Petrogenesis of diachronous mixed siliciclastic-carbonate megafacies in the cool-water Oligocene Tikorangi Formation, Taranaki Basin, New Zealand

The Oligocene (Whaingaroan-Waitakian) Tikorangi Formation is a totally subsurface, lithostratigraphically complex, mixed siliciclastic-limestone-rich sequence forming an important fracture reservoir within Taranaki Basin, New Zealand. Petrographically the formation comprises a spectrum of interbedded rock types ranging from calcareous mudstone to wackestone to packstone to clean sparry grainstone. Skeletal and textural varieties within these rock types have aided in the identification of three environmentally distinctive megafacies for the Tikorangi Formation rocks-shelfal, foredeep, and basinal. Data from these megafacies have been used to detail previous conclusions on the petrogenesis and to further refine depositional paleoenvironmental models for the Tikorangi Formation in the central eastern Taranaki Basin margin.Shelfal Megafacies 1 rocks (reference well Hu Road-1A) are latest Oligocene (early Waitakian) in age and formed on or proximal to the Patea-Tongaporutu-Herangi basement high. They are characterised by coarse, skeletal-rich, pure sparry grainstone comprising shallow water, high energy taxa (bryozoans, barnacles, red algae) and admixtures of coarse well-rounded lithic sand derived from Mesozoic basement greywacke. This facies type has previously gone unrecorded in the Tikorangi Formation. Megafacies 2 is a latest Oligocene (early Waitakian) foredeep megafacies (formerly named shelfal facies) formed immediately basinward and west of the shelfal basement platform. It accumulated relatively rapidly (>20 cm/ka) from redeposition of shelfal megafacies biota that became intermixed with bathyal taxa to produce a spectrum of typically mudstone through to sparry grainstone. The resulting skeletal mix (bivalve, echinoderm, planktic and benthic foraminiferal, red algal, bryozoan, nannofossil) is unlike that in any of the age-equivalent limestone units in neighbouring onland King Country Basin. Megafacies 3 is an Oligocene (Whaingaroan-Waitakian) offshore basinal megafacies (formerly termed bathyal facies) of planktic foraminiferal-nannofossil-siliciclastic wackestone and mudstone formed away from redepositional influences. The siliciclastic input in this distal basinal setting (sedimentation rates <7 mm/ka) was probably sourced mainly from oceanic currents carrying suspended sediment from South Island provenances exposed at this time.Tikorangi Formation rocks record the Taranaki Basin’s only period of carbonate-dominated sedimentation across a full range of shelfal, foredeep, and basinal settings. Depositional controls on the three contrasting megafacies were fundamentally the interplay of an evolving and complex plate tectonic setting, including development of a carbonate foredeep, changes in relative sea level within an overall transgressive regime, and changing availability, sources, and modes of deposition of both bioclastic and siliciclastic sediments. The mixed siliciclastic-carbonate nature of the formation, and its skeletal assemblages, low-Mg calcite mineralogy, and delayed deep burial diagenetic history, are features consistent with formation in temperate-latitude cool waters

Textural variations in Neogene pelagic carbonate ooze at DSDP Site 593, southern Tasman Sea, and their paleoceanographic implications

Changes in Neogene sediment texture in pelagic carbonate-rich oozes on the Challenger Plateau, southern Tasman Sea, are used to infer changes in depositional paleocurrent velocities. The most obvious record of textural change is in the mud:sand ratio. Increases in the sand content are inferred to indicate a general up-core trend towards increasing winnowing of sediments resulting from increasing flow velocity of Southern Component Intermediate Water (SCIW), the forerunner of Antarctic Intermediate Water. In particular, the intervals c. 19-14.5 Ma, c. 9.5-8 Ma, and after 5 Ma are suggested to be times of increased SCIW velocity and strong sediment winnowing. Within the mud fraction, the fine silt to coarse clay sizes from 15.6 to 2 µm make the greatest contribution to the sediments and are composed of nannofossil plates. During extreme winnowing events it is the fine silt to very coarse clay material (13-3 µm) within this range that is preferentially removed, suggesting the 10 µm cohesive silt boundary reported for siliciclastic sediments does not apply to calcitic skeletal grains. The winnowed sediment comprises coccolithophore placoliths and spheres, represented by a mode at 4-7 µm. Further support for seafloor winnowing is gained from the presence in Hole 593 of a condensed sedimentary section from c. 18 to 14 Ma where the sand content increases to c. 20% of the bulk sample. Associated with the condensed section is a 6 m thick orange unit representing sediments subjected to particularly oxygen-rich, late early to early middle Miocene SCIW. Together these are inferred to indicate increased SCIW velocity resulting in winnowed sediment associated with faster arrival of oxygen-rich surface water subducted to form SCIW. Glacial development of Antarctica has been recorded from many deep-sea sites, with extreme glacials providing the mechanism to increase watermass flow. Miocene glacial zones Mi1b-Mi6 are identified in an associated oxygen isotope record from Hole 593, and correspond with times of particularly invigorated paleocirculation, bottom winnowing, and sediment textural changes

Decoupling seasonal fluctuations in fluvial discharge from the tidal signature in ancient deltaic deposits: an example from the Neuquén Basin, Argentina

Fluvial discharge fluctuations are a fundamental characteristic of almost all modern rivers and can produce distinctive deposits that are rarely described from ancient fluvial or mixed-energy successions. Large-scale outcrops from the Middle Jurassic Lajas Formation (Argentina) expose a well-constrained stratigraphic succession of marginal-marine deposits with a strong fluvial influence and well-known tidal indicators. The studied deposits show decimetre-scale interbedding of coarser- and finer-grained facies with mixed fluvial and tidal affinities. The alternation of these two types of beds forms non-cyclic successions that are interpreted to be the result of seasonal variation in river discharge, rather than regular and predictable changes in current velocity caused by tides. Seasonal bedding is present in bar deposits that form within or at the mouth of minor and major channels. Seasonal bedding is not preserved in channel thalweg deposits, where river flood processes were too powerful, or in floodplain, muddy interdistributary-bay, prodelta and transgressive deposits, where the river signal was weak and sporadic. The identification of sedimentary facies characteristic of seasonal river discharge variations is important for accurate interpretation of ancient deltaic process regime

Retinal glycoprotein enrichment by concanavalin a enabled identification of novel membrane autoantigen synaptotagmin-1 in equine recurrent uveitis.

Complete knowledge of autoantigen spectra is crucial for understanding pathomechanisms of autoimmune diseases like equine recurrent uveitis (ERU), a spontaneous model for human autoimmune uveitis. While several ERU autoantigens were identified previously, no membrane protein was found so far. As there is a great overlap between glycoproteins and membrane proteins, the aim of this study was to test whether pre-enrichment of retinal glycoproteins by ConA affinity is an effective tool to detect autoantigen candidates among membrane proteins. In 1D Western blots, the glycoprotein preparation allowed detection of IgG reactions to low abundant proteins in sera of ERU patients. Synaptotagmin-1, a Ca2+-sensing protein in synaptic vesicles, was identified as autoantigen candidate from the pre-enriched glycoprotein fraction by mass spectrometry and was validated as a highly prevalent autoantigen by enzyme-linked immunosorbent assay. Analysis of Syt1 expression in retinas of ERU cases showed a downregulation in the majority of ERU affected retinas to 24%. Results pointed to a dysregulation of retinal neurotransmitter release in ERU. Identification of synaptotagmin-1, the first cell membrane associated autoantigen in this spontaneous autoimmune disease, demonstrated that examination of tissue fractions can lead to the discovery of previously undetected novel autoantigens. Further experiments will address its role in ERU pathology

The relationship of testosterone levels with sprint performance in young professional track and field athletes

Evidence suggests that higher testosterone levels may provide an athletic advantage. Therefore, it is of practical interest to examine the association between testosterone levels and power- and strength-related traits in young professional track and field athletes, and to consider the factors that determine testosterone levels. The study involved 68 young professional athletes (45 females, 17.3 ± 2.6 years; 23 males, 18.2 ± 1.9 years). Testosterone levels were assessed via liquid chromatography-mass spectrometry. All subjects performed two 20 m and two 30 m sprint trials, and countermovement jump without arm-swing. A bioimpedance analysis of body composition was carried out and biological maturity was examined using the Khamis-Roche method. The average testosterone levels were 26.4 ± 9.6 nmol/l and 1.5 ± 0.7 nmol/l in males and females, respectively. In female athletes, testosterone levels did not correlate with any of traits. Males with the highest testosterone levels were significantly faster in the 20 m (p = 0.033) and 30 m (p = 0.014) sprint trials compared to males with lower testosterone levels. Testosterone levels in males were positively associated with fat mass (p = 0.027), and degree of biological maturation (p = 0.003). In conclusion, we found a positive relationship between testosterone levels and sprint performance in young male athletes

Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension

Effective killing of the human pathogen Candida albicans by a specific inhibitor of non-essential mitotic kinesin Kip1p

Kinesins from the bipolar (Kinesin-5) family are conserved in eukaryotic organisms and play critical roles during the earliest stages of mitosis to mediate spindle pole body separation and formation of a bipolar mitotic spindle. To date, genes encoding bipolar kinesins have been reported to be essential in all organisms studied. We report the characterization of CaKip1p, the sole member of this family in the human pathogenic yeast Candida albicans. C. albicans Kip1p appears to localize to the mitotic spindle and loss of CaKip1p function interferes with normal progression through mitosis. Inducible excision of CaKIP1 revealed phenotypes unique to C. albicans, including viable homozygous Cakip1 mutants and an aberrant spindle morphology in which multiple spindle poles accumulate in close proximity to each other. Expression of the C. albicans Kip1 motor domain in Escherichia coli produced a protein with microtubule-stimulated ATPase activity that was inhibited by an aminobenzothiazole (ABT) compound in an ATP-competitive fashion. This inhibition results in ‘rigor-like’, tight association with microtubules in vitro. Upon treatment of C. albicans cells with the ABT compound, cells were killed, and terminal phenotype analysis revealed an aberrant spindle morphology similar to that induced by loss of the CaKIP1 gene. The ABT compound discovered is the first example of a fungal spindle inhibitor targeted to a mitotic kinesin. Our results also show that the non-essential nature and implementation of the bipolar motor in C. albicans differs from that seen in other organisms, and suggest that inhibitors of a non-essential mitotic kinesin may offer promise as cidal agents for antifungal drug discovery

Continental-scale geographic change across zealandia during paleogene subduction initiation

Data from International Ocean Discovery Program (IODP) Expedition 371 reveal vertical movements of 1-3 km in northern Zealandia during early Cenozoic subduction initiation in the western Pacific Ocean. Lord Howe Rise rose from deep (~1 km) water to sea level and subsided back, with peak uplift at 50 Ma in the north and between 41 and 32 Ma in the south. The New Caledonia Trough subsided 2-3 km between 55 and 45 Ma. We suggest these elevation changes resulted from crust delamination and mantle flow that led to slab formation. We propose a "subduction resurrection" model in which (1) a subduction rupture event activated lithospheric-scale faults across a broad region during less than ~5 m.y., and (2) tectonic forces evolved over a further 4-8 m.y. as subducted slabs grew in size and drove plate-motion change. Such a subduction rupture event may have involved nucleation and lateral propagation of slip-weakening rupture along an interconnected set of preexisting weaknesses adjacent to density anomalies

Patient-reported outcomes in metastatic castration-resistant prostate cancer

Many novel therapies are available for use in patients with metastatic castration-resistant prostate cancer (mCRPC), some of which convey substantial progression-free survival and overall survival benefits. Delaying disease progression and providing palliation of symptoms are primary therapeutic aims of treating patients with mCRPC; therefore, ensuring that the benefit-to-harm ratios are acceptable to patients, through systematic measurement of patient-reported outcomes (PROs) using validated tools, is vital. In this Perspectives, we appraised the published reports from clinical trials testing treatments of mCRPC over the past 5 years and found that PROs were either not being measured routinely, or if used, were often not reported adequately, thus hampering evaluation of the true effects of many of these treatments on patients' quality of life. Improvements are needed because data collected directly from patients, not just physician-collected safety data and adverse events, are crucial to inform clinical decision-making on treatment options

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Background Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.Objective To present the results from the APCCC 2019.Design, setting, and participants Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysis The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitations Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.Conclusions These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summary The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making