be formed via amorphous guanine during the sample preparation process. Besides {beta}-AG and -AG, amorphous guanine was found in the eyes of juvenile scallops with size of 2.5 mm according to the Raman spectra. A formation mechanism was proposed for the biogenic twinning guanine platelets. Firstly, amorphous guanine is formed as an intermediate phase, which transforms into single crystalline {beta}-AG nanoplatelets, or, dissolve and recrystallize to single crystalline {beta}-AG nanoplatelets. Then, a second layer of {beta}-AG forms on the top of the original single crystalline {beta}-AG nanoplatelets, forming twinning {beta}-AG nanoplatelets with two c axes with a certain angle, 83{degrees} or 14{degrees}. Each layer of the {beta}-AG nanoplatelets is calculated to be about 14 {+/-} 2 nm. This is the first time to report the formation mechanism of biogenic twinning {beta}-AG microplatelets. Uncovering the formation mechanism of twinning platelets of organic crystals may shed light on the formation of functional synthetic twinning organic crystals in the laboratories.

biochemistry↗

bioRxiv2022

Macaque Brainnetome Atlas with Fine-grained Parcellations and Reliable Connections

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas that identifies anatomically and functionally distinct regions is fundamental to biomedical and evolutionary research. However, even though connectivity information is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were comprehensively evaluated with multi-contrast MRI, invasive neuronal-tracing, and Nissl-stained images collected from a single subject and with open-access datasets from other cohorts. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, block-face, and section images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

neuroscience↗

bioRxiv2022

Innate immune sensing of self-derived double-stranded RNA by RIG-I-MAVS-TNF-α regulates the survival and senescence fate of SARS-2-S syncytia

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without denovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy. Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNF-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

cell biology↗

bioRxiv2022

Systematic characterization of chromodomain proteins revealsan H3K9me1/2 reader regulating aging in C. elegans

The chromatin organization modifier domain (chromodomain) is an evolutionally conserved motif across eukaryotic species. The chromodomain mainly functions as a histone methyl-lysine reader to modulate gene expression, chromatin spatial conformation and genome stability. Mutations or aberrant expression of chromodomain proteins can result in cancer and other human diseases. Here, we systematically tagged chromodomain proteins with green fluorescent protein (GFP) using CRISPR/Cas9 technology in C. elegans. By combining ChIP-seq analysis and imaging, we delineated a comprehensive expression and functional map of chromodomain proteins. We then conducted a candidate-based RNAi screening and identified factors that regulate the expression and subcellular localization of the chromodomain proteins. Specifically, we revealed a new H3K9me1/2 reader, CEC-5, both by in vitro biochemistry and in vivo ChIP assays. MET-2, an H3K9me1/2 writer, is required for CEC-5 association with heterochromatin. Both MET-2 and CEC-5 are required for the normal lifespan of C. elegans. Furthermore, a forward genetic screening identified a conserved Arginine124 of CEC-5s chromodomain, which was essential for CEC-5s association with chromatin and life span regulation. Thus, our work will serve as a reference to explore chromodomain functions and regulation in C. elegans and allow potential applications in aging-related human diseases.

molecular biology↗

bioRxiv2022

Segmented MS/MS acquisition of a1 ion-based strategy for in-depth proteome quantitation

In-depth proteome quantitation is of great significance for understanding protein functions, advancing biological, medical, environmental and metabolic engineering research. Herein, benefiting from the high formation efficiencies and intensities of dimethyl-labeled a1 ions for accurate quantitation, we developed an in-depth a1 ion-based proteome quantitation method, named deep-APQ, by a sequential MS/MS acquisition of the high mass range for identification and the low mass range for a1 ion intensity extraction to increase quantitative protein number and sequence coverage. By the analysis of HeLa protein digests, our developed method showed deeper quantitative coverage than our previously reported a1 ion-based quantitation method without mass range segmentation and lower missing values than widely-used label-free quantitation method. It also exhibited excellent accuracy and precision within a 20-fold dynamic range. We further integrated a workflow combining the deep-APQ method with highly efficient sample preparation, high-pH and low-pH reversed-phase separation and high-field asymmetric waveform ion mobility spectrometry (FAIMS) to study E. coli proteome responses under the nutritional conditions of glucose and acetate. A total of 3447 proteins were quantified, representing 82% of protein-coding genes, with the average sequence coverage up to 40%, demonstrating the high coverage of quantitation results. We found that most of the quantified proteins related to chemotaxis were differentially expressed, including the low-abundance proteins such as trg, fliL, and cheA, indicating that chemotaxis would play an important role for E. coli cell to survive from acetate toxicity. The above results demonstrated that the deep-APQ method is of great promising to achieve the deep-coverage proteome quantitation with high confidence. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/501662v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1457bdeorg.highwire.dtl.DTLVardef@c74e53org.highwire.dtl.DTLVardef@e72e9forg.highwire.dtl.DTLVardef@1a5cc43_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Inhibitory effects of GT0918 on acute lung injury and the molecular mechanisms of anti-inflammatory response

Coronavirus disease 2019 (COVID-19) has caused the public health crisis in the whole world. Anti-androgens block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and protect against severe clinical COVID-19 outcomes. GT0918, a novel androgen receptor antagonist, accelerated viral clearance and increased recovery rate in outpatients by blocking SARS-CoV-2 infection though down-regulating ACE2 and TMPRSS2 expression. Further clinical study showed that GT0918 reduced mortality rate and shortened hospital stay in hospitalized COVID-19 patients. GT0918 also exhibits protective efficacy in severe COVID-19 patient in critical care. However, the mechanism of GT0918 treatment for severe COVID-19 disease is unknown. Here, we found GT0918 decreased the expression and secretion of proinflammatory cytokines through NF-{kappa}B signaling pathway. The acute lung injury induced by LPS or Poly(I:C) was also attenuated in GT0918-treated mice, compared with vehicle control group. Moreover, GT0918 elevated the NRF2 protein level but not mRNA transcription activity. GT0918 induced proinflammatory cytokines downregulation was partially dependent on NRF2. In conclusion, our data demonstrate that GT0918 reduced cytokine release and suppressed inflammatory responses through inhibiting NF-{kappa}B signaling and activating NRF2. GT0918 is not only effective for treatment of mild to moderate COVID-19 patients, but also a potential therapeutic drug for severe COVID-19 patients by reducing the risk of cytokine storm and acute respiratory distress syndrome.

cell biology↗

bioRxiv2022

Structural connectivity gradient associated with a dichotomy reveals the topographic organization of the macaque insular cortex

Histology studies revealed that the macaque insular cortex was characterized by the gradual organizations containing agranular, dysgranular and granular insula. However, no consensus has been reached on the elaborate subdivisions of macaque insula. Until now, no neuroimaging study to our knowledge combining connectivity-based gradients and parcellation has been performed to investigate the topographic organization of the macaque insular cortex. In this study, we used high-resolution ex vivo diffusion-weighted imaging data to explore the macaque insular cortexs global gradient organization and subdivisions. We found a rostrocaudal organization of the dominant gradient in the macaque insula using a diffusion map embedding. Meanwhile, extracting the 25% top and bottom components from the dominant and second gradient, which explained variance over 60% in total within ten gradients, the connectivity-based parcellation method was performed to subdivide each component into two subregions confirmed by the cross-validation analysis. Furthermore, permutations tests identified that two subregions from each component showed significant differences between their connectivity fingerprints. Finally, we found that the dominant and second gradients were significantly correlated with the T1w/T2w and cortical thickness maps in the macaque insula. Taken together, the global gradients combining the subdivisions examined the topographic organization of the macaque insular cortex based on the structural connectivity, which may contribute to a better understanding of the intricate insular cortex anatomy.

neuroscience↗

bioRxiv2021

An early Cambrian polyp reveals an anemone-like ancestor for medusozoan cnidarians

Extant cnidarians are a disparate phylum of non-bilaterians and their diploblastic body plan represents a key step in animal evolution. Anthozoans (anemones, corals) are benthic polyps, while adult medusozoans (jellyfishes) are dominantly pelagic medusae. A sessile polyp is present in both groups and is widely conceived as the ancestral form of their last common ancestor. However, the nature and anatomy of this ancestral polyp, particularly of medusozoans, are controversial, owing to the divergent body plans of both groups in the extant lineages and the rarity of medusozoan soft tissues in the fossil record. Here we redescribe the enigmatic Conicula striata Luo et Hu from the early Cambrian Chengjiang biota, south China, which has previously been interpreted as a polyp, lophophorate or deuterostome. We show that C. striata possessed features of both anthozoans and medusozoans. Its stalked polyp and fully encasing conical, annulated organic skeleton (periderm) are features of medusozoans. However, the gut is partitioned by [~]28 mesenteries, and has a tubular pharynx, resembling anthozoans. Our phylogenetic analysis recovers C. striata as a stem medusozoan, indicating that the enormously diverse medusozoans were derived from an anemone-like ancestor, with the pharynx lost and number of mesenteries reduced prior to the origin of crown group Medusozoa.

paleontology↗

bioRxiv2021

pGlycoQuant with a deep residual network for precise and minuscule-missing-value quantitative glycoproteomics enabling the functional exploration of site-specific glycosylation

Interpreting large-scale glycoproteomic data for intact glycopeptide identification has been tremendously advanced by software tools. However, software tools for quantitative analysis of intact glycopeptides remain lagging behind, which greatly hinders exploring the differential expression and functions of site-specific glycosylation in organisms. Here, we report pGlycoQuant, a generic software tool for accurate and convenient quantitative intact glycopeptide analysis, supporting both primary and tandem mass spectrometry quantitation for multiple quantitative strategies. pGlycoQuant enables intact glycopeptide quantitation with very low missing values via a deep residual network, thus greatly expanding the quantitative function of several powerful search engines, currently including pGlyco 2.0, pGlyco3, Byonic and MSFragger-Glyco. The pGlycoQuant-based site-specific N-glycoproteomic study conducted here quantifies 6435 intact N-glycopeptides in three hepatocellular carcinoma cell lines with different metastatic potentials and, together with in vitro molecular biology experiments, illustrates core fucosylation at site 979 of the L1 cell adhesion molecule (L1CAM) as a potential regulator of HCC metastasis. pGlycoQuant is freely available at https://github.com/expellir-arma/pGlycoQuant/releases/. We have demonstrated pGlycoQuant to be a powerful tool for the quantitative analysis of site-specific glycosylation and the exploration of potential glycosylation-related biomarker candidates, and we expect further applications in glycoproteomic studies.

systems biology↗

bioRxiv2021

Total virome characterizations of game animals in China reveals a spectrum of emerging viral pathogens

Game animals are wildlife species often traded and consumed as exotic food, and are potential reservoirs for SARS-CoV and SARS-CoV-2. We performed a meta-transcriptomic analysis of 1725 game animals, representing 16 species and five mammalian orders, sampled across China. From this we identified 71 mammalian viruses, with 45 described for the first time. Eighteen viruses were considered as potentially high risk to humans and domestic animals. Civets (Paguma larvata) carried the highest number of potentially high risk viruses. We identified the transmission of Bat coronavirus HKU8 from a bat to a civet, as well as cross-species jumps of coronaviruses from bats to hedgehogs and from birds to porcupines. We similarly identified avian Influenza A virus H9N2 in civets and Asian badgers, with the latter displaying respiratory symptoms, as well as cases of likely human-to-wildlife virus transmission. These data highlight the importance of game animals as potential drivers of disease emergence. HighlightsO_LI1725 game animals from five mammalian orders were surveyed for viruses C_LIO_LI71 mammalian viruses were discovered, 18 with a potential risk to humans C_LIO_LICivets harbored the highest number of potential high risk viruses C_LIO_LIA species jump of an alphacoronavirus from bats to a civet was identified C_LIO_LIH9N2 influenza virus was detected in a civet and an Asian badger C_LIO_LIHumans viruses were also identified in game animals C_LI

zoology↗

bioRxiv2021

Circuit-specific sonogenetic stimulation of the deep brain elicits distinct signaling and behaviors in freely moving mice

Sonogenetics uses heterologously-expressed proteins to sensitize neurons to ultrasound, enabling selective, non-invasive, and deep brain stimulation. However, its ability to modulate specific circuits or induce behavioral changes remains to be studied and characterized. Here, we demonstrate that sonogenetics enables efficient activation of well-defined neural circuits by transcranial low-intensity, low-frequency ultrasonic stimulation with high spatiotemporal resolution. Targeted neurons in subcortical regions were made to express a mechanosensitive ion channel (MscL-G22S). Ultrasound could trigger activity in MscL-expressing neurons in the dorsal striatum without increased activation in neighboring regions, and increase locomotion in freely-moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. In MscL-expressing cells, neuronal responses to ultrasound pulses were rapid, reversible and repeatable. Altogether, we show that sonogenetics can selectively manipulate targeted cells to activate defined neural pathways and affect behaviors.

neuroscience↗

bioRxiv2021

Palaeogenomics reveal a hybrid origin of the world's largest Camelus species

The extinct Camelus knoblochi is known as the largest camel in genus Camelus, but its relationship to modern Camelus species remains unclear. In this study, we reported the first mitochondrial and nuclear analyses of seven Late Pleistocene C. knoblochi samples from Northeastern China. We found that they are inseparable to wild Bactrian camel on the matrilineal side, but belong to a distinct cluster on the biparental nuclear side. Further admixture proportion analyses suggested hybrid ancestry between both the ancestors of the modern wild and domesticated Bactrian camels, with ~65% contribution from the former and ~35% from the later. By calculating the coalescence time for three Camelus species above, we estimated the hybridization event occurred between approximately 0.8 and 0.33 Ma. We also used Bayesian skyline to reconstruct the maternal demographic trajectories for different Camelus to better compare their evolutionary histories. Our results provide molecular insights into C. knoblochi and fill in a vital piece in understanding the genus Camelus.

molecular biology↗

bioRxiv2021

Before trilobite legs: Pygmaclypeatus daziensis reconsidered and the ancestral appendicular organization of Cambrian artiopods

The Cambrian Stage 3 Chengjiang biota in South China is one of the most influential Konservat-Lagerstatten worldwide thanks to the fossilization of diverse non-biomineralizing organisms through pyritization. Despite their contributions to understanding the evolution of early animals, several Chengjiang species remain poorly known due to their scarcity and/or incomplete preservation. Here, we use micro-computed tomography to reveal in detail the ventral appendage organization of the enigmatic non-trilobite artiopod Pygmaclypeatus daziensis - one of the rarest euarthropods in Chengjiang - and explore its functional ecology and broader evolutionary significance. Pygmaclypeatus daziensis possesses a set of uniramous antennae and 14 pairs of post-antennal biramous appendages, the latter of which show an unexpectedly high degree of heteronomy based on the localized differentiation of the protopodite, endopodite and exopodite along the antero-posterior body axis. The small body size (less than 2 cm), presence of delicate spinose endites, and well-developed exopodites with multiple paddle-shaped lamellae on the appendages of P. daziensis indicate a nekto-benthic mode of life, and a scavenging/detritus feeding strategy. Pygmaclypeatus daziensis shows that appendage heteronomy is phylogenetically widespread within Artiopoda - the megadiverse clade that includes trilobites and their relatives with non-biomineralizing exoskeletons - and suggests that a single exopodite lobe with paddle-like lamellae is ancestral for this clade. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/456779v1_ufig1.gif" ALT="Figure 1"> View larger version (111K): org.highwire.dtl.DTLVardef@b4ddaaorg.highwire.dtl.DTLVardef@44f686org.highwire.dtl.DTLVardef@1950095org.highwire.dtl.DTLVardef@1596739_HPS_FORMAT_FIGEXP M_FIG C_FIG Cover image: Morphological reconstruction of the non-trilobite artiopod Pygmaclypeatus daziensis from the early Cambrian (Stage 3) Chengjiang biota in south China. Artwork by Holly Sullivan (https://www.sulscientific.com/).

paleontology↗

bioRxiv2021

Arabidopsis ROOT UV-B SENSITIVE 1 and 2 Interact with Aminotransferases to Regulate Vitamin B6 Homeostasis

Pyridoxal-5-phosphate (PLP), the enzymatic cofactor form of Vitamin B6 (vitB6), is a versatile compound that has essential roles in metabolism. Cellular PLP homeostasic regulation is currently not well understood. Here we report that in Arabidopsis, biosynthesized PLP is sequestered by specific aminotransferases (ATs), and that the proteins ROOT UV-B SENSITIVE 1 (RUS1) and RUS2 function with ATs to regulate PLP homeostasis. The stunted growth phenotypes of rus1 and rus2 mutants were previously shown to be rescuable by exogenously supplied vitB6. Specific residue changes near the PLP-binding pocket in ASPARTATE AMINOTRANSFERASE2 (ASP2) also rescued rus1 and rus2 phenotypes. In this study, saturated suppressor screens identified 14 additional suppressor of rus (sor) alleles in four aminotransferase genes (ASP1, ASP2, ASP3, or ALANIN AMINOTRANSFERASE1 (AAT1)), which suppressed the rus phenotypes to varying degrees. Each of the sor mutations altered an amino acid in the PLP-binding pocket of the protein, and sor proteins were found to have reduced levels of PLP conjugation. Genetic data revealed that the availability of PLP normally requires both RUS1 and RUS2, and that increasing the number of sor mutants additively enhanced the suppression of rus phenotypes. Biochemical results showed that RUS1 and RUS2 physically interacted with ATs. Our studies suggest a mechanism in which RUS1, RUS2 and specific ATs work together to regulate PLP homeostasis in Arabidopsis.

genetics↗

bioRxiv2021

A cell atlas of chromatin accessibility across 25 adult human tissues

Current catalogs of regulatory sequences in the human genome are still incomplete and lack cell type resolution. To profile the activity of human gene regulatory elements in diverse cell types and tissues in the human body, we applied single cell chromatin accessibility assays to 25 distinct human tissue types from multiple donors. The resulting chromatin maps comprising [~]500,000 nuclei revealed the status of open chromatin for over 750,000 candidate cis-regulatory elements (cCREs) in 54 distinct cell types. We further delineated cell type-specific and tissue-context dependent gene regulatory programs, and developmental stage specificity by comparing with a recent human fetal chromatin accessibility atlas. We finally used these chromatin maps to interpret the noncoding variants associated with complex human traits and diseases. This rich resource provides a foundation for the analysis of gene regulatory programs in human cell types across tissues and organ systems.

genomics↗

bioRxiv2021

An exceptionally preserved euarthropod with unique feather-like appendages from the Chengjiang biota

Micro-CT scanning of the Cambrian euarthropod Chuandianella ovata reveals unprecedented three-dimensional soft-part details. It has an elongate uniramous antennule and a short uniramous second appendage, followed by ten homonomous biramous appendages, each comprising a short paddle-shaped exopod and a unique feather-like endopod with at least 27 podomeres each of which bears a long blade-like endite with a short terminal seta. Based on its carapace and previously known soft-part anatomy C. ovata was compared with the Burgess Shale mandibulate euarthropod Waptia. However, Waptia has recently been shown to bear specialized head appendages that are interpreted as a mandible and maxillula, posterior to which are four appendages each with five-segmented endopods. In contrast, we interpret Chuandianella as an upper stem-group euarthropod that possessed neither a differentiated mandible nor a maxillula. Chuandianella further demonstrates that early Cambrian upper stem-group euarthropods were experimenting with a range of different limb arrangements and morphologies.

evolutionary biology↗

bioRxiv2021

Identifying long non-coding RNAs and characterizing their functional roles in swine mammary gland from colostrogenesis to lactogenesis

Long non-coding RNAs (lncRNAs) play important regulatory roles in milk biological processes. While, little is known about the identification and function of swine lncRNAs in response to mammary gland development. Here, we identified 286 differentially expressed (DE) lncRNAs in mammary gland at different stages from 14 days prior to (-) parturition to day 1 after (+) parturition using the published RNA-seq data. The expression pattern of these DE lncRNAs was examined, and most of lncRNAs expressions were strongly changed from Day -2 to Day +1. Functional annotation revealed that the DE lncRNAs were mainly involved in the mammary gland developing, lactation developing, milk composition metabolism and colostrum function. By performing the weighted gene co-expression network analysis (WGCNA), we identified 7 out of 12 lncRNA-mRNA modules, including 35 lncRNAs and 319 mRNAs, which were highly associated with the mammary gland at Day -14, Day -2 and Day +1. Integrated analysis of the DE lncRNAs expression pattern examination, targets prediction, function annotation and WGCNA suggested that 18 lncRNAs (such as, XLOC_020627, ENSSSCG00000051193, XLOC_025150, ENSSSCG00000042618, XLOC_963181, ENSSSCG00000051701, XLOC_018030, and XLOC_025146) and their 20 target genes (such as, ACTN4, ADCY1, CSN3, SMO, CSN2, PRKAG2, FIBCD1, and GALNT7), were considered as the promising candidates for swine parturition and colostrum occurrence processes. Our research provided the insights into lncRNA profiles and their regulating mechanisms from colostrogenesis to lactogenesis in swine.

genetics↗

bioRxiv2020

Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During PARP Inhibitor Resistance Development

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated in the tumor, leading to homologous recombination deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived xenograft PH039, which lacks demonstrable repair gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by repeated 21-day niraparib treatments in vivo. PH039 acquired PARPi resistance by the third cycle of treatment and demonstrated unimpeded growth during subsequent exposure to either niraparib or rucaparib. Transcriptional profiling throughout the time course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of RAD51C methylation in patient tumor samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated that loss of RAD51C methylation prior to on-study biopsy was associated with limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide an important model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

cancer biology↗