Cross-clause planning in Nungon (Papua New Guinea): Eye-tracking evidence.

Hundreds of languages worldwide use a sentence structure known as the "clause chain," in which 20 or more clauses can be stacked to form a sentence. The Papuan language Nungon is among a subset of clause chaining languages that require "switch-reference" suffixes on nonfinal verbs in chains. These suffixes announce whether the subject of each upcoming clause will differ from the subject of the previous clause. We examine two major issues in psycholinguistics: predictive processing in comprehension, and advance planning in production. Whereas previous work on other languages has demonstrated that sentence planning can be incremental, switch-reference marking would seem to prohibit strictly incremental planning, as it requires speakers to plan the next clause before they can finish producing the current one. This suggests an intriguing possibility: planning strategies may be fundamentally different in Nungon. We used a mobile eye-tracker and solar-powered laptops in a remote village in Papua, New Guinea, to track Nungon speakers' gaze in two experiments: comprehension and production. Curiously, during comprehension, fixation data failed to find evidence that switch-reference marking is used for predictive processing. However, during production, we found evidence for advance planning of switch-reference markers, and, by extension, the subjects they presage. We propose that this degree of advance syntactic planning pushes the boundaries of what is known about sentence planning, drawing on data from a novel morpheme type in an understudied language.

Selective deuteration of bupropion slows epimerization and reduces metabolism.

Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion's toxicity. Four deuterated analogues were synthesized incorporating deuterium at sites of metabolism and epimerization with the aim of altering the metabolic profile of bupropion. Spectroscopic binding and metabolism studies with bupropion and R-or S-d4 and R-or S-d10 analogs were performed with recombinant CYP2B6, human liver microsomes, and human hepatocytes. Results demonstrate that deuterated bupropion analogues exhibited 20-25% decrease in racemization and displayed a significant decrease in the formation of CYP2B6-mediated R,R - or S,S-hydroxybupropion with recombinant protein and human liver microsomes. In primary human hepatocytes, metabolism of deuterated analogs to R,R - and S,S-hydroxybupropion and threo- and erythro-hydrobupropion was significantly less than R/S-d0 bupropion. Selective deuterium substitution at metabolic soft spots in bupropion has the potential to provide a drug with a simplified pharmacokinetic profile, reduced toxicity and improved tolerability in patients.

Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor with Differentiated Pharmacokinetics for Clinical Development.

Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor. Ivacaftor is administered twice daily and is extensively converted in humans to major metabolites M1 and M6; therefore, the corresponding deuterated metabolites were also prepared. Both CTP-656 and d18-ivacaftor showed in vitro pharmacologic potency similar to that in ivacaftor, and the deuterated M1 and M6 metabolites showed pharmacology equivalent to that in the corresponding metabolites of ivacaftor, which is consistent with the findings of previous studies of deuterated compounds. However, CTP-656 exhibited markedly enhanced stability when tested in vitro. The deuterium isotope effects for CTP-656 metabolism (DV = 3.8, DV/K = 2.2) were notably large for a cytochrome P450-mediated oxidation. The pharmacokinetic (PK) profile of CTP-656 and d18-ivacaftor were assessed in six healthy volunteers in a single-dose crossover study, which provided the basis for advancing CTP-656 in development. The overall PK profile, including the 15.9-hour half-life for CTP-656, suggests that CTP-656 may be dosed once daily, thereby enhancing patient adherence. Together, these data continue to validate deuterium substitution as a viable approach for creating novel therapeutic agents with properties potentially differentiated from existing drugs.

Efficient assessment of peripheral blood lymphocytosis in adults: developing new thresholds for blood smear review by pathologists.

BACKGROUND: Peripheral smear review is a critical, but labor intensive adjunct for evaluation of lymphocytosis. Standard practice based on consensus guidelines is to review cases with absolute lymphocyte count (ALC) >5×109/L. We hypothesize that identifying cases for review by applying appropriately adjusted ALC and age discriminators will decrease laboratory workload without compromising patient care. METHODS: 1170 complete blood counts with ALCs >5×109/L analyzed in the core laboratory during a 2-year period were included. Patients were categorized into diagnostic groups based on follow-up criteria. A total of 402 patients with new onset lymphocytosis who met criteria for reactive lymphocytosis (82%) or lymphoproliferative disorder (18%) were used to establish optimal ALC and age thresholds from receiver operating characteristic (ROC) curve analysis. RESULTS: ALC as a discriminator for neoplastic lymphocytosis had an ROC area under the curve (AUC) of 0.732. Selecting cases with ALC >10×109/L enriched the proportion of neoplastic cases in the review pool (90% specificity); however, many cases with ALC below this threshold were also neoplastic (52% sensitivity). For cases with ALC between 5 and 10×109/L, age as a discriminator had an ROC AUC of 0.886. Selecting patients >50 years old in this group for review captured the neoplastic cases while excluding the reactive cases (93% sensitivity, 62% specificity). When applied to a validation cohort, the predictive performance of the thresholds was maintained while reducing smears reviewed by 50%. CONCLUSIONS: We show that modifying the standard 5×109/L ALC smear review threshold through retrospective analysis of institutional data can reduce laboratory workload without compromising quality.

A low-activity cortical network selectively encodes syntax.

Syntax, the abstract structure of language, is a hallmark of human cognition. Despite its importance, its neural underpinnings remain obscured by inherent limitations of non-invasive brain measures and a near total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover three syntactic networks that are broadly distributed across traditional language regions, but with focal concentrations in middle and inferior frontal gyri. In contrast to previous findings from comprehension studies, these networks process syntax mostly to the exclusion of words and meaning, supporting a cognitive architecture with a distinct syntactic system. Most strikingly, our data reveal an unexpected property of syntax: it is encoded independent of neural activity levels. We propose that this "low-activity coding" scheme represents a novel mechanism for encoding information, reserved for higher-order cognition more broadly.

Preservice Teacher Perceptions of Using Video Discussions to Foster a Community of Inquiry-Does the Learning Environment Matter?

The creation of an engaging online learning environment where students feel a sense of belonging is a challenge for all educators. With the rise of online courses, discussion forums are commonly used to connect students with course content, peers, and instructors. However, these discussions are often text-based in nature. The purpose of this quantitative study examined preservice teacher perceptions of Flipgrid in an introductory educational technology course. Statistically significant relationships between groups were found related to two of the three components of the Community of Inquiry framework. Specifically, the findings suggest those enrolled in a hybrid course perceived Flipgrid as a more effective platform to create cognitive and teaching presence than those online. Additionally, hybrid learners were significantly more likely to use Flipgrid in their own teaching practices. In this article, an analysis of findings will be discussed and provide suggestions for future research.

Optimisation of 3D Printing for Microcellular Polymers.

Polymers are extensively used in various industries due to their versatility, durability and cost-effectiveness. To ensure functionality and longevity, polymer parts must have sufficient strength to endure external forces without deformation or breakage. Traditional approaches to increasing part strength involve adding more material; however, balancing strength to weight relationships is challenging. This paper explorers the viability of manufacturing lightweight components using a microcellular foaming polymer. Microcellular foaming has emerged as a helpful tool to achieve an optimal strength-to-weight ratio; offering advantages such as lightweight, improved mechanical properties, reduced material usage, better insulation and improved cost-effectiveness. It can also contribute to improved fuel efficiency and reduced carbon emissions, making them environmentally favourable. The combination of additive manufacturing (AM) and microcellular foaming has opened new possibilities for design innovation. This text highlights the challenges and efforts in incorporating foaming techniques into 3D printing processes, specifically fused filament fabrication (FFF). This study reveals that microcellular polymers are a viable option when balancing part strength and weight. The experiments completed during the formulation of this paper demonstrated that lightweight LW-PLA parts were significantly lighter than standard PLA parts and that a design of experiments approach can be used to optimise strength properties and provide insights into optimising manufacturability. Microcellular polymers present an opportunity for lighter and stronger 3D printed parts, offering potential energy and material savings for sustainable manufacturing practices.

Lasting effects of the COVID-19 pandemic on language processing.

A central question in understanding human language is how people store, access, and comprehend words. The ongoing COVID-19 pandemic presented a natural experiment to investigate whether language comprehension can be changed in a lasting way by external experiences. We leveraged the sudden increase in the frequency of certain words (mask, isolation, lockdown) to investigate the effects of rapid contextual changes on word comprehension, measured over 10 months within the first year of the pandemic. Using the phonemic restoration paradigm, in which listeners are presented with ambiguous auditory input and report which word they hear, we conducted four online experiments with adult participants across the United States (combined N = 899). We find that the pandemic has reshaped language processing for the long term, changing how listeners process speech and what they expect from ambiguous input. These results show that abrupt changes in linguistic exposure can cause enduring changes to the language system.

Beyond input: Language learners produce novel relative clause types without exposure.

Syntax famously consists of abstract hierarchical representations, essentially instructions for combining words into larger units like sentences. Less famously, most theories of syntax also assume a higher level of abstract representation. Representations at this level comprise instructions for creating the hierarchical representations used to create sentences. To date, however there is no experimental evidence for this additional level of abstraction. Here, we explain why the existence of such representations would imply that, under certain circumstances, speakers should be able to produce structures they have never been exposed to, and we test this prediction directly. We ask: Given the right type of input, can speakers learn a syntactic structure without direct exposure? In particular, different types of relative clauses have different surface word orders. These may be represented in two ways: with many individual representations or one general representation. If the latter, then learning one type of relative clause amounts to learning all types. We teach participants a novel grammar for only some relative clause types (e.g., just subject relative clauses) and test their knowledge of other types (e.g., object relative clauses). Across experiments, participants consistently produced untrained types, implicating the existence of this higher level of abstract syntactic knowledge.

Shared syntax between comprehension and production: Multi-paradigm evidence that resumptive pronouns hinder comprehension.

Language comprehension and production are generally assumed to use the same representations, but resumption poses a problem for this view: This structure is regularly produced, but judged highly unacceptable. Production-based solutions to this paradox explain resumption in terms of processing pressures, whereas the Facilitation Hypothesis suggests resumption is produced to help listeners comprehend. Previous research purported to support the Facilitation Hypothesis did not test its keystone prediction: that resumption improves accuracy of interpretation. Here, we test this prediction directly, controlling for factors that previous work did not. Results show that resumption in fact hinders comprehension in the same sentences that native speakers produced, a finding which replicated across four high-powered experiments with varying paradigms: sentence-picture matching (N=300), self-paced reading (N=96), visual world eye-tracking (N=96), and multiple-choice comprehension question (N=150). These findings are consistent with production-based accounts, indicating that comprehension and production may indeed share representations, although our findings point toward a limit on the degree of overlap. Methodologically speaking, the findings highlight the importance of measuring interpretation when studying comprehension.

Toward a Database of Intracranial Electrophysiology during Natural Language Presentation.

Intracranial electrophysiology (iEEG) studies using cognitive tasks contribute to the understanding of the neural basis of language. However, though iEEG is recorded continuously during clinical treatment, due to patient considerations task time is limited. To increase the usefulness of iEEG recordings for language study, we provided patients with a tablet pre-loaded with media filled with natural language, wirelessly synchronized to clinical iEEG. This iEEG data collected and time-locked to natural language presentation is particularly applicable for studying the neural basis of combining words into larger contexts. We validate this approach with pilot analyses involving words heard during a movie, tagging syntactic properties and verb contextual probabilities. Event-related averages of high-frequency power (70-170Hz) identified bilateral perisylvian electrodes with differential responses to syntactic class and a linear regression identified activity associated with contextual probabilities, demonstrating the usefulness of aligning media to iEEG. We imagine future multi-site collaborations building an 'intracranial neurolinguistic corpus'.

Characterization of a pyrene-degrading Mycobacterium sp. strain CH-2.

Mycobacterium sp strain CH-2 was isolated from a manufactured gas plant contaminated with polycyclic aromatic hydrocarbons (PAHs) and was identified by analysis of 16S rDNA sequences. Strain CH-2 was capable of mineralizing 3- and 4- ring PAHs, including phenanthrene, pyrene, and fluoranthene. In addition, strain CH-2 could utilize phenanthrene, pyrene and a wide range of alkanes as a sole carbon and energy source. Primers based upon the sequences of the polycyclic aromatic hydrocarbon (PAH) dioxygenases nidAB (from Mycobacterium vanbaalenii strain PYR-1) and pdoA2B2 (from Mycobacterium sp. Strain 6PY1) were used as molecular probes to amplify the dioxygenases. Degenerate primers were used to amplify a portion of an alkane monooxygenase gene. Mineralization assays and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis indicated that the alkane monooxygenase was constitutively expressed, while nidAB and pdoA2B2 were expressed only in the presence of PAHs. A genomic library of strain CH-2 was created and then screened for the presence of biodegradative operons using the amplified PAH dioxygenases. The pdolocus included a partial pdoF, as well as pdoA2, pdoB2, orf 72, and putative genes for a ferredoxin, an araC-type regulator, and a reductase. The nid locus included a partial nidC, as well as nidB, nidA, and a putative promoter. Primer extension analysis of the nidlocus located the transcriptional start site 68bp upstream of the nidB start codon. The putatively identified promoter region and a promoter fragment lacking the -10 region were amplified, and the products were cloned into pRW50. This plasmid carries the lac operon without a promoter. The plasmid containing the full length promoter expressed the lacZ reporter gene, while expression by the promoter fragment was equivalent to the expression of cells carrying pRW50.

Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures.

Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis. To our knowledge, this is the first reported case of synchronous and metastatic primary papillary and follicular carcinomas, and the first report of synchronous BRAF V600E mutated papillary and NRAS mutated follicular carcinoma.

Nonenzymatic peptide-based catalytic asymmetric phosphorylation of inositol derivatives.

The ability to use small peptides as catalysts for asymmetric phosphorylation provides opportunities for rapid syntheses of phosphate-containing compounds and natural products. This short review outlines the genesis of this concept and its reduction to practice in the context of concise syntheses of the enantiomeric D-I-1P and D-I-3P targets. The implications for the development of additional site-selective catalysts are discussed.

Biomechanical properties of materials used in static facial suspension.

OBJECTIVE: To compare the biomechanical properties of the superficial (human acellular dermis); (AlloDerm; LefeCell Corp, Branchburg, NJ) and deep layers of cadaveric dermis and expanded polytetrafluoroethylene (ePTFE); (Gore-Tex; W. L. Gore & Associates, Flagstaff, Ariz). METHODS: Sixteen samples of superficial dermis (AlloDerm), 12 samples of deep dermis, and 12 samples of ePTFE were axial loaded on a materials testing machine. Maximum load to failure and stiffness were calculated and statistical analysis was performed to compare the materials. RESULTS: Dermis samples had statistically greater mean stiffness compared with ePTFE samples. There was no statistical difference of maximum load to failure comparing ePTFE with superficial dermis. There was a statistical difference in maximum load to failure between ePTFE and deep dermis. There was no statistical difference between the superficial and deep layers of the dermis with respect to stiffness or maximum load to failure. CONCLUSIONS: Cadaveric dermis has some biomechanical properties to be a superior material for static facial suspension. There was larger than expected variability in both parameters (stiffness and maximum load to failure) tested in dermis samples, which may correlate with occasional clinical failure.

Value-based flow testing of chronic lymphoproliferative disorders: a quality improvement project to develop an algorithm to streamline testing and reduce costs.

OBJECTIVES: Flow cytometry is essential for the evaluation of lymphoproliferative disorders (LPDs) and their classification. Flow panels routinely incorporate a large array of antibodies, making testing complex and expensive; such panels are likely unnecessary in benign cases or those with straightforward diagnoses. Our aim was to develop a more cost-effective testing strategy based on a retrospective analysis of flow studies for possible LPDs in blood. METHODS: We identified LPD frequencies and types, as well as associated results with patient age and absolute lymphocyte count. RESULTS: We found that the likelihood of LPDs increased with patient age and absolute lymphocyte count and that CD5-positive LPD was the most common LPD diagnosed in our institution (71% of LPDs). Using these data, we devised flow-testing algorithms with a screening test for patients at low risk of disease and a focus on CD5-positive LPD detection, with reflexing as needed. CONCLUSIONS: We project this approach will result in a 40% decrease in antibody utilization.

A case series of primary central nervous system posttransplantation lymphoproliferative disorder: imaging and clinical characteristics.

BACKGROUND: Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is a rare complication after solid organ transplantation (SOT). With increasing rates of SOT, PCNS-PTLD incidence is increasing. OBJECTIVE: To describe the characteristics of PCNS-PTLD patients requiring neurosurgical intervention. METHODS: From 2000 to 2011, 10 patients with prior SOT underwent biopsy for evaluation of brain lesions and were diagnosed with PCNS-PTLD. Data collected included imaging characteristics, pathology, treatments administered, and survival outcomes. RESULTS: All patients had kidney transplantation, and 3 had concurrent pancreas transplantation. Median age at diagnosis was 49 years, with a median of 4.5 years from SOT to diagnosis (range, 1.8-11.4 years). Presenting symptoms most often included focal neurological deficits (n = 6), although several patients had nonspecific symptoms of headache and altered mental status. Brain lesions were generally multiple (n = 7), supratentorial (n = 8), and lobar or periventricular in distribution with ring enhancement. Diagnosis was established by stereotactic (n = 4) and open surgical (n = 6) biopsy. Treatments most frequently administered included reduction of immunosuppression (n = 10), dexamethasone (n = 10), rituximab (n = 8), high-dose methotrexate (n = 3), and whole-brain radiotherapy (n = 6). Six patients remain alive without PCNS-PTLD relapse, including 4 patients who have sustained remissions beyond 2 years from diagnosis of PCNS-PTLD. Of 4 observed deaths, 1 was related to progressive PCNS-PTLD. CONCLUSION: PCNS-PTLD must be considered in the differential diagnosis of any patient with prior SOT presenting with an intracranial lesion. Histological diagnosis with brain biopsy is imperative, given the risk for opportunistic infections that may have similar imaging findings and presentation. Prognosis is variable, although long-term survival has been reported.

High internal phase agar hydrogel dispersions in cocoa butter and chocolate as a route towards reducing fat content.

Reducing the fat content of chocolate formulations is a major challenge for the confectionery industry. We report the suspension of aqueous microgel agar particles of up to 80% v/v within sunflower oil, cocoa butter, and ultimately chocolate. The optimised emulsification process involves a shear-cooling step. We demonstrate the versatility of our method when applied to white, milk, and dark chocolate formulations, whilst preserving the desired polymorph V of the cocoa butter matrix. In addition, we show that this technology can be used as a strategy to disperse alcoholic beverages into chocolate confectionery.