The historical demography of the Martha's Vineyard signing community.

The deaf population of Martha's Vineyard has fascinated scholars for more than a century since Alexander Graham Bell's research on the frequent occurrence of deafness there and since Groce's book on the island's signing community (Groce, N. E. (1985). Everyone here spoke sign language: Hereditary deafness on Martha's Vineyard. Cambridge, MA: Harvard University Press.). In Groce's work, and in that of subsequent scholars, the Vineyard signing community has often been portrayed as remote and outlying, having developed independently of mainland signing communities for roughly 133 years until 1825. We re-examine that interpretation in light of historical, demographic, and genealogical evidence covering the period 1692-2008. We argue that the Vineyard signing community began in Chilmark in 1785, 93 years later than previously thought, and that it had had a brief period of independent development, roughly 40 years, before becoming well connected, through deaf education, to the nascent New England signing community. We consider the implications of the Vineyard community's history for our understanding of how village signing communities develop.

Low variability in the underlying cellular landscape adversely affects the performance of interaction-based approaches for conducting cell-specific analyses of DNA methylation in bulk samples.

Statistical methods that allow for cell type specific DNA methylation (DNAm) analyses based on bulk-tissue methylation data have great potential to improve our understanding of human disease and have created unprecedented opportunities for new insights using the wealth of publicly available bulk-tissue methylation data. These methodologies involve incorporating interaction terms formed between the phenotypes/exposures of interest and proportions of the cell types underlying the bulk-tissue sample used for DNAm profiling. Despite growing interest in such "interaction-based" methods, there has been no comprehensive assessment how variability in the cellular landscape across study samples affects their performance. To answer this question, we used numerous publicly available whole-blood DNAm data sets along with extensive simulation studies and evaluated the performance of interaction-based approaches in detecting cell-specific methylation effects. Our results show that low cell proportion variability results in large estimation error and low statistical power for detecting cell-specific effects of DNAm. Further, we identified that many studies targeting methylation profiling in whole-blood may be at risk to be underpowered due to low variability in the cellular landscape across study samples. Finally, we discuss guidelines for researchers seeking to conduct studies utilizing interaction-based approaches to help ensure that their studies are adequately powered.

A Bayesian framework for identifying consistent patterns of microbial abundance between body sites.

Recent studies have found that the microbiome in both gut and mouth are associated with diseases of the gut, including cancer. If resident microbes could be found to exhibit consistent patterns between the mouth and gut, disease status could potentially be assessed non-invasively through profiling of oral samples. Currently, there exists no generally applicable method to test for such associations. Here we present a Bayesian framework to identify microbes that exhibit consistent patterns between body sites, with respect to a phenotypic variable. For a given operational taxonomic unit (OTU), a Bayesian regression model is used to obtain Markov-Chain Monte Carlo estimates of abundance among strata, calculate a correlation statistic, and conduct a formal test based on its posterior distribution. Extensive simulation studies demonstrate overall viability of the approach, and provide information on what factors affect its performance. Applying our method to a dataset containing oral and gut microbiome samples from 77 pancreatic cancer patients revealed several OTUs exhibiting consistent patterns between gut and mouth with respect to disease subtype. Our method is well powered for modest sample sizes and moderate strength of association and can be flexibly extended to other research settings using any currently established Bayesian analysis programs.

digit-a tool for detection and identification of genomic interchromosomal translocations.

Structural variations (SVs) in genomic DNA can have profound effects on the evolution of living organisms, on phenotypic variations and on disease processes. A critical step in discovering the full extent of structural variations is the development of tools to characterize these variations accurately in next generation sequencing data. Toward this goal, we developed a software pipeline named digit that implements a novel measure of mapping ambiguity to discover interchromosomal SVs from mate-pair and pair-end sequencing data. The workflow robustly handles the high numbers of artifacts present in mate-pair sequencing and reduces the false positive rate while maintaining sensitivity. In the simulated data set, our workflow recovered 96% of simulated SVs. It generates a self-updating library of common translocations and allows for the investigation of patient- or group-specific events, making it suitable for discovering and cataloging chromosomal translocations associated with specific groups, traits, diseases or population structures.

Ontogeny-related pharmacogene changes in the pediatric liver transcriptome.

OBJECTIVES: The majority of drug dosing studies are based on adult populations, with modification of the dosing for children based on size and weight. This rudimentary approach for drug dosing children is limited, as biologically a child can differ from an adult in far more aspects than just size and weight. Specifically, understanding the ontogeny of childhood liver development is critical in dosing drugs that are metabolized through the liver, as the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Therefore, we set out to determine pharmacogenes that change over childhood development, followed by a secondary agnostic analysis, assessing changes transcriptome wide. MATERIALS AND METHODS: A total of 47 human liver tissue samples, with between 10 and 13 samples in four age groups spanning childhood development, underwent pair-end sequencing. Kruskal-Wallis and Spearman's rank correlation tests were used to determine the association of gene expression levels with age. Gene set analysis based on the pathways in KEGG utilized the gamma method. Correction for multiple testing was completed using q-values. RESULTS: We found evidence for increased expression of 'very important pharmacogenes', for example, coagulation factor V (F5) (P=6.7×10(-7)), angiotensin I converting enzyme (ACE) (P=6.4×10(-3)), and solute carrier family 22 member 1 (SLC22A1) (P=7.0×10(-5)) over childhood development. In contrast, we observed a significant decrease in expression of two alternative CYP3A7 transcripts (P=1.5×10(-5) and 3.0×10(-5)) over development. The analysis of genome-wide changes detected transcripts in the following genes with significant changes in mRNA expression (P<1×10(-9) with false discovery rate<5×0(-5)): ADCY1, PTPRD, CNDP1, DCAF12L1 and HIP1. Gene set analysis determined ontogeny-related transcriptomic changes in the renin-angiotensin pathway (P<0.002), with lower expression of the pathway, in general, observed in liver samples from younger participants. CONCLUSION: Considering that the renin-angiotensin pathway plays a central role in blood pressure and plasma sodium concentration, and our observation that ACE and PTPRD expression increased over the spectrum of childhood development, this finding could potentially impact the dosing of an entire class of drugs known as ACE-inhibitors in pediatric patients.

"We communicated that way for a reason": language practices and language ideologies among hearing adults whose parents are deaf.

Families with deaf parents and hearing children are often bilingual and bimodal, with both a spoken language and a signed one in regular use among family members. When interviewed, 13 American hearing adults with deaf parents reported widely varying language practices, sign language abilities, and social affiliations with Deaf and Hearing communities. Despite this variation, the interviewees' moral judgments of their own and others' communicative behavior suggest that these adults share a language ideology concerning the obligation of all family members to expend effort to overcome potential communication barriers. To our knowledge, such a language ideology is not similarly pervasive among spoken-language bilingual families, raising the question of whether there is something unique about family bimodal bilingualism that imposes different rights and responsibilities on family members than spoken-language family bilingualism does. This ideology unites an otherwise diverse group of interviewees, where each one preemptively denied being a "typical CODA [children of deaf adult]."

Simultaneous structures in sign languages: Acquisition and emergence.

The visual-gestural modality affords its users simultaneous movement of several independent articulators and thus lends itself to simultaneous encoding of information. Much research has focused on the fact that sign languages coordinate two manual articulators in addition to a range of non-manual articulators to present different types of linguistic information simultaneously, from phonological contrasts to inflection, spatial relations, and information structure. Children and adults acquiring a signed language arguably thus need to comprehend and produce simultaneous structures to a greater extent than individuals acquiring a spoken language. In this paper, we discuss the simultaneous encoding that is found in emerging and established sign languages; we also discuss places where sign languages are unexpectedly sequential. We explore potential constraints on simultaneity in cognition and motor coordination that might impact the acquisition and use of simultaneous structures.

The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs.

Tissue inhibitors of matrix metalloproteinases (TIMP) are a family of four endogenous proteins that primarily function to inhibit the activities of proteases such as the matrix metalloproteinases (MMP). Altered MMP/TIMP ratios are frequently observed in several human diseases. During aging and disease progression, the extracellular matrix (ECM) undergoes structural changes in which elastin and collagens serve an essential role. MMPs and TIMPs significantly influence the ECM. Classically, elevated levels of TIMPs are suggested to result in ECM accumulation leading to fibrosis, whereas loss of TIMP responses leads to enhanced matrix proteolysis. Here, we outline the known roles of the most abundant TIMP, TIMP2, in pulmonary diseases but also discuss future perspectives in TIMP2 research that could impact the lungs. TIMP2 directly inhibits MMPs, in particular MMP2, but TIMP2 is also required for the activation of MMP2 through its interaction with MMP14. The protease and antiprotease imbalance of MMPs and TIMPs are extensively studied in diseases but recent discoveries suggest that TIMPs, specifically, TIMP2 could play other roles in aging and inflammation processes.

Are palm reversals the pronoun reversals of sign language? Evidence from a fingerspelling task.

Acquisition of pronominal forms by children with autism spectrum disorder (ASD) continues to garner significant attention due to the unusual ways that such children produce and comprehend them. In particular, pronoun reversal errors (e.g., using the 2nd-person pronoun "you" to refer to oneself) have been noted in the speech of children with ASD since the very first report of the disorder. In more recent years, investigations of the signing of deaf children with ASD have documented a different phenomenon: palm orientation reversals, such that signs typically produced with an outward-facing palm are produced with the palm towards the signer, or vice versa. At the same time, true pronoun reversals have yet to be documented in the signing of deaf children on the autism spectrum. These two curious facts have led us to ask if there is evidence that palm orientation reversals in signed languages and pronoun reversals in spoken languages could be surface manifestations of the same underlying differences present in ASD. In this paper we seek to establish whether there is evidence for such an analogy, by comparing the ages at which the two phenomena appear in both typically-developing (TD) children and those with ASD, the frequency and consistency with which they appear, and their relationships with other linguistic and cognitive skills. Data are presented from a fingerspelling task given to a sample of 17 native-signing children with ASD and 24 native-signing TD children. We conclude that there are provocative parallels between pronoun reversals in spoken languages and palm reversals in signed languages, though more research is needed to definitively answer these questions.

A Rare Presentation of Tuberculosis-Related Septic Shock.

Septic shock with multi-organ dysfunction is an exceedingly rare, but known complication of untreated Mycobacterium tuberculosis (TB) infection. TB-associated cases of septic shock are predominantly reported in immunocompromised patients; however, it can manifest in a healthy individual if the infection is not treated. Through the interaction of lipoarabinomannan (LAM) on the mycobacterium cell wall with antigen-presenting cells, the bacteria may be able to survive in host cells for long periods of time. Without prompt treatment, TB may cause bronchiectasis and multi-organ failure. We report a case of a 24-year-old woman with untreated TB who developed widespread bronchiectasis and septic shock.

On the linguistic status of 'agreement' in sign languages.

In signed languages, the arguments of verbs can be marked by a system of verbal modification that has been termed "agreement" (more neutrally, "directionality"). Fundamental issues regarding directionality remain unresolved and the phenomenon has characteristics that call into question its analysis as agreement. We conclude that directionality marks person in American Sign Language, and the ways person marking interacts with syntactic phenomena are largely analogous to morpho-syntactic properties of familiar agreement systems. Overall, signed languages provide a crucial test for how gestural and linguistic mechanisms can jointly contribute to the satisfaction of fundamental aspects of linguistic structure.

Comparisons of oral, intestinal, and pancreatic bacterial microbiomes in patients with pancreatic cancer and other gastrointestinal diseases.

Background: Oral microbiota is believed to play important roles in systemic diseases, including cancer. Methods: We collected oral samples (tongue, buccal, supragingival, and saliva) and pancreatic tissue or intestinal samples from 52 subjects, and characterized 16S rRNA genes using high-throughput DNA sequencing. Results: Bray-Curtis plot showed clear separations between bacterial communities in the oral cavity and those in intestinal and pancreatic tissue samples. PERMANOVA tests indicated that bacterial communities from buccal samples were similar to supragingival and saliva samples, and pancreatic duct samples were similar to pancreatic tumor samples, but all other samples were significantly different from each other. A total of 73 unique Amplicon Sequence Variants (ASVs) were shared between oral and pancreatic or intestinal samples. Only four ASVs showed significant concordance, and two specific bacterial species (Gemella morbillorum and Fusobacterium nucleatum subsp. vincentii) showed consistent presence or absence patterns between oral and intestinal or pancreatic samples, after adjusting for within-subject correlation and disease status. Lastly, microbial co-abundance analyses showed distinct strain-level cluster patterns among microbiome members in buccal, saliva, duodenum, jejunum, and pancreatic tumor samples. Conclusions: Our findings indicate that oral, intestinal, and pancreatic bacterial microbiomes overlap but exhibit distinct co-abundance patterns in patients with pancreatic cancer and other gastrointestinal diseases.

The Source of Palm Orientation Errors in the Signing of Children with ASD: Imitative, Motoric, or Both?

Palm orientation reversal errors (e.g., producing the 'bye-bye' gesture with palm facing inward rather than outward as is customary in American culture) have been documented in the signing of deaf and hearing children with autism spectrum disorder (ASD) and in the imitation of gestures by signing and non-signing children with ASD. However the source of these unusual errors remains opaque. Given that children with ASD have documented difficulties with both imitation and motor skills, it is important to clarify the nature of these errors. Here we present a longitudinal case study of a single child with ASD, a hearing, signing child of Deaf parents. Samples of the child's signing were analyzed at ages 4;11, 6;2, 10;2, and 14;11. Lexical signs and fingerspelled letters were coded for the four parameters of sign articulation (handshape, location, movement, and palm orientation). Errors decreased for handshape, location, and movement after age 4;11, but increased on palm orientation from 4;11 and remained high, exceeding 55% of signs by 14;11. Fingerspelled letters contained a large proportion of 180-degree reversals, which suggest an origin in imitation differences, as well as midline-facing errors, suggestive of a motor origin. These longitudinal data suggest that palm orientation errors could be rooted in both imitation differences and motoric difficulties.

Improving survival prediction using a novel feature selection and feature reduction framework based on the integration of clinical and molecular data.

The accurate prediction of a cancer patient's risk of progression or death can guide clinicians in the selection of treatment and help patients in planning personal affairs. Predictive models based on patient-level data represent a tool for determining risk. Ideally, predictive models will use multiple sources of data (e.g., clinical, demographic, molecular, etc.). However, there are many challenges associated with data integration, such as overfitting and redundant features. In this paper we aim to address those challenges through the development of a novel feature selection and feature reduction framework that can handle correlated data. Our method begins by computing a survival distance score for gene expression, which in combination with a score for clinical independence, results in the selection of highly predictive genes that are non-redundant with clinical features. The survival distance score is a measure of variation of gene expression over time, weighted by the variance of the gene expression over all patients. Selected genes, in combination with clinical data, are used to build a predictive model for survival. We benchmark our approach against commonly used methods, namely lasso- as well as ridge-penalized Cox proportional hazards models, using three publicly available cancer data sets: kidney cancer (521 samples), lung cancer (454 samples) and bladder cancer (335 samples). Across all data sets, our approach built on the training set outperformed the clinical data alone in the test set in terms of predictive power with a c.Index of 0.773 vs 0.755 for kidney cancer, 0.695 vs 0.664 for lung cancer and 0.648 vs 0.636 for bladder cancer. Further, we were able to show increased predictive performance of our method compared to lasso-penalized models fit to both gene expression and clinical data, which had a c.Index of 0.767, 0.677, and 0.645, as well as increased or comparable predictive power compared to ridge models, which had a c.Index of 0.773, 0.668 and 0.650 for the kidney, lung, and bladder cancer data sets, respectively. Therefore, our score for clinical independence improves prognostic performance as compared to modeling approaches that do not consider combining non-redundant data. Future work will concentrate on optimizing the survival distance score in order to achieve improved results for all types of cancer.

Evolutionary Analysis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reveals Genomic Divergence with Implications for Universal Vaccine Efficacy.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the pressing contemporary public health challenges. Investigations into the genomic structure of SARS-CoV-2 may inform ongoing vaccine development efforts and/or provide insights into vaccine efficacy to fight against COVID-19. Evolutionary analysis of 540 genomes spanning 20 different countries/territories was conducted and revealed an increase in the genomic divergence across successive generations. The ancestor of the phylogeny was found to be the isolate from the 2019/2020 Wuhan outbreak. Its transmission was outlined across 20 countries/territories as per genomic similarity. Our results demonstrate faster evolving variations in the genomic structure of SARS-CoV-2 when compared to the isolates from early stages of the pandemic. Genomic alterations were predominantly located and mapped onto the reported vaccine candidates of structural genes, which are the main targets for vaccine candidates. S protein showed 34, N protein 25, E protein 2, and M protein 3 amino acid variations in 246 genomes among 540. Among identified mutations, 23 in S protein, 1 in E, 2 from M, and 7 from N protein were mapped with the reported vaccine candidates explaining the possible implications on universal vaccines. Hence, potential target regions for vaccines would be ideally chosen from the structural regions of the genome that lack high variation. The increasing variations in the genome of SARS-CoV-2 together with our observations in structural genes have important implications for the efficacy of a successful universal vaccine against SARS-CoV-2.

Optimizing Sample Size Allocation and Power in a Bayesian Two-Stage Drop-The-Losers Design.

When a researcher desires to test several treatment arms against a control arm, a two-stage adaptive design can be more efficient than a single-stage design where patients are equally allocated to all treatment arms and the control. We see this type of approach in clinical trials as a seamless Phase II - Phase III design. These designs require more statistical support and are less straightforward to plan and analyze than a standard single-stage design. To diminish the barriers associated with a Bayesian two-stage drop-the-losers design, we built a user-friendly point-and-click graphical user interface with R Shiny to aid researchers in planning such designs by allowing them to easily obtain trial operating characteristics, estimate statistical power and sample size, and optimize patient allocation in each stage to maximize power. We assume that endpoints are distributed normally with unknown but common variance between treatments. We recommend this software as an easy way to engage statisticians and researchers in two-stage designs as well as to actively investigate the power of two-stage designs relative to more traditional approaches. The software is freely available at https://github.com/stefangraw/Allocation-Power-Optimizer.

The Microbiomes of Pancreatic and Duodenum Tissue Overlap and Are Highly Subject Specific but Differ between Pancreatic Cancer and Noncancer Subjects.

BACKGROUND: In mice, bacteria from the mouth can translocate to the pancreas and impact pancreatic cancer progression. In humans, oral bacteria associated with periodontal disease have been linked to pancreatic cancer risk. It is not known if DNA bacterial profiles in the pancreas and duodenum are similar within individuals. METHODS: Tissue samples were obtained from 50 subjects with pancreatic cancer or other conditions requiring foregut surgery at the Rhode Island Hospital (RIH), and from 34 organs obtained from the National Disease Research Interchange. 16S rRNA gene sequencing was performed on 189 tissue samples (pancreatic duct, duodenum, pancreas), 57 swabs (bile duct, jejunum, stomach), and 12 stool samples. RESULTS: Pancreatic tissue samples from both sources (RIH and National Disease Research Interchange) had diverse bacterial DNA, including taxa typically identified in the oral cavity. Bacterial DNA across different sites in the pancreas and duodenum were highly subject specific in both cancer and noncancer subjects. Presence of genus Lactobacillus was significantly higher in noncancer subjects compared with cancer subjects and the relative abundance of Fusobacterium spp., previously associated with colorectal cancer, was higher in cancer subjects compared with noncancer subjects. CONCLUSIONS: Bacterial DNA profiles in the pancreas were similar to those in the duodenum tissue of the same subjects, regardless of disease state, suggesting that bacteria may be migrating from the gut into the pancreas. Whether bacteria play a causal role in human pancreatic cancer needs to be further examined. IMPACT: Identifying bacterial taxa that differ in cancer patients can provide new leads on etiologically relevant bacteria.

Learning an Embodied Visual Language: Four Imitation Strategies Available to Sign Learners.

The parts of the body that are used to produce and perceive signed languages (the hands, face, and visual system) differ from those used to produce and perceive spoken languages (the vocal tract and auditory system). In this paper we address two factors that have important consequences for sign language acquisition. First, there are three types of lexical signs: one-handed, two-handed symmetrical, and two-handed asymmetrical. Natural variation in hand dominance in the population leads to varied input to children learning sign. Children must learn that signs are not specified for the right or left hand but for dominant and non-dominant. Second, we posit that children have at least four imitation strategies available for imitating signs: anatomical (Activate the same muscles as the sign model), which could lead learners to inappropriately use their non-dominant hand; mirroring (Produce a mirror image of the modeled sign), which could lead learners to produce lateral movement reversal errors or to use the non-dominant hand; visual matching (Reproduce what you see from your perspective), which could lead learners to produce inward-outward movement and palm orientation reversals; and reversing (Reproduce what the sign model would see from his/her perspective). This last strategy is the only one that always yields correct phonological forms in signed languages. To test our hypotheses, we turn to evidence from typical and atypical hearing and deaf children as well as from typical adults; the data come from studies of both sign acquisition and gesture imitation. Specifically, we posit that all children initially use a visual matching strategy but typical children switch to a mirroring strategy sometime in the second year of life; typical adults tend to use a mirroring strategy in learning signs and imitating gestures. By contrast, children and adults with autism spectrum disorder (ASD) appear to use the visual matching strategy well into childhood or even adulthood. Finally, we present evidence that sign language exposure changes how adults imitate gestures, switching from a mirroring strategy to the correct reversal strategy. These four strategies for imitation do not exist in speech and as such constitute a unique problem for research in language acquisition.

Sign Language Echolalia in Deaf Children With Autism Spectrum Disorder.

Purpose: We present the first study of echolalia in deaf, signing children with autism spectrum disorder (ASD). We investigate the nature and prevalence of sign echolalia in native-signing children with ASD, the relationship between sign echolalia and receptive language, and potential modality differences between sign and speech. Method: Seventeen deaf children with ASD and 18 typically developing (TD) deaf children were video-recorded in a series of tasks. Data were coded for type of signs produced (spontaneous, elicited, echo, or nonecho repetition). Echoes were coded as pure or partial, and timing and reduplication of echoes were coded. Results: Seven of the 17 deaf children with ASD produced signed echoes, but none of the TD deaf children did. The echoic children had significantly lower receptive language scores than did both the nonechoic children with ASD and the TD children. Modality differences also were found in terms of the directionality, timing, and reduplication of echoes. Conclusions: Deaf children with ASD sometimes echo signs, just as hearing children with ASD sometimes echo words, and TD deaf children and those with ASD do so at similar stages of linguistic development, when comprehension is relatively low. The sign language modality might provide a powerful new framework for analyzing the purpose and function of echolalia in deaf children with ASD.