Soft-tissue specimens from pre-European extinct birds of New Zealand

We provide the first complete review of soft tissue remains from New Zealand birds that became extinct prior to European settlement (c. AD 1800). These rare specimens allow insights into the anatomy and appearance of the birds that are not attainable from bones. Our review includes previously unpublished records of ‘lost’ specimens, and descriptions of recently discovered specimens such as the first evidence of soft tissues from the South Island goose (Cnemiornis calcitrans). Overall, the soft tissue remains are dominated by moa (with specimens from each of the six genera), but also include specimens from Finsch's duck (Chenonetta finschi) and the New Zealand owlet-nightjar (Aegotheles novaezealandiae). All desiccated soft tissue specimens that have radiocarbon or stratigraphic dates are late Holocene in age, and most have been found in the semi-arid region of Central Otago

Polynomial matrix formulation-based Capon beamformer

This paper demonstrates the ease with which broadband array problems can be generalised from their well-known, straightforward narrowband equivalents when using polynomial matrix formulations. This is here exemplified for the Capon beamformer, which presents a solution to the minimum variance distortionless response problem. Based on the space-time covariance matrix of the array and the definition of a broadband steering vector, we formulate a polynomial MVDR problem. Results from its solution in the polynomial matrix domain are presented

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

A versatile approach to multiple gene RNA interference using microRNA-based short hairpin RNAs

Background: Effective and stable knockdown of multiple gene targets by RNA interference is often necessary to overcome isoform redundancy, but it remains a technical challenge when working with intractable cell systems. Results: We have developed a flexible platform using RNA polymerase II promoter-driven expression of microRNA-like short hairpin RNAs which permits robust depletion of multiple target genes from a single transcript. Recombination-based subcloning permits expression of multi-shRNA transcripts from a comprehensive range of plasmid or viral vectors. Retroviral delivery of transcripts targeting isoforms of cAMP-dependent protein kinase in the RAW264.7 murine macrophage cell line emphasizes the utility of this approach and provides insight to cAMP-dependent transcription. Conclusion: We demonstrate functional consequences of depleting multiple endogenous target genes using miR-shRNAs, and highlight the versatility of the described vector platform for multiple target gene knockdown in mammalian cells

Thiamine pyrophosphokinase deficiency causes a Leigh disease like phenotype in a sibling pair: Identification through whole exome sequencing and management strategies

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical cours

Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form

Synergistic Ca^(2+) Responses by Gα_i- and Gα_q-coupled G-protein-coupled Receptors Require a Single PLCβ Isoform That Is Sensitive to Both Gβ_γ and Gα_q

Cross-talk between Gα_i- and Gα_q-linked G-protein-coupled receptors yields synergistic Ca^(2+) responses in a variety of cell types. Prior studies have shown that synergistic Ca^(2+) responses from macrophage G-protein-coupled receptors are primarily dependent on phospholipase Cβ3 (PLCβ3), with a possible contribution of PLCβ2, whereas signaling through PLCβ4 interferes with synergy. We here show that synergy can be induced by the combination of Gβγ and Gαq activation of a single PLCβ isoform. Synergy was absent in macrophages lacking both PLCβ2 and PLCβ3, but it was fully reconstituted following transduction with PLCβ3 alone. Mechanisms of PLCβ-mediated synergy were further explored in NIH-3T3 cells, which express little if any PLCβ2. RNAi-mediated knockdown of endogenous PLCβs demonstrated that synergy in these cells was dependent on PLCβ3, but PLCβ1 and PLCβ4 did not contribute, and overexpression of either isoform inhibited Ca^(2+) synergy. When synergy was blocked by RNAi of endogenous PLCβ3, it could be reconstituted by expression of either human PLCβ3 or mouse PLCβ2. In contrast, it could not be reconstituted by human PLCβ3 with a mutation of the Y box, which disrupted activation by Gβγ, and it was only partially restored by human PLCβ3 with a mutation of the C terminus, which partly disrupted activation by Gα_q. Thus, both Gβγ and Gα_q contribute to activation of PLCβ3 in cells for Ca^(2+) synergy. We conclude that Ca^(2+) synergy between Gα_i-coupled and Gα_q-coupled receptors requires the direct action of both Gβγ and Gαq on PLCβ and is mediated primarily by PLCβ3, although PLCβ2 is also competent

The biological carbon pump in CMIP6 models: 21st century trends and uncertainties

The biological carbon pump (BCP) stores ∼1,700 Pg C from the atmosphere in the ocean interior, but the magnitude and direction of future changes in carbon sequestration by the BCP are uncertain. We quantify global trends in export production, sinking organic carbon fluxes, and sequestered carbon in the latest Coupled Model Intercomparison Project Phase 6 (CMIP6) future projections, finding a consistent 19 to 48 Pg C increase in carbon sequestration over the 21st century for the SSP3-7.0 scenario, equivalent to 5 to 17% of the total increase of carbon in the ocean by 2100. This is in contrast to a global decrease in export production of –0.15 to –1.44 Pg C y–1. However, there is significant uncertainty in the modeled future fluxes of organic carbon to the deep ocean associated with a range of different processes resolved across models. We demonstrate that organic carbon fluxes at 1,000 m are a good predictor of long-term carbon sequestration and suggest this is an important metric of the BCP that should be prioritized in future model studies

Brain Biomarkers and Pre-Injury Cognition are Associated with Long-Term Cognitive Outcome in Children with Traumatic Brain Injury

BACKGROUND: Children with traumatic brain injury (TBI) are frequently at risk of long-term impairments of attention and executive functioning but these problems are difficult to predict. Although deficits have been reported to vary with injury severity, age at injury and sex, prognostication of outcome remains imperfect at a patient-specific level. The objective of this proof of principle study was to evaluate a variety of patient variables, along with six brain-specific and inflammatory serum protein biomarkers, as predictors of long-term cognitive outcome following paediatric TBI. METHOD: Outcome was assessed in 23 patients via parent-rated questionnaires related to attention deficit hyperactivity disorder (ADHD) and executive functioning, using the Conners 3rd Edition Rating Scales (Conners-3) and Behaviour Rating Inventory of Executive Function (BRIEF) at a mean time since injury of 3.1 years. Partial least squares (PLS) analyses were performed to identify factors measured at the time of injury that were most closely associated with outcome on (1) the Conners-3 and (2) the Behavioural Regulation Index (BRI) and (3) Metacognition Index (MI) of the BRIEF. RESULTS: Higher levels of neuron specific enolase (NSE) and lower levels of soluble neuron cell adhesion molecule (sNCAM) were associated with higher scores on the inattention, hyperactivity/impulsivity and executive functioning scales of the Conners-3, as well as working memory and initiate scales of the MI from the BRIEF. Higher levels of NSE only were associated with higher scores on the inhibit scale of the BRI. CONCLUSIONS: NSE and sNCAM show promise as reliable, early predictors of long-term attention-related and executive functioning problems following paediatric TBI