Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.

BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

Ferroic multipolar order and disorder in cyanoelpasolite molecular perovskites.

We use a combination of variable-temperature high-resolution synchrotron X-ray powder diffraction measurements and Monte Carlo simulations to characterize the evolution of two different types of ferroic multipolar order in a series of cyanoelpasolite molecular perovskites. We show that ferroquadrupolar order in [C3N2H5]2Rb[Co(CN)6] is a first-order process that is well described by a four-state Potts model on the simple cubic lattice. Likewise, ferrooctupolar order in [NMe4]2B[Co(CN)6] (B = K, Rb, Cs) also emerges via a first-order transition that now corresponds to a six-state Potts model. Hence, for these particular cases, the dominant symmetry breaking mechanisms are well understood in terms of simple statistical mechanical models. By varying composition, we find that the effective coupling between multipolar degrees of freedom-and hence the temperature at which ferromultipolar order emerges-can be tuned in a chemically sensible manner. This article is part of the theme issue 'Mineralomimesis: natural and synthetic frameworks in science and technology'.

A systematic surveillance programme for infectious salmon anaemia virus supports its absence in the Pacific Northwest of the United States.

In response to reported findings of infectious salmon anaemia virus (ISAV) in British Columbia (BC), Canada, in 2011, U.S. national, state and tribal fisheries managers and fish health specialists developed and implemented a collaborative ISAV surveillance plan for the Pacific Northwest region of the United States. Accordingly, over a 3-1/2-year period, 4,962 salmonids were sampled and successfully tested by real-time reverse-transcription PCR. The sample set included multiple tissues from free-ranging Pacific salmonids from coastal regions of Alaska and Washington and farmed Atlantic salmon (Salmo salar L.) from Washington, all representing fish exposed to marine environments. The survey design targeted physiologically compromised or moribund animals more vulnerable to infection as well as species considered susceptible to ISAV. Samples were handled with a documented chain of custody and testing protocols, and criteria for interpretation of test results were defined in advance. All 4,962 completed tests were negative for ISAV RNA. Results of this surveillance effort provide sound evidence to support the absence of ISAV in represented populations of free-ranging and marine-farmed salmonids on the northwest coast of the United States.

A review of craniofacial and dental findings of the RASopathies.

OBJECTIVES: The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. METHODS: Review of the literature. RESULTS: Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. CONCLUSIONS: Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development.

Emergence of Long-Range Order in BaTiO_{3} from Local Symmetry-Breaking Distortions.

By using a symmetry motivated basis to evaluate local distortions against pair distribution function data, we show without prior bias, that the off-center Ti displacements in the archetypal ferroelectric BaTiO_{3} are zone centered and rhombohedral-like across its known ferroelectric and paraelectric phases. We construct a simple Monte Carlo model that captures our main experimental findings and demonstrate how the rich crystallographic phase diagram of BaTiO_{3} emerges from correlations of local symmetry-breaking distortions alone. Our results strongly support the order-disorder picture for these phase transitions, but can also be reconciled with the soft-mode theory of BaTiO_{3} that is supported by some spectroscopic techniques.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Fecal detection of enterotoxigenic Bacteroides fragilis.

Bacteroides fragilis is a common colonic symbiote of which one subtype, enterotoxigenic Bacteroides fragilis (ETBF), causes inflammatory diarrhea. However, asymptomatic ETBF colonization is common. Through its primary virulence factor, B. fragilis toxin (BFT), ETBF causes asymptomatic, chronic colitis in C57BL/6 mice and increased colon tumorigenesis in multiple intestinal neoplasia mice. Human studies suggest an association between ETBF infection, inflammatory bowel disease, and colon cancer. Additional studies on ETBF epidemiology are, therefore, crucial. The goal of this study is to develop a reliable fecal diagnostic for ETBF. To develop a sensitive assay for ETBF, we tested multiple protocols on mouse stools spiked with serially diluted ETBF. Each assay was based on either touchdown or quantitative polymerase chain reaction (qPCR) and used primers targeted to bft to detect ETBF. Using touchdown PCR or qPCR, the mean ETBF detection limit was 1.55 × 10(6) colony-forming units (CFU)/g stool and 1.33 × 10(4) CFU/g stool, respectively. Augmentation of Bacteroides spp. growth in fecal samples using PYGB (Peptone Yeast Glucose with Bile) broth enhanced ETBF detection to 2.93 × 10(2) CFU/g stool using the touchdown PCR method and 2.63 × 10(2) CFU/g stool using the qPCR method. Fecal testing using combined culture-based amplification and bft touchdown PCR is a sensitive assay for the detection of ETBF colonization and should be useful in studying the role of ETBF colonization in intestinal diseases, such as inflammatory bowel disease and colon cancer. We conclude that touchdown PCR with culture-based amplification may be the optimal ETBF detection strategy, as it performs as well as qPCR with culture-based amplification, but is a less expensive technique.

Multimodality imaging to assess immediate response to irreversible electroporation in a rat liver tumor model.

PURPOSE: To compare changes on ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) images after irreversible electroporation (IRE) ablation of liver and tumor tissues in a rodent hepatoma model. MATERIALS AND METHODS: Studies received approval from the institutional animal care and use committee. Forty-eight rats were used, and N1-S1 tumors were implanted in 24. Rats were divided into groups and allocated for studies with each modality. Imaging was performed in normal liver tissues and tumors before and after IRE. MR imaging was performed in one group before and after IRE after hepatic vessel ligation. US images were graded to determine echogenicity changes, CT attenuation was measured (in Hounsfield units), and MR imaging signal-to-noise ratio (SNR) was measured before and after IRE. Student t test was used to compare attenuation and SNR measurements before and after IRE (P < .05 indicated a significant difference). RESULTS: IRE ablation produced greater alterations to echogenicity in normal tissues than in tumors. Attenuation in ablated liver tissues was reduced compared with that in control tissues (P < .001), while small attenuation differences between ablated (42.11 HU ± 2.11) and control (45.14 HU ± 2.64) tumors trended toward significance (P = .052). SNR in ablated normal tissues was significantly altered after IRE (T1-weighted images: pre-IRE, 145.95 ± 24.32; post-IRE, 97.80 ± 18.03; P = .004; T2-weighted images, pre-IRE, 47.37 ± 18.31; post-IRE, 90.88 ± 37.15; P = .023). In tumors, SNR differences before and after IRE were not significant. No post-IRE signal changes were observed after hepatic vessel ligation. CONCLUSION: IRE induces rapid changes on gray-scale US, unenhanced CT, and MR images. These changes are readily visible and may assist a performing physician to delineate ablation zones from the unablated surrounding parenchyma.

Fecal short-chain fatty acids of very-low-birth-weight preterm infants fed expressed breast milk or formula.

OBJECTIVES: In preterm infants, the metabolic responses of gastrointestinal (GI) bacteria to different diets are poorly understood despite the possible effects on GI health. Therefore, we tested the hypothesis that diet influences bacterial metabolism by measuring short-chain fatty acids (SCFAs) in stool samples from very-low-birth-weight (VLBW) preterm infants without GI disorder as surrogate biomarkers of bacterial metabolism. METHODS: Ion chromatography was used to measure fecal SCFAs (acetate, formate, propionate, butyrate, and isobutyrate), lactate, and chloride in fresh stool samples collected from 32 preterm infants (without major congenital anomalies, GI disorders, or a recent history of antibiotic administration and on full feed of either expressed maternal breast milk [EBM; n = 13] or a formula for preterm infants [Similac Special Care Formula; preterm formula, PTF; n = 19]). RESULTS: The mean birth weight was 972 g, the mean gestational age was 27 weeks, and the mean postnatal age at first stool sample was 36 days. When adjusted for gestational age, the stools of EBM infants had higher concentrations (micromoles per gram of stool) of total SCFA (128 vs 68; P = 0.002), acetate (41 vs 13; P = 0.005), propionate (15.1 vs 4.4; P = 0.003), and chloride (21,814 vs 10,652; P = 0.02). Interactions between postnatal age and diet were detected for lactate (P = 0.05), propionate (P = 0.03), and butyrate (P = 0.03). CONCLUSIONS: Diets fed to VLBW preterm infants influence fecal SCFA profiles, and hence the metabolism of the GI bacteria, and potentially the health of preterm infants. The responses of bacterial metabolism to diet are influenced with postnatal age and gestational age at birth.

Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis.

Cardio-facio-cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high-arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC.

Clinical and dermoscopic characteristics of new naevi in adults: results from a cohort study.

BACKGROUND: Naevogenesis is a process known to occur throughout life. To date, investigators have made conclusions about new naevi in adults based on results of cross-sectional studies. OBJECTIVES: To determine the incidence of new naevus development in adults and to describe the dermoscopic morphology of new naevi. METHODS: A cohort of 182 patients seen at the outpatient dermatology clinic at Memorial Sloan-Kettering Cancer Center between 2000 and 2009 was evaluated with baseline total body photographs. The patients were aged 17 years or older and had presented for routine follow-up surveillance examination at least 3 months after baseline total body photographs. The number of new naevi and the dermoscopic morphology of these naevi were recorded. RESULTS: Of the 182 patients evaluated, 50 (27%) developed at least one new naevus during follow-up. The incidence of new naevi was 202 per 1000 person-years of follow-up. The most common types of naevi were reticular (47·1%), followed by the homogeneous (22·1%) and complex (reticuloglobular) patterns (15·4%). CONCLUSIONS: Our results provide support for the theory that there are two distinct pathways of naevogenesis, a dynamic process occurring throughout life. This study demonstrates that the predominant dermoscopic morphology of newly acquired naevi in adults is reticular.

Chlamydia trachomatis hijacks intra-Golgi COG complex-dependent vesicle trafficking pathway.

Chlamydia spp. are obligate intracellular bacteria that replicate inside the host cell in a bacterial modified unique compartment called the inclusion. As other intracellular pathogens, chlamydiae exploit host membrane trafficking pathways to prevent lysosomal fusion and to acquire energy and nutrients essential for their survival and replication. The Conserved Oligomeric Golgi (COG) complex is a ubiquitously expressed membrane-associated protein complex that functions in a retrograde intra-Golgi trafficking through associations with coiled-coil tethers, SNAREs, Rabs and COPI proteins. Several COG complex-interacting proteins, including Rab1, Rab6, Rab14 and Syntaxin 6 are implicated in chlamydial development. In this study, we analysed the recruitment of the COG complex and GS15-positive COG complex-dependent vesicles to Chlamydia trachomatis inclusion and their participation in chlamydial growth. Immunofluorescent analysis revealed that both GFP-tagged and endogenous COG complex subunits associated with inclusions in a serovar-independent manner by 8 h post infection and were maintained throughout the entire developmental cycle. Golgi v-SNARE GS15 was associated with inclusions 24 h post infection, but was absent on the mid-cycle (8 h) inclusions, indicating that this Golgi SNARE is directed to inclusions after COG complex recruitment. Silencing of COG8 and GS15 by siRNA significantly decreased infectious yield of chlamydiae. Further, membranous structures likely derived from lysed bacteria were observed inside inclusions by electron microscopy in cells depleted of COG8 or GS15. Our results showed that C. trachomatis hijacks the COG complex to redirect the population of Golgi-derived retrograde vesicles to inclusions. These vesicles likely deliver nutrients that are required for bacterial development and replication.

Persistence of viral RNA in fish infected with VHSV-IVb at 15°C and then moved to warmer temperatures after the onset of disease.

Smallmouth bass, Micropterus dolomieu Lacepède, bluegill, Lepomis macrochirus Rafinesque (coppernose strain), koi carp, Cyprinus carpio L., and channel catfish Ictalurus punctatus (Rafinesque), were infected by intraperitoneal injection with viral haemorrhagic septicaemia virus genotype IVb (VHSV-IVb) at 15 °C. When clinical signs of disease developed, one-third of the fish was moved to 20°C and one-third to 25°C. Mortality in challenged fish at all three temperatures ranged from 25 to 45% in smallmouth bass and from 70 to 90% in bluegill. No koi carp or channel catfish died during the study. Viral copy numbers detected by quantitative real-time reverse transcriptase PCR (qrt-RTPCR) in fish dying at 20 and 25°C decreased over time. In survivors of the challenge, viral copy numbers were higher in the more susceptible species (smallmouth bass and bluegill) than in the more VHSV-IVb disease-resistant species (koi carp and channel catfish). In fish surviving 28days post-infection, prevalence of infection was 66-100% depending on species and temperature, and VHSV-IVb was detected at 10(3) -10(5) copies µg(-1) host RNA. Our results show that qrt-RTPCR is a useful tool to investigate fish kills even 28days after temperatures are elevated above those known to be permissive for VHSV replication.

Histochemical and ultrastructural analysis of pathology and cell responses in gills of channel catfish affected with proliferative gill disease.

Pond-reared channel catfish Ictalurus punctatus with proliferative gill disease (PGD), caused by the myxozoan parasite Henneguya spp., were examined with light and transmission electron microscopy to better characterize the inflammatory response during infection. The early stages of disease are characterized by the destruction of collagen in the matrix of the gill filament cartilage causing weakness and breaks within the gill filaments. These early lesions lacked a notable inflammatory response around the disrupted cartilage, a chondrocyte response was not apparent, and the parasite was not present, suggesting that the cartilage breaks occur prior to inflammation and arrival of the parasite in the gill. In later lesions, a significant inflammatory response was generated in areas of disrupted cartilage, and the inflammatory infiltrate was composed of a mixed population of granulocytes including neutrophils and cells that resembled eosinophils. The majority of eosinophil-like cells demonstrated evidence of degranulation. Trophozoites of Henneguya spp. were surrounded by a uniform population of cells believed to be neutrophils. The granulocytes were infiltrated within the dense collagen layer of the gill filament cartilage and often appeared within chondrocyte lacunae in place of the chondrocyte. The gill lamellae adjacent to the lesions were fused and contained an inflammatory infiltrate containing granulocytes and cells with pericentriolar granules that resembled previous descriptions of Langerhans-like cells. These cells were abundant within damaged lamellar epithelium, but were only rarely found within the gill filament. Lesions that appeared to be recovering lacked the dense collagenous layer around the cartilage and contained hyperplastic and hypertrophic chondrocytes that formed a callus. Other chondrocytes in the lesions had ultrastructural features indicative of cell death.

Adaptive response of a metal-organic framework through reversible disorder-disorder transitions.

The ultrahigh porosity and varied functionalities of porous metal-organic frameworks make them excellent candidates for applications that range widely from gas storage and separation to catalysis and sensing. An interesting feature of some frameworks is the ability to open their pores to a specific guest, enabling highly selective separation. A prerequisite for this is bistability of the host structure, which enables the framework to breathe, that is, to switch between two stability minima in response to its environment. Here we describe a porous framework DUT-8(Ni)-which consists of nickel paddle wheel clusters and carboxylate linkers-that adopts a configurationally degenerate family of disordered states in the presence of specific guests. This disorder originates from the nonlinear linkers arranging the clusters in closed loops of different local symmetries that in turn propagate as complex tilings. Solvent exchange stimulates the formation of distinct disordered frameworks, as demonstrated by high-resolution transmission electron microscopy and diffraction techniques. Guest exchange was shown to stimulate repeatable switching transitions between distinct disorder states.

Cutaneous afferents from the monkeys fingers: responses to tangential and normal forces.

Control of tangential force plays a key role in everyday manipulations. In anesthetized monkeys, forces tangential to the skin were applied at a range of magnitudes comparable to those used in routine manipulations and in eight different directions. The paradigm used enabled separation of responses to tangential force from responses to the background normal force. For slowly adapting type I (SAI) afferents, tangential force responses ranged from excitatory through no response to suppression, with both a static and dynamic component. For fast adapting type I (FAI) afferents, responses were dynamic and excitatory only. Responses of both afferent types were scaled by tangential force magnitude, elucidating the neural basis for previous human psychophysical scaling data. Most afferents were direction selective with a range of preferred directions and a range in sharpness of tuning. Both the preferred direction and the degree of tuning were independent of the background normal force. Preferred directions were distributed uniformly over 360 degrees for SAI afferents, but for FAI afferents they were biased toward the proximo-ulnar direction. Afferents from all over the glabrous skin of the distal segment of the finger responded; there was no evident relationship between the position of an afferent's receptive field on the finger and its preferred direction or its degree of tuning. Nor were preferred directions biased either toward or away from the receptive field center. In response to the relatively large normal forces, some afferents saturated and others did not, regardless of the positions of their receptive fields. Total afferent response matched human psychophysical scaling functions for normal force.

Validation of a qPCR assay for the detection of Ictalurid herpesvirus-2 (IcHV-2) in fish tissues and cell culture supernatants.

Ictalurid herpesvirus-2 (IcHV-2) is a pathogen of cultured black bullhead, Ameiurus melas (Rafinesque), and has been shown to produce high mortality in experimental exposures of channel catfish, Ictalurus punctatus (Rafinesque). During acute infections, the virus grows readily in cell cultures but produces a cytopathic effect (CPE) similar to that of Ictalurid herpesvirus-1 (IcHV-1) and the channel catfish reovirus. We have developed a quantitative PCR assay that can be used to detect IcHV-2 in fish tissues and cell culture supernatants. The assay does not amplify other fish herpesviruses tested or host DNA. It is quantitative over a range of eight logs, and the limit of detection is <10 copies per reaction. In replicate assays carried out on different days, the coefficient of variability was 10%. The best organs for the detection of acute IcHV-2 infections by our assay are the spleen and kidney. This assay should be useful for the diagnosis of IcHV-2 disease, the identification of syncytial CPEs in cell cultures, and for the detection of latent infections in carrier fish.

YAP/TAZ Regulate Elevation and Bone Formation of the Mouse Secondary Palate.

Clefting of the secondary palate is one of the most common congenital anomalies, and the multiple corrective surgeries that individuals with isolated cleft palate undergo are associated with major costs and morbidities. Secondary palate development is a complex, multistep process that includes the elevation of the palatal shelves from a vertical to horizontal position, a process that is not well understood. The Hippo signaling cascade is a mechanosensory pathway that regulates morphogenesis, homeostasis, and regeneration by controlling cell proliferation, apoptosis, and differentiation, primarily via negative regulation of the downstream effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). We deleted Yap/Taz throughout the palatal shelf mesenchyme as well as specifically in the posterior palatal shelf mesenchyme, using the Osr2Cre and Col2Cre drivers, respectively, which resulted in palatal shelf elevation delay and clefting of the secondary palate. In addition, the deletion resulted in undersized bones of the secondary palate. We next determined downstream targets of YAP/TAZ in the posterior palatal shelves, which included Ibsp and Phex, genes involved in mineralization, and Loxl4, which encodes a lysyl oxidase that catalyzes collagen crosslinking. Ibsp, Phex, and Loxl4 were expressed at decreased levels in the ossification region in the posterior palatal shelf mesenchyme upon deletion of Yap/Taz. Furthermore, collagen levels were decreased specifically in the same region prior to elevation. Thus, our data suggest that YAP/TAZ may regulate collagen crosslinking in the palatal shelf mesenchyme, thus controlling palatal shelf elevation, as well as mineralization of the bones of the secondary palate.

Infant EEG theta modulation predicts childhood intelligence.

Intellectual functioning is a critical determinant of economic and personal productivity. Identifying early neural predictors of cognitive function in infancy will allow us to map the neurodevelopmental pathways that underpin individual differences in intellect. Here, in three different cohorts we investigate the association between a putative neurophysiological indicator of information encoding (change in frontal theta during a novel video) in infancy and later general cognitive outcome. In a discovery cohort of 12-month-old typically developing infants, we recorded EEG during presentation of dynamic movies of people and objects. Frontal theta power (3-6 Hz) significantly increased during the course of viewing each video. Critically, increase in frontal theta during viewing of a video was associated with a differential response to repetition of that specific video, confirming relation to learning. Further, individual differences in the magnitude of change in frontal theta power were related to concurrent nonverbal cognitive level. We then sought to extend this association in two independent samples enriched for variation in cognitive outcome due to the inclusion of infants at familial risk for autism. We observed similar patterns of theta EEG change at 12 months, and found a predictive relation to verbal and nonverbal cognitive skills measured at 2, 3 and 7 years of age. For the subset of high-risk infants later diagnosed with autism, infant theta EEG explained over 80% of the variance in nonverbal skills at age 3 years. We suggest that EEG theta change in infancy is an excellent candidate predictive biomarker that could yield substantial insight into the mechanisms that underlie individual differences in childhood intelligence, particularly in high risk populations.