A multilineage screen identifies actionable synthetic lethal interactions in human cancers.

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions.

Gender and age biases in the assessment of speech accuracy: A study of speech-language clinicians' ratings of /s/ accuracy.

Purpose: Typically developing children assigned male at birth (AMAB) and children assigned female at birth (AFAB) produce the fricative /s/ differently: AFAB children produce /s/ with a higher spectral peak frequency. This study examined whether implicit knowledge of these differences affects speech-language pathologists'/speech and language therapists' (SLPs'/SLTs') ratings of /s/ accuracy, by comparing ratings made in conditions where SLPs/SLTs were blind to children's sex assigned at birth (SAB) to conditions in which they were told this information.

Methods: SLPs (n = 95) varying in clinical experience rated the accuracy of word-initial /s/ productions (n = 87) of eight children with speech sound disorder in one of four conditions: one in which no information about the children was revealed, one in which children's SAB was revealed, one in which children's age was revealed, and one in which both were revealed.

De novo generation of multi-target compounds using deep generative chemistry.

Polypharmacology drugs-compounds that inhibit multiple proteins-have many applications but are difficult to design. To address this challenge we have developed POLYGON, an approach to polypharmacology based on generative reinforcement learning. POLYGON embeds chemical space and iteratively samples it to generate new molecular structures; these are rewarded by the predicted ability to inhibit each of two protein targets and by drug-likeness and ease-of-synthesis.

Clinical Focus: The Development and Description of a Palette of Transmasculine Voices.

Purpose: The study of gender and speech has historically excluded studies of transmasculine individuals. Consequently, generalizations about speech and gender are based on cisgender individuals. This lack of representation hinders clinical training and clinical service delivery, particularly by speech-language pathologists providing gender-affirming communication services.

The everyday speech environments of preschoolers with and without cochlear implants.

Children who receive cochlear implants develop spoken language on a protracted timescale. The home environment facilitates speech-language development, yet it is relatively unknown how the environment differs between children with cochlear implants and typical hearing. We matched eighteen preschoolers with implants (31-65 months) to two groups of children with typical hearing: by chronological age and hearing age.

Relating Acoustic Measures to Listener Ratings of Children's Productions of Word-Initial /ɹ/ and /w/.

Purpose: The /ɹ/ productions of young children acquiring American English are highly variable and often inaccurate, with [w] as the most common substitution error. One acoustic indicator of the goodness of children's /ɹ/ productions is the difference between the frequency of the second formant (F2) and the third formant (F3), with a smaller F3-F2 difference being associated with a perceptually more adultlike /ɹ/. This study analyzed the effectiveness of automatically extracted F3-F2 differences in characterizing young children's productions of /ɹ/-/w/ in comparison with manually coded measurements.

Verbs Matter: A Tutorial for Determining Verb Difficulty.

Purpose: Research indicates that when teaching grammatical forms to children, the verbs used to model specific grammatical inflections matter. When learning grammatical forms, children have higher performance when they hear many unique verb forms that vary in their frequency and phonological complexity. In this tutorial, we demonstrate a method for identifying and characterizing a large number of verbs based on their frequency and complexity.

Multimodal perturbation analyses of cyclin-dependent kinases reveal a network of synthetic lethalities associated with cell-cycle regulation and transcriptional regulation.

Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs.

Preschoolers rely on rich speech representations to process variable speech.

To learn language, children must map variable input to categories such as phones and words. How do children process variation and distinguish between variable pronunciations ("shoup" for soup) versus new words? The unique sensory experience of children with cochlear implants, who learn speech through their device's degraded signal, lends new insight into this question. In a mispronunciation sensitivity eyetracking task, children with implants (N = 33), and typical hearing (N = 24; 36-66 months; 36F, 19M; all non-Hispanic white), with larger vocabularies processed known words faster.

Trends in postgraduate dental training in the United States.

Objective: This study examines the individual, educational, and policy factors that predict dentists pursuing postgraduate dental (PGD) training.

Methods: Individual dentist records from the 2017 American Dental Association Masterfile were linked with pre-doctoral training attributes and state-level dental policy factors. Generalized logistic models, adjusted for individual, educational, and policy factors, were used to predict: (1) attending any PGD program, and (2) primary (i.

Practice patterns of postgraduate trained dentists in the United States.

Objective: Postgraduate dental (PGD) primary care training has grown significantly. This study examines the individual, educational, community, and policy factors that predict practice patterns of PGD-trained dentists.

Study Design: Individual dentist records from the 2017 American Dental Association Masterfile, with indicators of Medicaid participation and practice in a Federally Qualified Health Center (FQHC), were linked to postdoctoral training, community/practice location, and state policy factors.

Effects of Long-duration Microgravity and Gravitational Transitions on Fine Motor Skills.

Objective: Assess the effects of long-duration microgravity and gravitational transitions on fine motor skills using a tablet-based test battery of four fine motor tasks: Pointing, Dragging, Shape Tracing, and Pinch-Rotate.

Background: While there have been some studies on fine motor skills in microgravity, few have measured the fine motor skills that are core components of interaction with computer-based devices, and none have measured performance systematically, to include preflight, inflight, and postflight space mission time periods.

Methods: Seven astronauts completed the Fine Motor Skills test battery 30-40 times before, during, and up to 30 days after standard duration International Space Station missions, while a matching set of seven ground-based control participants also completed the battery over a comparable period of time.

The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults.

Inpatient populations are at increased risk of hyperglycemia due to factors such as medications, physical inactivity and underlying illness, which increases morbidity and mortality. Unfortunately, clinicians have limited tools available to prospectively identify those at greatest risk. We evaluated the ability of 10 common genetic variants associated with development of type 2 diabetes to predict impaired glucose metabolism.

Individual Differences in the Development of Gendered Speech in Preschool Children: Evidence From a Longitudinal Study.

Purpose: We evaluated whether naive listeners' ratings of the gender typicality of the speech of children assigned male at birth (AMAB) and children assigned female at birth (AFAB) were different at two time points: one at which children were 2.5-3.5 years old and one when they were 4.

Written standard sentence materials convey social information.

The Harvard/IEEE (henceforth H/I) sentences are widely used for testing speech recognition in English. This study examined whether two talker characteristics, race and gender, are conveyed by 80 of the H/I sentences in their written form, and by a comparison set of sentences from the internet message board Reddit, which were expected to convey social information. As predicted, a significant proportion of raters reported perceiving race and gender information in the H/I sentences.

Uncovering Tumorigenesis Circuitry with Combinatorial CRISPR.

Oncogenesis relies on the alteration of multiple driver genes, but precisely which groups of alterations lead to cancer is not well understood. To chart these combinations, Zhao and colleagues use the CRISPR-Cas9 system to knockout all pairwise combinations among 52 tumor suppressor genes, with the goal of identifying groups of alterations that collaborate to promote cell growth. Interaction screens are performed across multiple models of tumorigenesis in cell cultures and mice, revealing clear cooperation among , , and in multiple models.

Making Race Visible in the Speech, Language, and Hearing Sciences: A Critical Discourse Analysis.

Purpose: The purpose of this critical discourse analytic study is to identify how two key professional standards documents in the Speech, Language and Hearing Sciences field-the Standards for Certification document and the Essential Functions rubric-contribute to the discursive construction of the ideal speech-language pathologist and audiologist, and to examine whether the experiences and needs of people of color are taken into consideration in these documents.

Method: Critical discourse analysis was used as both a conceptual and methodological lens for the systematic analysis of the targeted text.

Results: The findings show that considerations of race and racism were almost entirely absent from both documents and thus reflected a discourse of race neutrality that is ideologically consistent with color-blind racism.

Perceiving gender while perceiving language: Integrating psycholinguistics and gender theory.

There is a substantial body of literature showing that men and women speak differently and that these differences are endemic to the speech signal. However, the psycholinguistic mechanisms underlying the integration of social category perception and language are still poorly understood. Speaker attributes such as emotional state, age, sex, and race have often been treated in the literature as dissociable, but perceptual systems for social categories demonstrably rely on interdependent cognitive processes.

Auditory feedback experience in the development of phonetic production: Evidence from preschoolers with cochlear implants and their normal-hearing peers.

Previous work has found that preschoolers with greater phonological awareness and larger lexicons, who speak more throughout the day, exhibit less intra-syllabic coarticulation in controlled speech production tasks. These findings suggest that both linguistic experience and speech-motor control are important predictors of spoken phonetic development. Still, it remains unclear how preschoolers' speech practice when they talk drives the development of coarticulation because children who talk more are likely to have both increased fine motor control and increased auditory feedback experience.

Practice and experience predict coarticulation in child speech.

Much research in child speech development suggests that young children coarticulate more than adults. There are multiple, not mutually-exclusive, explanations for this pattern. For example, children may coarticulate more because they are limited by immature motor control.

The influence of lexical characteristics and talker accent on the recognition of English words by native speakers of Korean.

This study investigated the influences of lexical characteristics and talker accent on English spoken word recognition by first-language (L1) Korean second-language (L2) speakers of English. Stimuli were words that varied in phonological neighborhood density (PND) and word frequency (WF), produced by a L1 English speaker (L1 talker) and a L1 Korean speaker (L2 talker). Participants were 60 listeners from three groups: 20 L1 English speakers, 20 Korean L2 English speakers studying in the United States, and 20 Korean L2 English speakers studying in Korea.

Effects of Device Limitations on Acquisition of the /t/-/k/ Contrast in Children With Cochlear Implants.

Objectives: The present study investigated how development of the /t/-/k/ contrast is affected by the unique perceptual constraints imposed on young children using cochlear implants (CIs). We hypothesized that children with CIs would demonstrate unique patterns of speech acquisition due to device limitations, rather than straightforward delays due to a lack of auditory input in the first year of life before implantation. This study focused on the contrast between /t/ and /k/ because it is acquired early in the sequence of development, requires less advanced motor control than later-acquired place contrasts, is differentiated by spectral cues (which are particularly degraded when processed by CIs), and is not easily differentiated by visual cues alone.