POLQ inhibition elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma via cGAS/STING signaling.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.

Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

Emerging Cholesterol Modulators for Atherosclerotic Cardiovascular Disease.

Experimental and clinical studies have conclusively demonstrated that lowering elevated low-density lipoprotein cholesterol levels results in fewer major adverse cardiac events. Over the past few decades, statins have become the mainstay of lipid-lowering therapy, contributing significantly to the reduction of lipids, and providing patients with a cost-effective approach. However, with growing evidence in support of combination therapies providing increased benefits to certain patient populations, such as those intolerant to statins, there is an urgent need to investigate the safety and efficacy of alternative lipid-lowering drugs. In this paper, we review the current alternative and adjuvant cholesterol targeting agents. We further discuss the clinical trials that have evaluated the safety and efficacy of these alternative and adjuvant therapies as well as their implications for practical use. These drugs target levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or lipoprotein(a) as treatments for hyperlipidemia and atherosclerotic cardiovascular disease.

The bouba/kiki effect is robust across cultures and writing systems.

The bouba/kiki effect-the association of the nonce word bouba with a round shape and kiki with a spiky shape-is a type of correspondence between speech sounds and visual properties with potentially deep implications for the evolution of spoken language. However, there is debate over the robustness of the effect across cultures and the influence of orthography. We report an online experiment that tested the bouba/kiki effect across speakers of 25 languages representing nine language families and 10 writing systems. Overall, we found strong evidence for the effect across languages, with bouba eliciting more congruent responses than kiki. Participants who spoke languages with Roman scripts were only marginally more likely to show the effect, and analysis of the orthographic shape of the words in different scripts showed that the effect was no stronger for scripts that use rounder forms for bouba and spikier forms for kiki. These results confirm that the bouba/kiki phenomenon is rooted in crossmodal correspondence between aspects of the voice and visual shape, largely independent of orthography. They provide the strongest demonstration to date that the bouba/kiki effect is robust across cultures and writing systems. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part II)'.

Rethinking the frequency code: a meta-analytic review of the role of acoustic body size in communicative phenomena.

The widely cited frequency code hypothesis attempts to explain a diverse range of communicative phenomena through the acoustic projection of body size. The set of phenomena includes size sound symbolism (using /i/ to signal smallness in words such as teeny), intonational phonology (using rising contours to signal questions) and the indexing of social relations via vocal modulation, such as lowering one's voice pitch to signal dominance. Among other things, the frequency code is commonly interpreted to suggest that polite speech should be universally signalled via high pitch owing to the association of high pitch with small size and submissiveness. We present a cross-cultural meta-analysis of polite speech of 101 speakers from seven different languages. While we find evidence for cross-cultural variation, voice pitch is on average lower when speakers speak politely, contrary to what the frequency code predicts. We interpret our findings in the light of the fact that pitch has a multiplicity of possible communicative meanings. Cultural and contextual variation determines which specific meanings become manifest in a specific interactional context. We use the evidence from our meta-analysis to propose an updated view of the frequency code hypothesis that is based on the existence of many-to-many mappings between speech acoustics and communicative interpretations. This article is part of the theme issue 'Voice modulation: from origin and mechanism to social impact (Part I)'.

Novel vocalizations are understood across cultures.

Linguistic communication requires speakers to mutually agree on the meanings of words, but how does such a system first get off the ground? One solution is to rely on iconic gestures: visual signs whose form directly resembles or otherwise cues their meaning without any previously established correspondence. However, it is debated whether vocalizations could have played a similar role. We report the first extensive cross-cultural study investigating whether people from diverse linguistic backgrounds can understand novel vocalizations for a range of meanings. In two comprehension experiments, we tested whether vocalizations produced by English speakers could be understood by listeners from 28 languages from 12 language families. Listeners from each language were more accurate than chance at guessing the intended referent of the vocalizations for each of the meanings tested. Our findings challenge the often-cited idea that vocalizations have limited potential for iconic representation, demonstrating that in the absence of words people can use vocalizations to communicate a variety of meanings.

Loudness Trumps Pitch in Politeness Judgments: Evidence from Korean Deferential Speech.

Social meaning is not conveyed through words alone, but also through how words are produced phonetically. This paper investigates the role of loudness and pitch in determining the perception of politeness-related judgments in Korean. It has been proposed that high pitch is universally associated with polite or deferential social meanings. In contrast to this, Experiment 1 examined the perceptual effect of pitch and found no effect. Experiment 2 tested the effect of loudness, and found that listeners associate quieter speech with deference. Finally, Experiment 3 investigated the simultaneous effects of loudness and pitch, and found again that loudness had a consistent effect, whereas pitch only had a weak effect. Analyses of individual differences suggest that in contrast to loudness, which is interpreted uniformly across Korean listeners, pitch has more variegated social meanings: Some listeners associate high pitch with deferential meaning, others associate low pitch with deferential meaning. Thus, we find loudness to be a more unambiguous indicator of deferential speech than pitch. These findings shed light on how different acoustic properties contribute to the indexing of social stances, and they suggest that the role of pitch in conveying politeness may have been overstated in past research.

The Tasks and Characteristics of Supportive Support Brokers.

In the United States, under the Cash and Counseling or budget authority model of self-directed personal assistance where the participant manages his or her own services and supports, the Support Broker role was established to assist and coach the participant. The support broker role grew out of a person-centered planning process where focus groups and surveys helped ascertain what potential participants wanted to help them establish a self-directed alternative. But, despite this role being described in policy guidance from the Center for Medicare and Medicaid, little research has been conducted examining the functions, activities and usefulness of this position. This study draws on 76 ethnographic case studies with early Cash and Counseling participants, examines what participants and their caregivers actually saw the support broker doing, and looks at what the participants found helpful and less than helpful. Participants and family caregivers saw support broker duties as falling into four areas: Coaching, Problem Solving, Advocacy and Monitoring. Equally important was how the support broker performed these duties. Key aspects of quality included: Familiarity, Supportive Relationship, Proactive Engagement, Responsiveness, Knowledge and Cultural Friendliness. These findings can provide the basis for establishing quality indicators for self-direction.

Recurrence Patterns after Primary Excision of Invasive Melanoma with Melanoma in situ at the Margin.

The significance and management of melanoma in situ (MIS) at the margin of excision of invasive melanoma is debated. Patients undergoing excision of invasive melanoma from 2000 to 2016 with MIS at the margin were identified. A cohort without MIS was matched for age, gender, location, and Breslow depth. Thirty-two patients with 33 cases of MIS at the margin were identified. Melanoma was located on the head/neck (66.7%), extremities (24.2%), and trunk (9.1%). Median Breslow depth was 1.0 mm (range 0.25-10.80). Margin treatment included re-excision (45.5%), re-excision plus imiquimod (3.0%), imiquimod alone (9.1%), and observation alone (42.4%). At a median follow-up of 91 months (range 28-126), five patients (15.2%) with a median Breslow depth of 4.75 mm (range 1.10-6.70) developed local recurrence (LR). Three underwent re-excision of the positive margin and two were observed. Intervention for positive margins did not decrease LR compared with observation (P = 0.905, OR = 1.125, 95% confidence interval [CI] 0.162-7.824). All five patients with LR were alive at the last follow-up. There were two recurrences in the matched cohort (6.1%); both were alive at the last follow-up. Risk of LR is higher with MIS at the margin, but this does not seem to impact survival. Larger studies may elucidate predictive factors and interventions that decrease risk for LR.

An overview of take-home naloxone programs in Australia.

INTRODUCTION AND AIMS: Take-home naloxone (THN) programs commenced in Australia in 2012 in the Australian Capital Territory and programs now operate in five Australian jurisdictions. The purpose of this paper is to record the progress of THN programs in Australia, to provide a resource for others wanting to start THN projects, and provide a tool for policy makers and others considering expansion of THN programs in this country and elsewhere. DESIGN AND METHODS: Key stakeholders with principal responsibility for identified THN programs operating in Australia provided descriptions of program development, implementation and characteristics. Short summaries of known THN programs from each jurisdiction are provided along with a table detailing program characteristics and outcomes. RESULTS: Data collected across current Australian THN programs suggest that to date over 2500 Australians at risk of overdose have been trained and provided naloxone. Evaluation data from four programs recorded 146 overdose reversals involving naloxone that was given by THN participants. DISCUSSION AND CONCLUSIONS: Peer drug user groups currently play a central role in the development, delivery and scale-up of THN in Australia. Health professionals who work with people who use illicit opioids are increasingly taking part as alcohol and other drug-related health agencies have recognised the opportunity for THN provision through interactions with their clients. Australia has made rapid progress in removing regulatory barriers to naloxone since the initiation of the first THN program in 2012. However, logistical and economic barriers remain and further work is needed to expand access to this life-saving medication.

The Representation and Execution of Articulatory Timing in First and Second Language Acquisition.

The early acquisition of language-specific temporal patterns relative to the late development of speech motor control suggests a dissociation between the representation and execution of articulatory timing. The current study tested for such a dissociation in first and second language acquisition. American English-speaking children (5- and 8-year-olds) and Korean-speaking adult learners of English repeatedly produced real English words in a simple carrier sentence. The words were designed to elicit different language-specific vowel length contrasts. Measures of absolute duration and variability in single vowel productions were extracted to evaluate the realization of contrasts (representation) and to index speech motor abilities (execution). Results were mostly consistent with a dissociation. Native English-speaking children produced the same language-specific temporal patterns as native English-speaking adults, but their productions were more variable than the adults'. In contrast, Korean-speaking adult learners of English typically produced different temporal patterns than native English-speaking adults, but their productions were as stable as the native speakers'. Implications of the results are discussed with reference to different models of speech production.

Children's abstraction and generalization of English lexical stress patterns.

The current study investigated school-aged children's internalization of the distributional patterns of English lexical stress as a function of vocabulary size. Sixty children (5;3 to 8;3) participated in the study. The children were asked to blend two individually presented, equally stressed syllables to produce disyllabic nonwords with different resulting structures in one of two frame sentences. The frame sentences were designed to elicit either a noun or verb interpretation of the nonword. Children's receptive vocabulary was also assessed. The results indicated that children more readily blended syllable pairs that resulted in trochaic-compatible word structures than in iambic-compatible structures. This effect was strongest in young children with large vocabularies. As for stress placement, all children were sensitive to the effect of word structure, but only children with the largest vocabularies were sensitive to the biasing effect of grammatical category (noun = trochee; verb = iamb). The study results are discussed with reference to the observation that speech motor skills develop in tandem with lexical acquisition and the hypothesis that phonological knowledge emerges in part from abstraction across lexical representations.

FIXED TEMPORAL PATTERNS IN CHILDREN'S SPEECH DESPITE VARIABLE VOWEL DURATIONS.

The current study compared children's and adults' ability to produce inherent and context-specific vowel duration differences with their ability to repeatedly produce the same vowel in the same context. Children (5- and 8-year-olds) and adults produced real English words in a frame sentence multiple times. Mean vowel duration and variability in vowel duration were analysed as a function of the manipulated factors. Results were that children produced exactly the same contrasts as adults despite also exhibiting more variability in their production of individual vowels. The results are consistent with a model where the 'plan' is remembered relative timing information and execution is the achievement of motor goals at specified temporal intervals.

The production and phonetic representation of fake geminates in English.

The current study focused on the production of non-contrastive geminates across different boundary types in English to investigate the hypothesis that word-internal heteromorphemic geminates may differ from those that arise across a word boundary. In this study, word-internal geminates arising from affixation, and described as either assimilated or concatenated, were matched to heteromorphemic geminates arising from sequences of identical consonants that spanned a word boundary and to word-internal singletons. Word-internal geminates were found to be longer than matched singletons in absolute and relative terms. By contrast, heteromorphemic geminates that occurred at word boundaries were only longer than matched singletons in absolute terms. In addition, heteromorphemic geminates in two word phrases were typically "pulled apart" in careful speech; that is, speakers marked the boundaries between free morphemes with pitch changes and pauses. Morpheme boundaries in words with bound affixes were very rarely highlighted in this way. These results are taken to indicate that most word-internal heteromorphemic geminates are represented as a single long consonant in the speech plan rather than as a consonant sequence. Only those geminates that arise in two word phrases exhibit phonetic characteristics that are fully consistent with the representation of two identical consonants crossing a morpheme boundary.

A one-year longitudinal study of English and Japanese vowel production by Japanese adults and children in an English-speaking setting.

The effect of age of acquisition on first- and second-language vowel production was investigated. Eight English vowels were produced by Native Japanese (NJ) adults and children as well as by age-matched Native English (NE) adults and children. Productions were recorded shortly after the NJ participants' arrival in the USA and then one year later. In agreement with previous investigations [Aoyama, et al., J. Phon. 32, 233-250 (2004)], children were able to learn more, leading to higher accuracy than adults in a year's time. Based on the spectral quality and duration comparisons, NJ adults had more accurate production at Time 1, but showed no improvement over time. The NJ children's productions, however, showed significant differences from the NE children's for English "new" vowels /ɪ/, /ε/, /ɑ/, /ʌ/ and /ʊ/ at Time 1, but produced all eight vowels in a native-like manner at Time 2. An examination of NJ speakers' productions of Japanese /i/, /a/, /u/ over time revealed significant changes for the NJ Child Group only. Japanese /i/ and /a/ showed changes in production that can be related to second language (L2) learning. The results suggest that L2 vowel production is affected importantly by age of acquisition and that there is a dynamic interaction, whereby the first and second language vowels affect each other.

REPRODUCING SINGLETONS AND FAKE GEMINATES.

Thirty-two native American-English speaking children and adults reliably reproduced a non-contrastive segmental length distinction encoded in a set of monomorphemic nonce words. However, participants were unable to explicitly identify the contrast in a same/different judgment task. The results support the view that grammatically irrelevant, lexically specific temporal patterns can be learned and are represented in the lexicon.