Mixture of Soft Prompts for Controllable Data Generation

Large language models (LLMs) effectively generate fluent text when the target output follows natural language patterns. However, structured prediction tasks confine the output format to a limited ontology, causing even very large models to struggle since they were never trained with such restrictions in mind. The difficulty of using LLMs for direct prediction is exacerbated in few-shot learning scenarios, which commonly arise due to domain shift and resource limitations. We flip the problem on its head by leveraging the LLM as a tool for data augmentation rather than direct prediction. Our proposed Mixture of Soft Prompts (MSP) serves as a parameter-efficient procedure for generating data in a controlled manner. Denoising mechanisms are further applied to improve the quality of synthesized data. Automatic metrics show our method is capable of producing diverse and natural text, while preserving label semantics. Moreover, MSP achieves state-of-the-art results on three benchmarks when compared against strong baselines. Our method offers an alternate data-centric approach for applying LLMs to complex prediction tasks.Comment: 19 pages, 13 Tables, 2 Figures. Accepted at EMNLP 202

Sex-Specific Effects of a Wartime-Like Radiation Exposure on Cognitive Function.

Evaluating the risk for central nervous system (CNS) effects after whole-body or partial-body irradiation presents challenges due in part to the varied exposure scenarios in the context of occupational, accidental or wartime releases. Risk estimations are further complicated by the fact that robust changes in brain function are unlikely to manifest until significantly late post exposure times. Collectively, the current data regarding CNS radiation risk are conflicting in humans and a survey of the animal model data shows that it is similarly inconsistent. Due to the sparseness of such data, the current study was conducted using male and female mice to evaluate the brain for the delayed effects of a 2 Gy whole-body exposure to c rays starting six months postirradiation. Behavioral testing indicated sex-specific differences in the induction of anxiety-like behaviors and in the ability to abolish fear memories. Molecular analyses showed alterations in post-synaptic protein levels that might affect synaptic plasticity and increased levels of global DNA methylation, suggesting a potential epigenetic mechanism that might contribute to radiation-induced cognitive dysfunction. These data add to the understanding of the CNS response to whole-body irradiation and may lead to improved risk assessment and provide guidance in the development of effective radiation countermeasures to protect military personnel and civilians alike

Functional equivalence of stem cell and stem cell-derived extracellular vesicle transplantation to repair the irradiated brain.

Cranial radiotherapy, although beneficial for the treatment of brain tumors, inevitably leads to normal tissue damage that can induce unintended neurocognitive complications that are progressive and debilitating. Ionizing radiation exposure has also been shown to compromise the structural integrity of mature neurons throughout the brain, an effect believed to be at least in part responsible for the deterioration of cognitive health. Past work has shown that cranially transplanted human neural stem cells (hNSCs) or their extracellular vesicles (EVs) afforded long-term beneficial effects on many of these cognitive decrements. To provide additional insight into the potential neuroprotective mechanisms of cell-based regenerative strategies, we have analyzed hippocampal neurons for changes in structural integrity and synaptic remodeling after unilateral and bilateral transplantation of hNSCs or EVs derived from those same cells. Interestingly, hNSCs and EVs similarly afforded protection to host neurons, ameliorating the impact of irradiation on dendritic complexity and spine density for neurons present in both the ipsilateral and contralateral hippocampi 1 month following irradiation and transplantation. These morphometric improvements were accompanied by increased levels of glial cell-derived growth factor and significant attenuation of radiation-induced increases in postsynaptic density protein 95 and activated microglia were found ipsi- and contra-lateral to the transplantation sites of the irradiated hippocampus treated with hNSCs or hNSC-derived EVs. These findings document potent far-reaching neuroprotective effects mediated by grafted stem cells or EVs adjacent and distal to the site of transplantation and support their potential as therapeutic agents to counteract the adverse effects of cranial irradiation

Population-genomic analysis identifies a low rate of global adaptive fixation in the proteins of the cyclical parthenogen Daphnia magna

Daphnia are well-established ecological and evolutionary models, and the interaction between D. magna and its microparasites is widely considered a paragon of the host-parasite coevolutionary process. Like other well-studied arthropods such as Drosophila melanogaster and Anopheles gambiae, D. magna is a small, widespread, and abundant species that is therefore expected to display a large long-term population size and high rates of adaptive protein evolution. However, unlike these other species, D. magna is cyclically asexual and lives in a highly structured environment (ponds and lakes) with moderate levels of dispersal, both of which are predicted to impact upon long-term effective population size and adaptive protein evolution. To investigate patterns of adaptive protein fixation, we produced the complete coding genomes of 36 D. magna clones sampled from across the European range (Western Palaearctic), along with draft sequences for the close relatives D. similis and D. lumholtzi, used as outgroups. We analyzed genome-wide patterns of adaptive fixation, with a particular focus on genes that have an a priori expectation of high rates, such as those likely to mediate immune responses, RNA interference against viruses and transposable elements, and those with a strongly male-biased expression pattern. We find that, as expected, D. magna displays high levels of diversity and that this is highly structured among populations. However, compared to Drosophila, we find that D. magna proteins appear to have a high proportion of weakly deleterious variants and do not show evidence of pervasive adaptive fixation across its entire range. This is true of the genome as a whole, and also of putative ‘arms race’ genes that often show elevated levels of adaptive substitution in other species. In addition to the likely impact of extensive, and previously documented, local adaptation, we speculate that these findings may reflect reduced efficacy of selection associated with cyclical asexual reproduction

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Mutations in <em>GRHL2</em> result in an autosomal-recessive ectodermal dysplasia syndrome

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease

A Computational Method for Prediction of Excretory Proteins and Application to Identification of Gastric Cancer Markers in Urine

A novel computational method for prediction of proteins excreted into urine is presented. The method is based on the identification of a list of distinguishing features between proteins found in the urine of healthy people and proteins deemed not to be urine excretory. These features are used to train a classifier to distinguish the two classes of proteins. When used in conjunction with information of which proteins are differentially expressed in diseased tissues of a specific type versus control tissues, this method can be used to predict potential urine markers for the disease. Here we report the detailed algorithm of this method and an application to identification of urine markers for gastric cancer. The performance of the trained classifier on 163 proteins was experimentally validated using antibody arrays, achieving >80% true positive rate. By applying the classifier on differentially expressed genes in gastric cancer vs normal gastric tissues, it was found that endothelial lipase (EL) was substantially suppressed in the urine samples of 21 gastric cancer patients versus 21 healthy individuals. Overall, we have demonstrated that our predictor for urine excretory proteins is highly effective and could potentially serve as a powerful tool in searches for disease biomarkers in urine in general

Increased prevalence of methicillin-resistant Staphylococcus aureus nasal colonization in household contacts of children with community acquired disease

<p>Abstract</p> <p>Background</p> <p>To measure Methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) nasal colonization prevalence in household contacts of children with current community associated (CA)-MRSA infections (study group) in comparison with a group of household contacts of children without suspected <it>Staphylococcus aureus </it>infection (a control group).</p> <p>Methods</p> <p>This is a cross sectional study. Cultures of the anterior nares were taken. Relatedness of isolated strains was tested using pulse field gel electrophoresis (PFGE).</p> <p>Results</p> <p>The prevalence of MRSA colonization in the study group was significantly higher than in the control group (18/77 (23%) vs 3/77 (3.9%); p ≤ 0.001). The prevalence of SA colonization was 28/77 (36%) in the study group and 16/77 (21%) in the control group (p = 0.032). The prevalence of SA nasal colonization among patients was 6/24 (25%); one with methicillin-susceptible <it>S. aureus </it>(MSSA) and 5 with MRSA. In the study (patient) group, 14/24 (58%) families had at least one household member who was colonized with MRSA compared to 2/29 (6.9%) in the control group (p = 0.001). Of 69 total isolates tested by PFGE, 40 (58%) were related to USA300. Panton-Valetine leukocidin (PVL) genes were detected in 30/52 (58%) tested isolates. Among the families with ≥1 contact colonized with MRSA, similar PFGE profiles were found between the index patient and a contact in 10/14 families.</p> <p>Conclusions</p> <p>Prevalence of asymptomatic nasal carriage of MRSA is higher among household contacts of patients with CA-MRSA disease than control group. Decolonizing such carriers may help prevent recurrent CA-MRSA infections.</p