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The purpose of this study was to identify changes in case management within public sector mental health, following the implementation of managed care. Case managers in the State of Oregon completed surveys in 1992 and 2000 regarding aspects of case management. Results showed that current case managers are more experienced and expect longer tenure than previously. Caseload sizes have increased. Meanwhile, case managers' activities and functions have not changed across time periods. The results suggest that mental health personnel have changed in the past decade, though the practice of case management has remained largely the same. [ABSTRACT FROM AUTHOR]

Recent work has shown significant sublexical effects of long-term memory in nonword repetition (NWR) using a dichotomous consonant age of acquisition (CAoA) variable (Moore, 2018; Moore, Fiez, and Tompkins, 2017). Performance consistently decreased when stimuli comprised consonants acquired later versus earlier in speech development. To address potential confounds related to stimulus design and linearity, the purpose of this study was to test whether performance decreases as the CAoA value of stimuli increases in various linguistic tasks using a continuous CAoA variable. Thirty-one college students completed NWR and other linguistic tasks in which the stimuli varied in average CAoA values. Data were analyzed using multilevel modeling. After accounting for phonotactic probability, CAoA was a statistically significant predictor of performance across the models reported. The relationship was more complex in some of the models in which CAoA showed a statistically significant nonlinear relationship with the outcome measure. Results from this study support previous work showing that CAoA affects performance on NWR and other linguistic tasks that vary in their memory, auditory perceptual, and articulatory demands. Importantly, this line of work was extended here by demonstrating that the CAoA effect is robust across novel stimulus sets and study designs, and may be more complex than previously understood when using a dichotomous CAoA variable. Quadratic results suggest that the CAoA variable has a differential effect on performance for low to moderate CAoA values, but for higher CAoA values the effect is similarly negative. The nonlinear relationship between CAoA and measures of speed and accuracy on some of the tasks warrants further study into the complex relationship between various predictive factors that contribute to language performance., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Phonological processing is a fundamental component of language, can be impaired in people with hearing loss, and involves several confounded subprocesses. The purpose of this study was to systematically examine several phonological subprocesses - i.e., the spectral quality of auditory input and phonological short-term and long-term memory - in order to better understand how they interact with one another in basic linguistic tasks. Using an experimental, within-subjects design, 30 typically-hearing adults completed nonword repetition (NWR) and auditory lexical decision (ALD) tasks varying in spectral quality (normal versus spectrally-degraded), consonant age of acquisition (CAoA; i.e. early-acquired versus late-acquired consonants), syllable length (NWR task), and lexical status (ALD task). In NWR, spectral degradation muted the word length effect, though performance differed depending on how familiar participants were with the degraded stimuli. ALD findings showed that the magnitude of the degradation effect varied between stimuli comprising early-acquired versus late-acquired consonants. The robust effect of spectral degradation on phonological short-term and long-term memory provides a model of the interactive nature of these subprocesses in typical adults. Future work with populations with hearing loss can provide a comparison to help understand how the typical and clinical phonological systems differ.

Excavations at Saruq al-Hadid, Dubai, UAE, discovered a stone tool technology with backed microliths dating to the Wadi Suq period and Late Bronze Age (ca. 1750-1300 BCE). The stone technology is a contemporary with metal production in the region, and the assemblage was recovered from a thick bone midden deposit at this multi-period site on the edge of the Rub' al-Khali Desert. Small cobbles of chert were imported to the site and were reduced into flakes by hard-hammer percussion. Cores were frequently rotated during knapping and the reduction strategy was ad hoc, lacking hierarchical reduction stages. Flake tools were used as-is or modified by retouching. Some flakes were selected for backing into geometric microliths, and backing techniques often reflected high levels of stoneworking skill to produce stylised scalene shapes. A review of contemporary archaeological evidence, and the context of the Saruq al-Hadid assemblage, suggest that microliths may have been made as stone armatures for arrows despite the contemporary use of copper-based arrowheads., Competing Interests: The authors have declared that no competing interests exist.

Purpose The aim of the study was to investigate the effects of specific acoustic patterns on word learning and segmentation in 8- to 11-year-old children and in college students. Method Twenty-two children (ages 8;2-11;4 [years;months]) and 36 college students listened to synthesized "utterances" in artificial languages consisting of six iterated "words," which followed either a phonetically natural lenition-fortition pattern or an unnatural (cross-linguistically unattested) antilenition pattern. A two-alternative forced-choice task tested whether they could discriminate between occurring and nonoccurring sequences. Participants were exposed to both languages, counterbalanced for order across subjects, in sessions spaced at least 1 month apart. Results Children showed little evidence for learning in either the phonetically natural or unnatural condition nor evidence of differences in learning across the two conditions. Adults showed the predicted (and previously attested) interaction between learning and phonetic condition: The phonetically natural language was learned better. The adults also showed a strong effect of session: Subjects performed much worse during the second session than the first. Conclusions School-age children not only failed to demonstrate the phonetic asymmetry demonstrated by adults in previous studies but also failed to show strong evidence for any learning at all. The fact that the phonetic asymmetry (and general learning effect) was replicated with adults suggests that the child result is not due to inadequate stimuli or procedures. The strong carryover effect for adults also suggests that they retain knowledge about the sound patterns of an artificial language for over a month, longer than has been reported in laboratory studies of purely phonetic/phonological learning. Supplemental Material https://doi.org/10.23641/asha.13641284.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

Purpose Perceptual learning and production practice are basic mechanisms that children depend on to acquire adult levels of speech accuracy. In this study, we examined perceptual learning and production practice as they contributed to changes in speech accuracy in 3- and 4-year-old children. Our primary focus was manipulating the order of perceptual learning and production practice to better understand when and how these learning mechanisms interact. Method Sixty-five typically developing children between the ages of 3 and 4 years were included in the study. Children were asked to produce CVCCVC (C = consonant, V = vowel) nonwords like /bozjəm/ and /tʌvtʃəp/ that were described as the names of make-believe animals. All children completed two separate experimental blocks: a control block in which participants heard each nonword once and repeated it, and a test block in which the perceptual input frequency of each nonword varied between 1 and 10. Half of the participants completed a control-test order; half completed a test-control order. Results Greater accuracy was observed for nonwords produced in the second experimental block, reflecting a production practice effect. Perceptual learning resulted in greater accuracy during the test for nonwords that participants heard 3 times or more. However, perceptual learning did not carry over to control productions in the test-control design, suggesting that it reflects a kind of temporary priming. Finally, a post hoc analysis suggested that the size of the production practice effect depended on the age of acquisition of the consonants that comprised the nonwords. Conclusions The study provides new details about how perceptual learning and production practice interact with each other and with phonological aspects of the nonwords, resulting in complex effects on speech accuracy and learning of form-referent pairs. These findings may ultimately help speech-language pathologists maximize their clients' improvement in therapy. Supplemental Material https://doi.org/10.23641/asha.12971411.

Background: Circulating tumor (ct) DNA assays performed in clinical laboratories provide tumor biomarker testing support for biopharmaceutical clinical trials. Yet it is neither practical nor economically feasible for many of these clinical laboratories to internally develop their own liquid biopsy assay. Commercially available ctDNA kits are a potential solution for laboratories seeking to incorporate liquid biopsy into their test menus. However, the scarcity of characterized patient samples and cost of purchasing validation reference standards creates a barrier to entry. In the current study, we evaluated the analytical performance of the AVENIO ctDNA liquid biopsy platform (Roche Sequencing Solutions) for use in our clinical laboratory., Method: Intra-laboratory performance evaluation of AVENIO ctDNA Targeted, Expanded, and Surveillance kits (Research Use Only) was performed according to College of American Pathologists (CAP) guidelines for the validation of targeted next generation sequencing assays using purchased reference standards, de-identified human plasma cell-free (cf) DNA samples, and contrived samples derived from commercially purchased normal and cancer human plasma. All samples were sequenced at read depths relevant to clinical settings using the NextSeq High Output kit (Illumina)., Results: At the clinically relevant read depth, Avenio ctDNA kits demonstrated 100% sensitivity in detecting single nucleotide variants (SNVs) at ≥0.5% allele frequency (AF) and 50% sensitivity in detecting SNVs at 0.1% AF using 20-40 ng sample input amount. The assay integrated seamlessly into our laboratory's NGS workflow with input DNA mass, target allele frequency (TAF), multiplexing, and number of reads optimized to support a high-throughput assay appropriate for biopharmaceutical trials., Conclusions: Our study demonstrates that AVENIO ctDNA liquid biopsy platform provides a viable alternative for efficient incorporation of liquid biopsy assays into the clinical laboratory for detecting somatic alterations as low as 0.5%. Accurate detection of variants lower than 0.5% could potentially be achieved by deeper sequencing when clinically indicated and economically feasible.

The Kimberley region of Western Australia is one of the largest and most diverse rock art provenances in the world, with a complex stylistic sequence spanning at least 16 ka, culminating in the modern art-making of the Wunumbal people. The Gunu Site Complex, in the remote Mitchell River region of the northwest Kimberley, is one of many local expressions of the Kimberley rock art sequence. Here we report excavations at two sites in this complex: Gunu Rock, a sand sheet adjacent to rock art panels; and Gunu Cave, a floor deposit within an extensive rockshelter. Excavations at Gunu Rock provide evidence for two phases of occupation, the first from 7-8 to 2.7 ka, and the second from 1064 cal BP. Excavations at Gunu Rock provide evidence for occupation from the end of the second phase to the recent past. Stone for tools in the early phase were procured from a variety of sources, but quartz crystal reduction dominated the second occupation phase. Small quartz crystals were reduced by freehand percussion to provide small flake tools and blanks for manufacturing small points called nguni by the Wunambal people today. Quartz crystals were prominent in historic ritual practices associated with the Wanjina belief system. Complex methods of making bifacially-thinned and pressure flaked quartzite projectile points emerged after 2.7 ka. Ochre pigments were common in both occupation phases, but evidence for occupation contemporaneous with the putative age of the oldest rock art styles was not discovered in the excavations. Our results show that developing a complete understanding of rock art production and local occupation patterns requires paired excavations inside and outside of the rockshelters that dominate the Kimberley., Competing Interests: The authors have the following interests: The Kandiwal Aboriginal Corporation, an incorporated body encompassing members of the Kandiwal community (about 45 people) provided support during field work and knowledge about sites in their country, under a research agreement with the ARC (as a Linkage Partner). Slingair and Heliwork Pty Ltd provided a discount on air travel across the northwest Kimberley under a research agreement with the ARC (as a Linkage Partner). There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS One policies on sharing data and materials, as detailed online in the guide for authors.

Homo erectus is the founding early hominin species of Island Southeast Asia, and reached Java (Indonesia) more than 1.5 million years ago 1,2 . Twelve H. erectus calvaria (skull caps) and two tibiae (lower leg bones) were discovered from a bone bed located about 20 m above the Solo River at Ngandong (Central Java) between 1931 and 1933 3,4 , and are of the youngest, most-advanced form of H. erectus 5-8 . Despite the importance of the Ngandong fossils, the relationship between the fossils, terrace fill and ages have been heavily debated 9-14 . Here, to resolve the age of the Ngandong evidence, we use Bayesian modelling of 52 radiometric age estimates to establish-to our knowledge-the first robust chronology at regional, valley and local scales. We used uranium-series dating of speleothems to constrain regional landscape evolution; luminescence, 40 argon/ 39 argon ( 40 Ar/ 39 Ar) and uranium-series dating to constrain the sequence of terrace evolution; and applied uranium-series and uranium series-electron-spin resonance (US-ESR) dating to non-human fossils to directly date our re-excavation of Ngandong 5,15 . We show that at least by 500 thousand years ago (ka) the Solo River was diverted into the Kendeng Hills, and that it formed the Solo terrace sequence between 316 and 31 ka and the Ngandong terrace between about 140 and 92 ka. Non-human fossils recovered during the re-excavation of Ngandong date to between 109 and 106 ka (uranium-series minimum) 16 and 134 and 118 ka (US-ESR), with modelled ages of 117 to 108 thousand years (kyr) for the H. erectus bone bed, which accumulated during flood conditions 3,17 . These results negate the extreme ages that have been proposed for the site and solidify Ngandong as the last known occurrence of this long-lived species.

Molecular profiling of prostate cancer with liquid biopsies, such as circulating tumor cells (CTCs) and cell-free nucleic acid analysis, yields informative yet distinct data sets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We conducted an initial proof-of-principle study aimed at piloting this multiparametric approach. Peripheral blood samples from men with metastatic castrate-resistant prostate cancer were analyzed simultaneously for CTC enumeration, single-cell copy number variations, CTC DNA and matched cell-free DNA mutations, and plasma cell-free RNA levels of androgen receptor (AR) and AR splice variant (ARV7). In addition, liquid biopsies were compared with matched tumor profiles when available, and a second liquid biopsy was drawn and analyzed at disease progression in a subset of patients. In this manner, multiparametric liquid biopsy profiles were successfully generated for each patient and time point, demonstrating the feasibility of this approach and highlighting shared as well as unique cancer-relevant alterations. With further refinement and validation in large cohorts, multiparametric liquid biopsies can optimally integrate disparate but clinically informative data sets and maximize their utility for molecularly directed, real-time patient management.

Learning to read specializes a portion of the left mid-fusiform cortex for printed word recognition, the putative visual word form area (VWFA). This study examined whether a VWFA specialized for English is sufficiently malleable to support learning a perceptually atypical second writing system. The study utilized an artificial orthography, HouseFont, in which house images represent English phonemes. House images elicit category-biased activation in a spatially distinct brain region, the so-called parahippocampal place area (PPA). Using house images as letters made it possible to test whether the capacity for learning a second writing system involves neural territory that supports reading in the first writing system, or neural territory tuned for the visual features of the new orthography. Twelve human adults completed two weeks of training to establish basic HouseFont reading proficiency and underwent functional neuroimaging pre and post-training. Analysis of three functionally defined regions of interest (ROIs), the VWFA, and left and right PPA, found significant pre-training versus post-training increases in response to HouseFont words only in the VWFA. Analysis of the relationship between the behavioral and neural data found that activation changes from pre-training to post-training within the VWFA predicted HouseFont reading speed. These results demonstrate that learning a new orthography utilizes neural territory previously specialized by the acquisition of a native writing system. Further, they suggest VWFA engagement is driven by orthographic functionality and not the visual characteristics of graphemes, which informs the broader debate about the nature of category-specialized areas in visual association cortex.

[This corrects the article DOI: 10.1371/journal.pone.0193025.].

Cancer genome copy number alterations (CNAs) assist clinicians in selecting targeted therapeutics. Solid tumor CNAs are most commonly evaluated in formalin-fixed, paraffin-embedded (FFPE) tissue by fluorescence in situ hybridization. Although fluorescence in situ hybridization is a sensitive and specific assay for interrogating preselected genomic regions, it provides no information about coexisting clinically significant copy number changes. Chromosomal microarray analysis is an alternative DNA-based method for interrogating genome-wide CNAs in solid tumors. However, DNA extracted from FFPE tumor tissue produces an essential, yet problematic, sample type. The College of American Pathologists/American Society of Clinical Oncology guidelines for optimal tumor tissue handling, published in 2007 for breast cancer and in 2016 for gastroesophageal adenocarcinomas, are lacking for other solid tumors. Thus, cold ischemia times are seldom monitored in non-breast cancer and non-gastroesophageal adenocarcinomas, and all tumor biospecimens are affected by chemical fixation. Although intended to preserve specimens for long-term storage, formalin fixation causes loss of genetic information through DNA damage. Herein, we describe a reference size matching, whole-genome amplification, and fluorescent labeling method for FFPE-derived DNA designed to improve chromosomal microarray results from suboptimal nucleic acids and salvage highly degraded samples. With this technological advance, whole-genome copy number analysis of tumor DNA can be reliably performed in the clinical laboratory for a wide variety of tissue conditions and tumor types., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

This paper presents a reassessment of the archaeological record at Leang Burung 2, a key early human occupation site in the Late Pleistocene of Southeast Asia. Excavated originally by Ian Glover in 1975, this limestone rock-shelter in the Maros karsts of Sulawesi, Indonesia, has long held significance in our understanding of early human dispersals into 'Wallacea', the vast zone of oceanic islands between continental Asia and Australia. We present new stratigraphic information and dating evidence from Leang Burung 2 collected during the course of our excavations at this site in 2007 and 2011-13. Our findings suggest that the classic Late Pleistocene modern human occupation sequence identified previously at Leang Burung 2, and proposed to span around 31,000 to 19,000 conventional 14C years BP (~35-24 ka cal BP), may actually represent an amalgam of reworked archaeological materials. Sources for cultural materials of mixed ages comprise breccias from the rear wall of the rock-shelter-remnants of older, eroded deposits dated to 35-23 ka cal BP-and cultural remains of early Holocene antiquity. Below the upper levels affected by the mass loss of Late Pleistocene deposits, our deep-trench excavations uncovered evidence for an earlier hominin presence at the site. These findings include fossils of now-extinct proboscideans and other 'megafauna' in stratified context, as well as a cobble-based stone artifact technology comparable to that produced by late Middle Pleistocene hominins elsewhere on Sulawesi.

Purpose: Most research examining long-term-memory effects on nonword repetition (NWR) has focused on lexical-level variables. Phoneme-level variables have received little attention, although there are reasons to expect significant sublexical effects in NWR. To further understand the underlying processes of NWR, this study examined effects of sublexical long-term phonological knowledge by testing whether performance differs when the stimuli comprise consonants acquired later versus earlier in speech development., Method: Thirty (Experiment 1) and 20 (Experiment 2) college students completed tasks that investigated whether an experimental phoneme-level variable (consonant age of acquisition) similarly affects NWR and lexical-access tasks designed to vary in articulatory, auditory-perceptual, and phonological short-term-memory demands. The lexical-access tasks were performed in silence or with concurrent articulation to explore whether consonant age-of-acquisition effects arise before or after articulatory planning., Results: NWR accuracy decreased on items comprising later- versus earlier-acquired phonemes. Similar consonant age-of-acquisition effects were observed in accuracy measures of nonword reading and lexical decision performed in silence or with concurrent articulation., Conclusion: Results indicate that NWR performance is sensitive to phoneme-level phonological knowledge in long-term memory. NWR, accordingly, should not be regarded as a diagnostic tool for pure impairment of phonological short-term memory., Supplemental Materials: https://doi.org/10.23641/asha.5435137.

Objectives: 1) To determine the ability of preoperative computed tomography (CT) to predict facial nerve stimulation (FNS) after cochlear implantation (CI). 2) To recognize the limitations of CT in predicting FNS., Study Design: Patient control study., Setting: Tertiary care academic medical center., Subjects: Adult patients with CI from 2003 to 2015., Methods: Patients with severe FNS (n = 4) were compared with randomly selected CI patients (n = 28). Three blinded reviewers evaluated preoperative temporal bone CT scans to measure the distance from the labyrinthine segment of the facial nerve to the basal turn of the cochlea and attempted to predict whether or not the subject had FNS after CI., Results: In total, 32 CT scans were evaluated representing 49 ears that underwent CI.The distances (mm) measured from the labyrinthine segment of the facial nerve to the basal turn of the cochlea in both the axial (0.3 ± 0.3 versus 0.6 ± 0.3) and coronal (0.4 ± 0.2 versus 0.6 ± 0.2) orientation were significantly different between the two groups (p = 0.0001 and p = 0.0034) respectively. The intraclass correlation coefficient demonstrated good (K > 0.7) reviewer correlation in both the reviewers' measurements and predictions. The sensitivity, specificity, positive predictive value, and negative predictive value for preoperative CT scans to predict FNS were 38.5, 85.1, 19.2, and 93.8% respectively. The reviewers were 23% accurate in predicting FNS., Conclusion: Based on a blinded retrospective patient-control study, CT scan measurements show a significantly reduced distance between the labyrinthine facial nerve and the basal turn of the cochlea in patients with FNS. However, it is difficult to predict who will have FNS based on these measurements.

The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell-derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium.

Wallacea, the zone of oceanic islands separating the continental regions of Southeast Asia and Australia, has yielded sparse evidence for the symbolic culture of early modern humans. Here we report evidence for symbolic activity 30,000-22,000 y ago at Leang Bulu Bettue, a cave and rock-shelter site on the Wallacean island of Sulawesi. We describe hitherto undocumented practices of personal ornamentation and portable art, alongside evidence for pigment processing and use in deposits that are the same age as dated rock art in the surrounding karst region. Previously, assemblages of multiple and diverse types of Pleistocene "symbolic" artifacts were entirely unknown from this region. The Leang Bulu Bettue assemblage provides insight into the complexity and diversification of modern human culture during a key period in the global dispersal of our species. It also shows that early inhabitants of Sulawesi fashioned ornaments from body parts of endemic animals, suggesting modern humans integrated exotic faunas and other novel resources into their symbolic world as they colonized the biogeographically unique regions southeast of continental Eurasia., Competing Interests: The authors declare no conflict of interest.

This commentary highlights the article by Birjandi et al showing that alterations in regulatory T cells can exacerbate lung fibrosis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Stone-flaking technology is the most enduring evidence for the evolving cognitive abilities of our early ancestors. Flake-making was mastered by African hominins ~3.3 ma, followed by the appearance of handaxes ~1.75 ma and complex stone reduction strategies by ~1.6 ma. Handaxes are stones flaked on two opposed faces ('bifacially'), creating a robust, sharp-edged tool, and complex reduction strategies are reflected in strategic prior flaking to prepare or 'predetermine' the nature of a later flake removal that served as a tool blank. These technologies are interpreted as major milestones in hominin evolution that reflect the development of higher-order cognitive abilities, and the presence and nature of these technologies are used to track movements of early hominin species or 'cultures' in the archaeological record. However, the warranting argument that certain variations in stone tool morphologies are caused by differences in cognitive abilities relies on analogy with technical replications by skilled modern stoneworkers, and this raises the possibility that researchers are projecting modern approaches to technical problems onto our non-modern hominin ancestors. Here we present the results of novel experiments that randomise flake removal and disrupt the modern stoneworker's inclination to use higher-order reasoning to guide the stone reduction process. Although our protocols prevented goal-directed replication of stone tool types, the experimental assemblage is morphologically standardised and includes handaxe-like 'protobifaces' and cores with apparently 'predetermined' flake removals. This shows that the geometrical constraints of fracture mechanics can give rise to what appear to be highly-designed stoneworking products and techniques when multiple flakes are removed randomly from a stone core.

Recent excavations at the early Middle Pleistocene site of Mata Menge in the So'a Basin of central Flores, Indonesia, have yielded hominin fossils attributed to a population ancestral to Late Pleistocene Homo floresiensis. Here we describe the age and context of the Mata Menge hominin specimens and associated archaeological findings. The fluvial sandstone layer from which the in situ fossils were excavated in 2014 was deposited in a small valley stream around 700 thousand years ago, as indicated by (40)Ar/(39)Ar and fission track dates on stratigraphically bracketing volcanic ash and pyroclastic density current deposits, in combination with coupled uranium-series and electron spin resonance dating of fossil teeth. Palaeoenvironmental data indicate a relatively dry climate in the So'a Basin during the early Middle Pleistocene, while various lines of evidence suggest the hominins inhabited a savannah-like open grassland habitat with a wetland component. The hominin fossils occur alongside the remains of an insular fauna and a simple stone technology that is markedly similar to that associated with Late Pleistocene H. floresiensis.

Writing systems vary in many ways, making it difficult to account for cross-linguistic neural differences. For example, orthographic processing of Chinese characters activates the mid-fusiform gyri (mFG) bilaterally, whereas the processing of English words predominantly activates the left mFG. Because Chinese and English vary in visual processing (holistic vs. analytical) and linguistic mapping principle (morphosyllabic vs. alphabetic), either factor could account for mFG laterality differences. We used artificial orthographies representing English to investigate the effect of mapping principle on mFG lateralization. The fMRI data were compared for two groups that acquired foundational proficiency: one for an alphabetic and one for an alphasyllabic artificial orthography. Greater bilateral mFG activation was observed in the alphasyllabic versus alphabetic group. The degree of bilaterality correlated with reading fluency for the learned orthography in the alphasyllabic but not alphabetic group. The results suggest that writing systems with a syllable-based mapping principle recruit bilateral mFG to support orthographic processing. Implications for individuals with left mFG dysfunction will be discussed.

Objective: Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells., Methods: We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice., Results: Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation., Conclusion: Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD., (© 2016, American College of Rheumatology.)

Sulawesi is the largest and oldest island within Wallacea, a vast zone of oceanic islands separating continental Asia from the Pleistocene landmass of Australia and Papua (Sahul). By one million years ago an unknown hominin lineage had colonized Flores immediately to the south, and by about 50 thousand years ago, modern humans (Homo sapiens) had crossed to Sahul. On the basis of position, oceanic currents and biogeographical context, Sulawesi probably played a pivotal part in these dispersals. Uranium-series dating of speleothem deposits associated with rock art in the limestone karst region of Maros in southwest Sulawesi has revealed that humans were living on the island at least 40 thousand years ago (ref. 5). Here we report new excavations at Talepu in the Walanae Basin northeast of Maros, where in situ stone artefacts associated with fossil remains of megafauna (Bubalus sp., Stegodon and Celebochoerus) have been recovered from stratified deposits that accumulated from before 200 thousand years ago until about 100 thousand years ago. Our findings suggest that Sulawesi, like Flores, was host to a long-established population of archaic hominins, the ancestral origins and taxonomic status of which remain elusive.

Background: The hypothesis was that an orexin 2 receptor (OX2R) agonist would prevent sleep-related disordered breathing., Methods: In C57BL/6J (B6) mice, body plethysmography was performed with and without EEG monitoring of state (wakefulness, NREM and REM sleep). Outcome was apnea rate/h during sleep-wake states at baseline and with an intracerebroventricular administration of vehicle, 4 nMol of agonist OB(DL), and 4 nMol of an antagonist, TCS OX2 29., Results: A significant reduction (p=0.035, f=2.99) in apneas/hour occurred, especially with the agonist. Expressed as a function of the change from baseline, there was a significant difference among groups in Wake (p=0.03, f=3.8), NREM (p=0.003, f=6.98) and REM (p=0.03, f=3.92) with the agonist reducing the rate of apneas during sleep from 29.7±4.7 (M±SEM) to 7.3±2.4 during sleep (p=0.001). There was also a reduction in apneas during wakefulness. Administration of the antagonist did not increase event rate over baseline levels., Conclusions: The B6 mouse is a preclinical model of wake-and sleep-disordered breathing, and the orexin receptor agonist at a dose of 4 nMol given intracerebroventricularly will reduce events in sleep and also wakefulness., (Published by Elsevier B.V.)

Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3-like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression--as defined by lung transplantation or death--and with scavenger receptor-expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations., (Copyright © 2014, American Association for the Advancement of Science.)

Age-related hearing loss (presbycusis) is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old) and aged (2-2.5 year-old) mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10(+) cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells) in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10(+) marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10(+) cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10(+) cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10(+) cells may also be associated with a decline in the repair capabilities of non-sensory cells in the aged ear.

Pulmonary fibrosis is a difficult to treat, often fatal disease whose pathogenesis involves dysregulated TGF-β1 signaling. CD4+CD25+FoxP3+ Regulatory T cells ("Tregs") exert important effects on host tolerance and arise from naïve CD4+ lymphocytes in response to TGF-β1. However, the precise contribution of Tregs to experimentally induced murine lung fibrosis remains unclear. We sought to better understand the role of Tregs in this context. Using a model of fibrosis caused by lung specific, doxycycline inducible overexpression of the bioactive form of the human TGF-β1 gene we find that Tregs accumulate in the lung parenchyma within 5 days of transgene activation and that this enhancement persists to at least 14 days. Anti-CD25 Antibody mediated depletion of Tregs causes increased accumulation of soluble collagen and of intrapulmonary CD45+Col Iα1 fibrocytes. These effects are accompanied by enhanced local concentrations of the classical inflammatory mediators CD40L, TNF-α, and IL-1α, along with the neuroimmune molecule fibroblast growth factor 9 (FGF-9, also known as "glial activating factor"). FGF-9 expression localizes to parenchymal cells and alveolar macrophages in this model and antibody mediated neutralization of FGF-9 results in attenuated detection of intrapulmonary collagen and fibrocytes without affecting Treg quantities. These data indicate that CD4+CD25+FoxP3+ Tregs attenuate TGF-β1 induced lung fibrosis and fibrocyte accumulation in part via suppression of FGF-9.

Numerous functional neuroimaging studies have shown that most orthographic stimuli, such as printed English words, produce a left-lateralized response within the fusiform gyrus (FG) at a characteristic location termed the visual word form area (VWFA). We developed an experimental alphabet (FaceFont) comprising 35 face-phoneme pairs to disentangle phonological and perceptual influences on the lateralization of orthographic processing within the FG. Using functional imaging, we found that a region in the vicinity of the VWFA responded to FaceFont words more strongly in trained versus untrained participants, whereas no differences were observed in the right FG. The trained response magnitudes in the left FG region correlated with behavioral reading performance, providing strong evidence that the neural tissue recruited by training supported the newly acquired reading skill. These results indicate that the left lateralization of the orthographic processing is not restricted to stimuli with particular visual-perceptual features. Instead, lateralization may occur because the anatomical projections in the vicinity of the VWFA provide a unique interconnection between the visual system and left-lateralized language areas involved in the representation of speech.

Skilled visual word recognition is thought to rely upon a particular region within the left fusiform gyrus, the visual word form area (VWFA). We investigated whether an individual (AA1) with pure alexia resulting from acquired damage to the VWFA territory could learn an alphabetic "FaceFont" orthography, in which faces rather than typical letter-like units are used to represent phonemes. FaceFont was designed to distinguish between perceptual versus phonological influences on the VWFA. AA1 was unable to learn more than five face-phoneme mappings, performing well below that of controls. AA1 succeeded, however, in learning and using a proto-syllabary comprising 15 face-syllable mappings. These results suggest that the VWFA provides a "linguistic bridge" into left hemisphere speech and language regions, irrespective of the perceptual characteristics of a written language. They also suggest that some individuals may be able to acquire a non-alphabetic writing system more readily than an alphabetic writing system., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The phosphatase and tensin homolog gene (PTEN) on chromosome 10q23.3 is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen-independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in situ hybridization (FISH) assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, androgen receptor, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, incurable lung disease of unknown etiology with only limited treatment options. Current paradigms of disease pathogenesis feature recurrent or prolonged epithelial injury and an ensuing inflammatory response that culminates in the appearance of activated myofibroblasts. These cells are believed central to the excessive deposition of extracellular matrix that eventually obliterates the alveolar space to cause respiratory failure. Because the factors driving the accumulation of myofibroblasts remain poorly understood, effective therapies remain elusive. This review focuses on recent understanding of myofibroblasts including their seemingly uncontrolled proliferation and survival, their controversial origin in pathological IPF tissues, and the local biochemical and biomechanical matrix factors that drive their behavior. In addition, novel antifibrotics under development for the treatment of lung disease will be discussed. As our understanding of fibroblast and myofibroblast biology regulation expands, these cells may prove to be effective therapeutic targets.

Background: Changing trends in head and neck cancer (HNC) merit an understanding of the late effects of therapy, but few studies examine dysphagia beyond 2 years of treatment., Methods: A case series was examined to describe the pathophysiology and outcomes in dysphagic HNC survivors referred for modified barium swallow (MBS) studies ≥ 5 years after definitive radiotherapy or chemoradiotherapy (January 2001 through May 2011). Functional measures included the penetration-aspiration scale (PAS), performance status scale-head and neck (PSS-HN), National Institutes of Health Swallowing Safety Scale (NIH-SSS), and MBS impairment profile (MBSImp)., Results: Twenty-nine patients previously treated with radiotherapy (38%) or chemoradiotherapy (62%) were included (median years posttreatment, 9; range, 5-19). The majority (86%) had oropharyngeal cancer; 52% were never-smokers. Seventy-five percent had T2 or T3 tumors; 52% were N+. The median age at diagnosis was 55 (range, 38-72). Abnormal late examination findings included: dysarthria/dysphonia (76%), cranial neuropathy (48%), trismus (38%), and radionecrosis (10%). MBS studies confirmed pharyngeal residue and aspiration in all dysphagic cases owing to physiologic impairment (median PAS, 8; median NIH-SSS, 10; median MBSImp, 18), whereas stricture was confirmed endoscopically in 7 (24%). Twenty-five (86%) developed pneumonia, half requiring hospitalization. Swallow postures/strategies helped 69% of cases, but no patient achieved durable improvement across functional measures at last follow-up. Ultimately, 19 (66%) were gastrostomy-dependent., Conclusions: Although functional organ preservation is commonly achieved, severe dysphagia represents a challenging late effect that may develop or progress years after radiation-based therapy for HNC. These data suggest that novel approaches are needed to minimize and better address this complication that is commonly refractory to many standard dysphagia therapies., (Copyright © 2012 American Cancer Society.)

Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse production and phenotyping.

The purpose was to determine if 2 weeks of buspirone suppressed post-hypoxic breathing instability and pauses in the C57BL/6J (B6) mouse. Study groups were vehicle (saline, n=8), low-dose (1.5 mg/kg, n=8), and high-dose buspirone (5.0 mg/kg, n=8). Frequency, measured by plethysmography, was the major metric, and a pause defined by breathing cessation >2.5 times the average frequency. Mice were tested after 16 days of ip injections of vehicle or drug. On day 17, 4 mice in each group were tested after buspirone and the 5-HT(1A) receptor antagonist, 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl] ethyl}-N-2-pyridinyl-benzamide (p-MPPI, 5 mg/kg). A post-hypoxic pause was present in 6/8 animals given vehicle and 1/16 animals given buspirone at either dose, but always present (8/8) with p-MPPI, regardless of buspirone dose. Post-hypoxic frequency decline was blunted by buspirone (-10% vehicle vs. -5% at both doses) and restored by p-MPPI; ventilatory stability as described by the coefficient of variation which was reduced by buspirone (p<0.04) was increased by p-MPPI (0.01). In conclusion, buspirone administration after 2 weeks acts through the 5-HT(1A) receptor to reduce post-hypoxic ventilatory instability in the B6 strain., (Published by Elsevier B.V.)

Therapeutics harnessing the power of personalized medicine have the potential to revolutionize healthcare. Companion diagnostics are critical to this goal and are increasingly relied upon to ensure the effective, safe development and use of a personalized therapeutic. Companion diagnostics are the focus of several recent regulatory guidance documents; the drug-diagnostic codevelopment process has become increasingly relevant and necessary. Despite this, the promise of companion diagnostics has not been fully realized and there are multiple difficulties that still need resolution. The path to codevelop a successful companion diagnostic with its complementary drug is complex, fragmented and fraught with several challenges. In this article, we discuss the logistic, strategic business, regulatory and financial challenges involved in drug-companion diagnostic codevelopment.

Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxia-induced periodic breathing and its absence in the C57BL/6J-Chr 1(A/J)/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1(A/J)/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis.

Unlabelled: Recently, a transoral robotic-assisted technique to access the thyroid gland has been introduced. Despite the advantages this approach may have over other minimally invasive and robotic-assisted techniques, we found that the placement of the camera through the floor of mouth led to restricted freedom of movement. We describe our modification to this technique to overcome this problem. In a study using two fresh human cadavers, the camera port of the da Vinci robot was placed in the midline oral vestibule instead of the floor of the mouth. A transoral thyroidectomy and central neck dissection was successfully performed. Our modification led to an unfettered view of the central neck and allowed for a total thyroidectomy and central neck dissection. Our modification of transoral robotic-assisted thyroidectomy provides superior access to the central compartment of the neck over other robotic-assisted thyroidectomy techniques., Electronic Supplementary Material: The online version of this article (doi:10.1007/s11701-011-0287-2) contains supplementary material, which is available to authorized users.

Retropharyngeal metastasis of papillary thyroid carcinoma is a rare but well recognized phenomenon. Traditional open surgical approaches to nodal metastasis located in the retropharyngeal space are particularly morbid considering the relatively indolent nature of some thyroid cancers. Minimally invasive surgical approaches offer a useful alternative that is both low in morbidity and high in levels of patient acceptance. To assess feasibility and safety, we report a case series of robotic lymphadenectomy in two patients with thyroid cancer metastatic to the retropharyngeal space. Two patients, ages 66 and 73, with unilateral recurrent papillary carcinoma of the retropharyngeal lymph nodes had previously undergone thyroidectomy, neck dissection, and radioactive iodine ablation prior to retropharyngeal resection. Retropharyngeal lymphadenectomy via transoral robotic surgery was performed for both patients: for the first, the oropharyngeal wound was left to heal by secondary intention, while for the other patient, simple pharyngeal flap closure was performed. Retropharyngeal lymph node dissections were successfully carried out using a transoral robotic retropharyngotomy with the da Vinci surgical robotic system. Both patients tolerated the procedure well. One patient did developed temporary dysphagia which resolved with conservative measures, not requiring a feeding tube. We report the first two cases of transoral robot-assisted resection of thyroid cancer metastatic to the retropharyngeal lymph nodes. The technique is feasible, minimally invasive, and appears to be as safe as conventional surgical methods in achieving the goals of management of regionally metastatic disease.