Segmentation aware probabilistic phenotyping of single-cell spatial protein expression data.

Spatial protein expression technologies can map cellular content and organization by simultaneously quantifying the expression of >40 proteins at subcellular resolution within intact tissue sections and cell lines. However, necessary image segmentation to single cells is challenging and error prone, easily confounding the interpretation of cellular phenotypes and cell clusters. To address these limitations, we present STARLING, a probabilistic machine learning model designed to quantify cell populations from spatial protein expression data while accounting for segmentation errors.

Dual Crystal-Liquid Thermal Transport Behavior in MAPbCl.

Phonon dynamics in organic-inorganic hybrid perovskites (OIHPs) exhibit inherent complexity driven by the intricate interactions between rotatable organic cations and dynamically disordered inorganic octahedra, mediated by hydrogen bonding. This study aims to address this complexity by investigating the thermal transport behavior of MAPbCl as a gateway to the OIHPs family. The results reveal that the ultralow thermal conductivity of MAPbCl arises from a synergistic interplay of exceptionally low phonon velocities, short phonon lifetimes, and phonon mean free paths approaching the Regel-Ioffe limit.

TSC2-mTORC1 axis regulates morphogenesis and neurological function of Gli1 adult-born dentate granule cells.

Aberrant adult hippocampal neurogenesis is implicated in neurological and mood disorders associated with dysregulation of the mechanistic target of rapamycin (mTOR). Understanding how the mTOR pathway shapes the functional development of different subpopulations of adult-born hippocampal neural stem cells will enable insight into potential therapeutic pathways for these disorders. Here we study how loss of TSC2, a regulator of mTOR pathway and a causal gene for tuberous sclerosis complex (TSC), affects dentate gyrus granule cell morphogenesis and hippocampal-dependent function.

Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems.

Gene therapy holds great therapeutic potential. Yet, controlling cargo expression in single cells is limited due to the variability of delivery methods. We implement an incoherent feedforward loop based on proteolytic cleavage of CRISPR-Cas activation or inhibition systems to reduce gene expression variability against the variability of vector delivery.

Identification of Molecular Profile of Ear Fibroblasts Derived from Spindle-Transferred Holstein Cattle with Ooplasts from Taiwan Yellow Cattle under Heat Stress.

Global warming has a significant impact on the dairy farming industry, as heat stress causes reproductive endocrine imbalances and leads to substantial economic losses, particularly in tropical-subtropical regions. The Holstein breed, which is widely used for dairy production, is highly susceptible to heat stress, resulting in a dramatic reduction in milk production during hot seasons. However, previous studies have shown that cells of cows produced from reconstructed embryos containing cytoplasm (o) from Taiwan yellow cattle (Y) have improved thermotolerance despite their nuclei (n) being derived from heat-sensitive Holstein cattle (H).

Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys.

Retinoic acid-induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith-Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

() haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural to body weight regulation remain unclear.

rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice.

Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele.

Loss of enhances hippocampal excitability and epileptogenesis in mouse models of Smith-Magenis syndrome.

Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, (), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns.

Effects of intracytoplasmic sperm injection timing and fertilization methods on the development of bovine spindle transferred embryos.

Cytoplasmic replacement by spindle transfer (ST) technique can be applied to improve the developmental competence of poor qualitied or aged oocytes. In cattle, ST technology has not been well established for producing embryos and the calves successfully using intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). The objective of this study was to develop a novel procedure for producing bovine ST embryos, which could be fundamental to applying ST technology in other mammals.

Temporal dissection of Rai1 function reveals brain-derived neurotrophic factor as a potential therapeutic target for Smith-Magenis syndrome.

Haploinsufficiency of retinoic acid-induced 1 (RAI1) is responsible for Smith-Magenis syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear.

Identification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations.

Annotations of evolutionary sequence constraint based on multi-species genome alignments and genome-wide maps of epigenomic marks and transcription factor binding provide important complementary information for understanding the human genome and genetic variation. Here we developed the Constrained Non-Exonic Predictor (CNEP) to quantify the evidence of each base in the genome being in an evolutionarily constrained non-exonic element from an input of over 60,000 epigenomic and transcription factor binding features. We find that the CNEP score outperforms baseline and related existing scores at predicting evolutionarily constrained non-exonic bases from such data.

Dosage-sensitive genes in autism spectrum disorders: From neurobiology to therapy.

Autism spectrum disorders (ASDs) are a group of heterogenous neurodevelopmental disorders affecting 1 in 59 children. Syndromic ASDs are commonly associated with chromosomal rearrangements or dosage imbalance involving a single gene. Many of these genes are dosage-sensitive and regulate transcription, protein homeostasis, and synaptic function in the brain.

E2F1 sumoylation as a protective cellular mechanism in oxidative stress response.

Oxidative stress is a ubiquitous threat to all aerobic organisms and has been implicated in numerous pathological conditions such as cancer. Here we demonstrate a pivotal role for E2F1, a cell cycle regulatory transcription factor, in cell tolerance of oxidative stress. Cells lacking E2F1 are hypersensitive to oxidative stress due to the defects in cell cycle arrest.

Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt.

Cdk2-dependent TopBP1-treslin interaction is critical for DNA replication initiation. However, it remains unclear how this association is terminated after replication initiation is finished. Here, we demonstrate that phosphorylation of TopBP1 by Akt coincides with cyclin A activation during S and G phases and switches the TopBP1-interacting partner from treslin to E2F1, which results in the termination of replication initiation.

Development of the Nurses' Occupational Stressor Scale.

Although nurses work in stressful environments, stressors in such environments have yet to be clearly assessed. This study aimed to develop a Nurses' Occupational Stressor Scale (NOSS) with high reliability and validity. Candidate questions for the NOSS were generated by expert consensus following focus group feedback, and were used to survey in 2013.

CGRRF1, a growth suppressor, regulates EGFR ubiquitination in breast cancer.

Background: CGRRF1 is a growth suppressor and consists of a transmembrane domain and a RING-finger domain. It functions as a RING domain E3 ubiquitin ligase involved in endoplasmic reticulum-associated degradation. The expression of CGRRF1 is decreased in cancer tissues; however, the role of CGRRF1 in breast cancer and the mechanism(s) of its growth suppressor function remain to be elucidated.

Cognitive and motor dual task gait training exerted specific training effects on dual task gait performance in individuals with Parkinson's disease: A randomized controlled pilot study.

Gait impairments in Parkinson's disease (PD) are aggravated under dual task conditions. Providing effective training to enhance different dual task gait performance is important for PD rehabilitation. This pilot study aimed to investigate the effects of cognitive and motor dual task gait training on dual task gait performance in PD.

Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin.

Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73.

Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain.

RNF144A, an E3 ubiquitin ligase for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), can promote DNA damage-induced cell apoptosis. Here we characterize an important regulation of RNF144A through its transmembrane (TM) domain. The TM domain of RNF144A is highly conserved among species.

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage.

Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNA-PKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner.

Co-regulation in embryonic stem cells via context-dependent binding of transcription factors.

Motivation: With the accumulation of genome-wide binding data for many transcription factors (TFs) in the same cell type or cellular condition, it is of great current interest to systematically infer the complex regulatory logic among multiple TFs. In particular, ChIP-Seq data have been generated for 14 core TFs critical to the maintenance and reprogramming of mouse embryonic stem cells (ESCs). This provides a great opportunity to study the regulatory collaboration and interaction among these TFs and with other unknown co-regulators.