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Porphyry Cu ore deposits are a rare product of arc magmatism that often form spatiotemporal clusters in magmatic arcs. The petrogenetic evolution of igneous rocks that cover the temporal window prior to and during porphyry Cu deposit formation may provide critical insights into magmatic processes that are key in generating these systems. This study documents the magmatic evolution of the Palaeocene–Eocene Yarabamba Batholith, Southern Peru, that was incrementally assembled between ~ 67 and ~ 59 Ma and hosts three, nearly contemporaneous, giant porphyry Cu–Mo deposits that formed at 57–54 Ma (Quellaveco, Toquepala and Cuajone). Whole-rock geochemistry, U–Pb geochronology and zircon trace element chemistry are reported from Yarabamba rocks that span the duration of plutonic activity, and from six porphyry intrusions at Quellaveco that bracket mineralisation. A change in whole-rock chemistry in Yarabamba intrusive rocks to high Sr/Y, high La/Yb and high Eu/Eu* is observed at ~ 60 Ma which is broadly coincident with a change in vector of the converging Nazca plate and the onset of regional compression and crustal thickening during the first stage of the Incaic orogeny. The geochemical changes are interpreted to reflect a deepening of the locus of lower crustal magma evolution in which amphibole ± garnet are stabilised as early and abundant fractionating phases and plagioclase is suppressed. Zircons in these rocks show a marked change towards higher Eu/Eu* (> 0.3) and lower Ti (< 9 ppm) compositions after ~ 60 Ma. Numerical modelling of melt Eu systematics and zircon-melt partitioning indicates that the time series of zircon Eu/Eu* in these rocks can be explained by a transition from shallower, plagioclase-dominated fractionation to high-pressure amphibole-dominated fractionation at deep crustal levels from ~ 60 Ma. Our modelling suggests that any redox effects on zircon Eu/Eu* are subordinate compared to changes in melt composition controlled by the fractionating mineral assemblage. We suggest that growth and intermittent recharge of the lower crustal magma reservoir from ~ 60 Ma produced a significant volume of hydrous and metallogenically fertile residual melt which ascended to the upper crust and eventually generated the three giant porphyry Cu–Mo deposits at Quellaveco, Toquepala and Cuajone from ~ 57 Ma. Our study highlights the importance of high-pressure magma differentiation fostered by strongly compressive tectonic regimes in generating world-class porphyry Cu deposits.

Background Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer’s disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy. Methods Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers. Results In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks. Conclusions These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD. Trial registration Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.clinicaltrials.gov/study/NCT03635047 .

Explanations for rapid species’ range expansions have typically been purely ecological, with little attention given to evolutionary processes. We tested predictions for the evolution of dispersal during range expansion using four species of wing‐dimorphic bush cricket (Conocephalus discolor,Conocephalus dorsalis,Metrioptera roeselii, andMetrioptera brachyptera). We observed distinct changes in dispersal in the two species with expanding ranges. Recently colonized populations at the range margin showed increased frequencies of dispersive, long‐winged (macropterous) individuals, compared with longer‐established populations in the range core. This increase in dispersal appeared to be short‐lived because 5–10 years after colonization populations showed similar incidences of macroptery to populations in the range core. These changes are consistent with evolutionary change; field patterns persisted when nymphs were reared under controlled environmental conditions, and range margin individuals reared in the laboratory flew farther than range core individuals in a wind tunnel. There was also a reproductive trade‐off with dispersal in both females and males, which could explain the rapid reversion to lower rates of dispersal once populations become established. The effect of population density on wing morphology differed between populations from the range core (no significant effect of density) and expanding range margins (negative density dependence), which we propose is part of the mechanism of the changes in dispersal. Transient changes in dispersal are likely to be common in many species undergoing range expansion and can have major population and biogeographic consequences.

Background Despite the availability of numerous antipsychotic medications, many patients with schizophrenia continue to experience side effects that contribute to the overall burden of the illness. The present survey of patients with schizophrenia and schizoaffective disorder aimed to assess patient attitudes toward antipsychotic treatment, and understand key factors about willingness to try a new medication. Methods A cross-sectional survey was administered to 250 patients with a primary clinical diagnosis of a schizophrenia spectrum disorder across five outpatient clinics in the United States. The survey included self-reported gender, age, weight, and height, and questions about the importance of efficacy and side effects on the decision to take a prescribed antipsychotic medication. Results Patients rated efficacy and side effects as important attributes of antipsychotic treatment, with 93.6% and 83.6% of patients listing these as “very” or the “most” important factors in taking prescribed medication. A total of 87.6% of respondents identified the ability to think more clearly as an important property of their medication. Patients identified weight gain, physical restlessness, and somnolence as important side effects of current treatments (“very” or “most” important by 61.6%, 60.8%, and 58.8%, respectively). When asked about willingness to change antipsychotic medication, anticipated weight gain had a negative influence on willingness to try the new treatment, with 22.0% declining to try a medication that would lead to weight gain of 2.7–4.5 kg (6–10 lb), 34.0% declining for anticipated weight gain of 5.0–9.1 kg (11–20 lb), and 52.4% declining for anticipated weight gain greater than 9 kg (20 lbs). Conclusion Patients living with schizophrenia spectrum disorders are influenced by many factors when considering whether to take their medication, including efficacy and side effects. It is important for clinicians to assess specific patient concerns to develop a comprehensive treatment plan that maximizes adherence to the prescribed therapy.

Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥5 cm by half, compared with olanzapine at week 24. Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.

The Portuguese engagement with the continent of Africa following the conquest of Ceuta in 1415 was framed, among numerous conditions, as a crusade (Portuguese: cruzada). However, crusading influences on Portuguese expansion are often sidelined in favour of economic motives. Unlike North and north-east Africa's connected histories with the Crusades (1095–1291) and the continual role of crusading in the following centuries, the fifteenth century offered a new arena. Kongo's adoption of Christianity in the late fifteenth century was the first time that an African power can be viewed as engaging in crusading ideology as a Latin Christian power. Significantly, Kongo was converted by Portuguese missionaries who were undertaking their own crusade. Yet, the crusading influence on Kongo's early development of its Christianity has hitherto been overlooked in Africanist scholarship. Similarly, the situation in Kongo remains a lacuna in Crusades scholarship too. This article calls for a closer discussion between the histories of Africa and the Crusades through the case of Kongo and comparative African examples, such as Benin and Ndongo, to highlight the need to better connect these histories.

Citrome L, Graham C, Simmons A, et al. Neuropsychiatr Dis Treat. 2021;17:2885-2904. The authors have advised there is an error in Figure 1C on page 2894. The key \"OLZ/SAM\" should read \"Olanzapine + samidorphan 10 mg\" and \"Olanzapine\" should read \"Olanzapine + placebo\". Figure 1 legend, the text \"Panel (C) In ALK3831-302, antipsychotic efficacy, as measured by the change from baseline in the PANSS total score at week 12 in the combined OLZ/SAM groups (OLZ/SAM 5/10 mg, 10/10 mg, and 20/10 mg) versus olanzapine was the primary endpoint; only the olanzapine + placebo and olanzapine + samidorphan 10-mg groups are presented here to allow cross-study comparisons\" should read \"Panel (C) In ALK3831-302, antipsychotic efficacy, as measured by the change from baseline in the PANSS total score at week 12, was the primary endpoint comparing the combined olanzapine + samidorphan groups versus the olanzapine + placebo group; to allow cross-study comparisons, only the olanzapine + samidorphan 10-mg and the olanzapine + placebo groups are presented here\". Read the original article

Introduction. Transmission of cytomegalovirus (CMV) via breast milk can lead to severe acute illness in very low-birth-weight (VLBW) preterm infants. Although the majority of CMV-seropositive women shed CMV in milk, symptomatic postnatal infection of VLBW infants occurs infrequently, suggesting that virologie or immunologie factors in milk may be associated with the risk and severity of postnatal CMV infection. Methods. We investigated the magnitude of CMV-specific cellular and humoral immune responses in milk of 30 seropositive mothers of VLWB preterm infants and assessed their relationship to milk CMV load and symptomatic CMV transmission. Results. Milk immunoglobulin G (IgG) avidity was inversely correlated to milk CMV load (r = -0.47; P = .009). However, milk CMV load and CMV-specific cellular and humoral immune responses were similar in mothers of VLBW infants with and those without symptomatic postnatal CMV infection. Conclusions. Similar immunologie parameters in milk of CMV-seropositive mothers of VLBW infants with and without symptomatic postnatal CMV infection indicate that screening milk by these parameters may not predict disease risk. However, the inverse correlation between milk CMV IgG avidity and CMV load may suggest that enhancement of maternal CMV-specific IgG responses could aid in reduction of CMV shedding into breast milk.

This is a fascinating encyclopedia comparing the most important adaptations and evolutions in the natural world with the most important discoveries and inventions of human history. Welcome to the amazing world of adaptations, where species—including humans—develop fascinating new capabilities to ensure a competitive edge in their environment, or in some cases, survival itself. Encyclopedia of Adaptations in the Natural World is a wide-ranging catalog of the most important of those adaptations—from photosynthesis to the the peculiar “vampire”-like behavior of the tiny life form called the prion. The seven chapters in the Encyclopedia cover the key survival challenges all organisms face. Entries within those chapters cover specific adaptations from all forms of life, including animals, plants, bacteria, algae, fungi, and viruses. For each adaptation, the book also describes a related technological breakthrough in the human world, showing how engineers today study natural processes to help them develop new inventions.