Database of word-level statistics for Mandarin Chinese (DoWLS-MAN).

In this article we present the Database of Word-Level Statistics for Mandarin Chinese (DoWLS-MAN). The database addresses the lack of agreement in phonological syllable segmentation specific to Mandarin by offering phonological features for each lexical item according to 16 schematic representations of the syllable (8 with tone and 8 without tone). Those lexical statistics that differ per phonological word and nonword due to changes in syllable segmentation are of the variant category and include subtitle lexical frequency, phonological neighborhood density measures, homophone density, and network science measures. The invariant characteristics consist of each items' lexical tone, phonological transcription, and syllable structure among others. The goal of DoWLS-MAN is to provide researchers both the ability to choose stimuli that are derived from a segmentation schema that supports an existing model of Mandarin speech processing, and the ability to choose stimuli that allow for the testing of hypotheses on phonological segmentation according to multiple schemas. In an exploratory analysis we illustrate how multiple schematic representations of the phonological mental lexicon can aid in hypothesis generation, specifically in terms of phonological processing when reading Chinese orthography. Users of the database can search among over 92,000 words, over 1600 out-of-vocabulary Chinese characters, and 4300 phonological nonwords according to either Chinese orthography, pinyin, or ASCII phonetic script. Users can also generate a list of phonological words and nonwords according to user-defined ranges and categories of lexical characteristics. DoWLS-MAN is available to the public for search or download at https://dowls.site .

The neural processing of pitch accents in continuous speech.

Pitch accents are local pitch patterns that convey differences in word prominence and modulate the information structure of the discourse. Despite the importance to discourse in languages like English, neural processing of pitch accents remains understudied. The current study investigates the neural processing of pitch accents by native and non-native English speakers while they are listening to or ignoring 45 min of continuous, natural speech. Leveraging an approach used to study phonemes in natural speech, we analyzed thousands of electroencephalography (EEG) segments time-locked to pitch accents in a prosodic transcription. The optimal neural discrimination between pitch accent categories emerged at latencies between 100 and 200 ms. During these latencies, we found a strong structural alignment between neural and phonetic representations of pitch accent categories. In the same latencies, native listeners exhibited more robust processing of pitch accent contrasts than non-native listeners. However, these group differences attenuated when the speech signal was ignored. We can reliably capture the neural processing of discrete and contrastive pitch accent categories in continuous speech. Our analytic approach also captures how language-specific knowledge and selective attention influences the neural processing of pitch accent categories.

Focus Marking and Prosodic Boundary Strength in French.

BACKGROUND/AIMS: In French, the size of a focus constituent is not reliably marked through pitch accent assignment as in many stress accent languages. While it has been argued that the distribution of lower-level prosodic boundaries plays a role, this is at best a weak cue to focus, leaving open the question of whether other marking strategies are available. In this study, we assess whether the right edge of a contrastive focus constituent is marked by differences in prosodic boundary strength. METHODS: We elicited utterances with target words in six combinations of focus and syntactic contexts using an interactive production task. RESULTS: The results show that if a given location is realized as an accentual phrase boundary in an all-focus context, then it is realized as an intermediate phrase boundary when it coincides with the right edge of a narrow-focus constituent. A location that is an intermediate phrase boundary in an all-focus context, however, remains unchanged under narrow focus. CONCLUSION: These findings suggest that focus constituents are constrained to align with a minimum prosodic domain size in French (i.e., the intermediate phrase), and that French does not rely on a general strategy of prosodic enhancement for marking focus.

The Accentual Phrase in Singapore English.

This paper reports on a speech production experiment that explores whether the accentual phrase (AP) represents an abstract level of prosodic phrasing in Singapore English. Specifically, it tests whether the right edge of the AP is associated with phrase-final lengthening, the degree of which can be distinguished from lengthening associated with the intonational phrase (IP). Target words were produced in matched sentence contexts in 3 phrasal positions: AP-medial (wordfinal), AP-final, and IP-final. As predicted, target words in AP-final position were longer than those in AP-medial position and shorter than those in IP-final position. Analysis of target duration and f0 together shows that AP boundaries are well discriminated from medial positions. Together, these results strongly support an AP level of phrasing for Singapore English and highlight its role in predicting timing variability.

The Status of the Initial Rise as a Marker of Focus in French.

This study addresses the relationship between information structure and intonation in French. Using an interactive speech production experiment, it tests the hypothesis that the French initial rise (LHi) is used to mark the left edge of a contrastively focused constituent. Since the occurrence of the initial rise is also known to be sensitive to the length of an Accentual Phrase (AP), AP length was manipulated within the same experiment in a 2 x 2 design. This made it possible to explore the issue of whether the initial rise represents a true marker of focus in the traditional sense, or whether the association is less direct. The results show that focus and phrase length make contributions to the distribution of the initial rise, but with no interaction. It is argued that these findings are incompatible with a model that assumes a direct mapping between focus and the initial rise, and that the relatively weak association can nevertheless be informative in a model of interpretation that integrates multiple probabilistic inputs to initial rise occurrence. These findings represent the first quantitative experimental assessment of focus realization in French in a non-corrective context, and establish a previously undocumented link between the initial rise and discourse-level meaning.

Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.

BACKGROUND: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. RESULTS: By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. CONCLUSIONS: Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.

Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry.

Bloom syndrome (BS) is caused by homozygous or compound heterozygous mutations in the RecQ DNA helicase gene BLM. Since the molecular isolation of BLM, characterization of BS-causing mutations has been carried out systematically using samples stored in the Bloom's Syndrome Registry. In a survey of 134 persons with BS from the Registry, 64 different mutations were identified in 125 of them, 54 that cause premature protein-translation termination and 10 missense mutations. In 102 of the 125 persons in whom at least one BLM mutation was identified, the mutation was recurrent, that is, it was shared by two or more persons with BS; 19 of the 64 different mutations were recurrent. Ethnic affiliations of the persons who carry recurrent mutations indicate that the majority of such persons inherit their BLM mutation identical-by-descent from a recent common ancestor, a founder. The presence of widespread founder mutations in persons with BS points to population genetic processes that repeatedly and pervasively generate mutations that recur in unrelated persons.

Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom's syndrome.

AIMS: To obtain an understanding of the etiology of proportional dwarfism and endocrinopathies of Bloom's syndrome BS. METHODS: Admission for 5-day periods to an NIH-supported Clinical Research Center of a randomly selected population of persons with BS (n = 11; mean age 11.5 years, range 9 months to 28.5 years) for clinical and genetic history-taking, physical examination, and endocrinological, gastroenterological and immunological testing. RESULTS: An oral glucose tolerance test was performed in all participants. Impaired glucose tolerance was present in 4 individuals, insulin resistance was observed in 6 individuals, and previously unrecognized diabetes was found in 1. Growth hormone provocation was normal in the 10 individuals tested. Overnight frequent GH sampling was suggestive of neurosecretory dysfunction in 3. Compensated hypothyroidism was found in 2 participants. Lipid profile abnormalities were present in 5 of 10 individuals. Low immunoglobulin concentrations (IgG and/or IgM) were seen in all tested. Intestinal absorption by D-xylose and/or fecal fat measurement was normal in all individuals tested as well. CONCLUSION: Altered carbohydrate metabolism is very common in BS, and is present from childhood. BS dwarfism is not related to growth hormone deficiency or malabsorption. The basis for the growth restriction in BS remains to be elucidated.

Evidence that xeroderma pigmentosum cells do not perform the first step in the repair of ultraviolet damage to their DNA. 1969.

Xeroderma pigmentosum (XP) is a recessively transmitted disorder of man characterized by increased sensitivity to ultraviolet light. Homozygous, affected individuals, upon exposure to sunlight, sustain severe damage to the skin; this damage is characteristically followed by multiple basal and squamous cell carcinomas and not uncommonly by other malignant neoplasia. A tissue culture cell line was derived from the skin of a man with XP. Our measurements of ultraviolet-induced pyrimidine dimers in cellular DNA show that normal diploid human skin fibroblasts excise up to 70 per cent of the dimers 24 hours, but that fibroblasts derived from the individual with XP excise less than 20 per cent in 48 hours. Alkaline gradient sedimentation experiments show that during the 24 hours after irradiation of normal cells a large number of single-stranded breaks appear and then disappear. Such changes are not observed in XP cells. XP cells apparently fail to start, the excision process because they lack the required function of an ultraviolet-specific endonuclease. These findings, plus earlier ones of Cleaver on the lack of repair replication in XP cells, raise the possibility that unexcised pyrimidine dimers can be implicated in the oncogenicity of ultraviolet radiation.

Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.

In addition to increased DNA-strand exchange, a cytogenetic feature of cells lacking the RecQ-like BLM helicase is a tendency for telomeres to associate. We also report additional cellular and biochemical evidence for the role of BLM in telomere maintenance. BLM co-localizes and complexes with the telomere repeat protein TRF2 in cells that employ the recombination-mediated mechanism of telomere lengthening known as ALT (alternative lengthening of telomeres). BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur. Additionally, TRF1 and TRF2 interact directly with BLM and regulate BLM unwinding activity in vitro. Whereas TRF2 stimulates BLM unwinding of telomeric and non-telomeric substrates, TRF1 inhibits BLM unwinding of telomeric substrates only. Finally, TRF2 stimulates BLM unwinding with equimolar concentrations of TRF1, but not when TRF1 is added in molar excess. These data suggest a function for BLM in recombination-mediated telomere lengthening and support a model for the coordinated regulation of BLM activity at telomeres by TRF1 and TRF2.

Enhanced tumor formation in mice heterozygous for Blm mutation.

Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.