Campaign-style U-Pb titanite petrochronology: along-strike variations in timing of metamorphism in the Himalayan Metamorphic Core

Present-day along-strike heterogeneities within the Himalayan orogen are seen at many scales, from variations within the deep architecture of the lithospheric mantle, to differences in geomorphologic surface processes. Here, we present an internally consistent petrochronologic dataset from the Himalayan metamorphic core (HMC), in order to document and investigate the causes of along-strike variations in its Oligocene–Miocene tectonic history. Laser ablation split-stream analysis was used to date and characterise the geochemistry of titanite from 47 calc-silicate rocks across >2000 km along the Himalaya. This combined U-Pb-REE-Zr single mineral dataset circumvents uncertainties associated with interpretations based on data compilations from different studies, mineral systems and laboratories, and allows for direct along-strike comparisons in the timing of metamorphic processes. Titanite dates range from ∼30 Ma to 12 Ma, recording (re-)crystallization between 625 °C and 815 °C. Titanite T-t data overlap with previously published P-T-t paths from interleaved peltic rocks, demonstrating the usefulness of titanite petrochronology for recording the metamorphic history in lithologies not traditionally used for thermobarometry. Overall, the data indicate a broad eastward-younging trend along the orogen. Disparities in the duration and timing of metamorphism within the HMC are best explained by along-strike variations in the position of ramps on the basal detachment controlling a two-stage process of preferential ductile accretion at depth followed by the formation of later upper-crust brittle duplexes. These processes, coupled with variable erosion, resulted in the asymmetric exhumation of a younger, thicker crystalline core in the eastern Himalaya. Keywords: Himalaya, Petrochronology, Titanite, Metamorphic petrolog

Argon behaviour in an inverted Barrovian sequence, Sikkim Himalaya: the consequences of temperature and timescale on ⁴⁰Ar/³⁹Ar mica geochronology

40Ar/39Ar dating of metamorphic rocks sometimes yields complicated datasets which are difficult to interpret in terms of timescales of the metamorphic cycle. Single-grain fusion and step-heating data were obtained for rocks sampled through a major thrust-sense shear zone (the Main Central Thrust) and the associated inverted metamorphic zone in the Sikkim region of the eastern Himalaya. This transect provides a natural laboratory to explore factors influencing apparent 40Ar/39Ar ages in similar lithologies at a variety of metamorphic pressure and temperature (P–T) conditions. The 40Ar/39Ar dataset records progressively younger apparent age populations and a decrease in within-sample dispersion with increasing temperature through the sequence. The white mica populations span ~ 2–9 Ma within each sample in the structurally lower levels (garnet grade) but only ~ 0–3 Ma at structurally higher levels (kyanite-sillimanite grade). Mean white mica single-grain fusion population ages vary from 16.2 ± 3.9 Ma (2σ) to 13.2 ± 1.3 Ma (2σ) from lowest to highest levels. White mica step-heating data from the same samples yields plateau ages from 14.27 ± 0.13 Ma to 12.96 ± 0.05 Ma. Biotite yield older apparent age populations with mean single-grain fusion dates varying from 74.7 ± 11.8 Ma (2σ) at the lowest structural levels to 18.6 ± 4.7 Ma (2σ) at the highest structural levels; the step-heating plateaux are commonly disturbed. Temperatures > 600 °C at pressures of 0.4–0.8 GPa sustained over > 5 Ma, appear to be required for white mica and biotite ages to be consistent with diffusive, open-system cooling. At lower temperatures, and/or over shorter metamorphic timescales, more 40Ar is retained than results from simple diffusion models suggest. Diffusion modelling of Ar in white mica from the highest structural levels suggests that the high-temperature rocks cooled at a rate of ~ 50–80 °C Ma− 1, consistent with rapid thrusting, extrusion and exhumation along the Main Central Thrust during the mid-Miocene

Using U-Th-Pb petrochronology to determine rates of ductile thrusting: time windows into the Main Central Thrust, Sikkim Himalaya

Quantitative constraints on the rates of tectonic processes underpin our understanding of the mechanisms that form mountains. In the Sikkim Himalaya, late structural doming has revealed time-transgressive evidence of metamorphism and thrusting that permit calculation of the minimum rate of movement on a major ductile fault zone, the Main Central Thrust (MCT), by a novel methodology. U-Th-Pb monazite ages, compositions, and metamorphic pressure-temperature determinations from rocks directly beneath the MCT reveal that samples from ~50 km along the transport direction of the thrust experienced similar prograde, peak, and retrograde metamorphic conditions at different times. In the southern, frontal edge of the thrust zone, the rocks were buried to conditions of ~550°C and 0.8 GPa between ~21 and 18 Ma along the prograde path. Peak metamorphic conditions of ~650°C and 0.8–1.0 GPa were subsequently reached as this footwall material was underplated to the hanging wall at ~17–14 Ma. This same process occurred at analogous metamorphic conditions between ~18–16 Ma and 14.5–13 Ma in the midsection of the thrust zone and between ~13 Ma and 12 Ma in the northern, rear edge of the thrust zone. Northward younging muscovite 40Ar/39Ar ages are consistently ~4 Ma younger than the youngest monazite ages for equivalent samples. By combining the geochronological data with the >50 km minimum distance separating samples along the transport axis, a minimum average thrusting rate of 10 ± 3 mm yr−1 can be calculated. This provides a minimum constraint on the amount of Miocene India-Asia convergence that was accommodated along the MCT

Tectonic interleaving along the Main Central Thrust, Sikkim Himalaya

Geochemical and geochronological analyses provide quantitative evidence about the origin, development and motion along ductile faults, where kinematic structures have been overprinted. The Main Central Thrust is a key structure in the Himalaya that accommodated substantial amounts of the India–Asia convergence. This structure juxtaposes two isotopically distinct rock packages across a zone of ductile deformation. Structural analysis, whole-rock Nd isotopes, and U–Pb zircon geochronology reveal that the hanging wall is characterized by detrital zircon peaks at c. 800–1000 Ma, 1500–1700 Ma and 2300–2500 Ma and an εNd(0) signature of –18.3 to –12.1, and is intruded by c. 800 Ma and c. 500–600 Ma granites. In contrast, the footwall has a prominent detrital zircon peak at c. 1800–1900 Ma, with older populations spanning 1900–3600 Ma, and an εNd(0) signature of –27.7 to –23.4, intruded by c. 1830 Ma granites. The data reveal a c. 5 km thick zone of tectonic imbrication, where isotopically out-of-sequence packages are interleaved. The rocks became imbricated as the once proximal and distal rocks of the Indian margin were juxtaposed by Cenozoic movement along the Main Central Thrust. Geochronological and isotopic characterization allows for correlation along the Himalayan orogen and could be applied to other cryptic ductile shear zones

Drug Discovery for Kinetoplastid Diseases : Future Directions

International audienceKinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases

TLR2 signaling in skin non-hematopoietic cells induces early neutrophil recruitment in response to Leishmania major infection

Neutrophils are rapidly recruited to the mammalian skin in response to infection with the cutaneous Leishmania pathogen. The parasites use neutrophils to establish the disease, however, the signals driving early neutrophil recruitment are poorly known. Here, we identified the functional importance of TLR2 signaling in this process. Using bone-marrow chimeras and immunohistology we identified the TLR2-expressing cells involved in this early neutrophil recruitment to be of non-hematopoietic origin. Keratinocytes are damaged and briefly in contact with the parasites during infection. We show that TLR2 triggering by L. major is required for their secretion of neutrophil-attracting chemokines. Furthermore, TLR2 triggering by L. major phosphoglycans is critical for neutrophil recruitment impacting negatively on disease development, as shown by better control of lesion size and parasite load in Tlr2-/- compared to wild type infected mice. Conversely, restoring early neutrophil presence in Tlr2-/- mice through injection of wild type neutrophils or CXCL1 at the onset of infection resulted in delayed disease resolution comparable to that observed in wild type mice. Taken together, our data demonstrate a new role for TLR2-expressing non-hematopoietic skin cells in the recruitment of the first wave of neutrophils following L. major infection, a process delaying disease control

Developing an inverted Barrovian sequence; insights from monazite petrochronology

In the Himalayan region of Sikkim, the well-developed inverted metamorphic sequence of the Main Central Thrust (MCT) zone is folded, thus exposing several transects through the structure that reached similar metamorphic grades at different times. In-situ LA-ICP-MS U–Th–Pb monazite ages, linked to pressure–temperature conditions via trace-element reaction fingerprints, allow key aspects of the evolution of the thrust zone to be understood for the first time. The ages show that peak metamorphic conditions were reached earliest in the structurally highest part of the inverted metamorphic sequence, in the Greater Himalayan Sequence (GHS) in the hanging wall of the MCT. Monazite in this unit grew over a prolonged period between ~37 and 16 Ma in the southerly leading-edge of the thrust zone and between ~37 and 14.5 Ma in the northern rear-edge of the thrust zone, at peak metamorphic conditions of ~790 ◦C and 10 kbar. Monazite ages in Lesser Himalayan Sequence (LHS) footwall rocks show that identical metamorphic conditions were reached ~4–6 Ma apart along the ~60 km separating samples along the MCT transport direction. Upper LHS footwall rocks reached peak metamorphic conditions of ~655 ◦C and 9 kbar between ~21 and 16 Ma in the more southerly-exposed transect and ~14.5–12 Ma in the northern transect. Similarly, lower LHS footwall rocks reached peak metamorphic conditions of ~580 ◦C and 8.5 kbar at ~16 Ma in the south, and 9–10 Ma in the north. In the southern transect, the timing of partial melting in the GHS hanging wall (~23–19.5 Ma) overlaps with the timing of prograde metamorphism (~21 Ma) in the LHS footwall, confirming that the hanging wall may have provided the heat necessary for the metamorphism of the footwall. Overall, the data provide robust evidence for progressively downwards-penetrating deformation and accretion of original LHS footwall material to the GHS hanging wall over a period of ~5 Ma. These processes appear to have occurred several times during the prolonged ductile evolution of the thrust. The preserved inverted metamorphic sequence therefore documents the formation of sequential ‘paleothrusts’ through time, cutting down from the original locus of MCT movement at the LHS–GHS protolith boundary and forming at successively lower pressure and temperature conditions. The petrochronologic methods applied here constrain a complex temporal and thermal deformation history, and demonstrate that inverted metamorphic sequences can preserve a rich record of the duration of progressive ductile thrusting

Low-intensity cognitive-behaviour therapy interventions for obsessive-compulsive disorder compared to waiting list for therapist-led cognitive-behaviour therapy: 3-arm randomised controlled trial of clinical effectiveness

Background Obsessive-compulsive disorder (OCD) is prevalent and without adequate treatment usually follows a chronic course. “High-intensity” cognitive-behaviour therapy (CBT) from a specialist therapist is current “best practice.” However, access is difficult because of limited numbers of therapists and because of the disabling effects of OCD symptoms. There is a potential role for “low-intensity” interventions as part of a stepped care model. Low-intensity interventions (written or web-based materials with limited therapist support) can be provided remotely, which has the potential to increase access. However, current evidence concerning low-intensity interventions is insufficient. We aimed to determine the clinical effectiveness of 2 forms of low-intensity CBT prior to high-intensity CBT, in adults meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for OCD. Methods and findings This study was approved by the National Research Ethics Service Committee North West–Lancaster (reference number 11/NW/0276). All participants provided informed consent to take part in the trial. We conducted a 3-arm, multicentre randomised controlled trial in primary- and secondary-care United Kingdom mental health services. All patients were on a waiting list for therapist-led CBT (treatment as usual). Four hundred and seventy-three eligible patients were recruited and randomised. Patients had a median age of 33 years, and 60% were female. The majority were experiencing severe OCD. Patients received 1 of 2 low-intensity interventions: computerised CBT (cCBT; web-based CBT materials and limited telephone support) through “OCFighter” or guided self-help (written CBT materials with limited telephone or face-to-face support). Primary comparisons concerned OCD symptoms, measured using the Yale-Brown Obsessive Compulsive Scale–Observer-Rated (Y-BOCS-OR) at 3, 6, and 12 months. Secondary outcomes included health-related quality of life, depression, anxiety, and functioning. At 3 months, guided self-help demonstrated modest benefits over the waiting list in reducing OCD symptoms (adjusted mean difference = −1.91, 95% CI −3.27 to −0.55). These effects did not reach a prespecified level of “clinically significant benefit.” cCBT did not demonstrate significant benefit (adjusted mean difference = −0.71, 95% CI −2.12 to 0.70). At 12 months, neither guided self-help nor cCBT led to differences in OCD symptoms. Early access to low-intensity interventions led to significant reductions in uptake of high-intensity CBT over 12 months; 86% of the patients allocated to the waiting list for high-intensity CBT started treatment by the end of the trial, compared to 62% in supported cCBT and 57% in guided self-help. These reductions did not compromise longer-term patient outcomes. Data suggested small differences in satisfaction at 3 months, with patients more satisfied with guided self-help than supported cCBT. A significant issue in the interpretation of the results concerns the level of access to high-intensity CBT before the primary outcome assessment. Conclusions We have demonstrated that providing low-intensity interventions does not lead to clinically significant benefits but may reduce uptake of therapist-led CBT

Treating frailty-a practical guide

Frailty is a common syndrome that is associated with vulnerability to poor health outcomes. Frail older people have increased risk of morbidity, institutionalization and death, resulting in burden to individuals, their families, health care services and society. Assessment and treatment of the frail individual provide many challenges to clinicians working with older people. Despite frailty being increasingly recognized in the literature, there is a paucity of direct evidence to guide interventions to reduce frailty. In this paper we review methods for identification of frailty in the clinical setting, propose a model for assessment of the frail older person and summarize the current best evidence for treating the frail older person. We provide an evidence-based framework that can be used to guide the diagnosis, assessment and treatment of frail older people

The metamorphic and magmatic record of collisional orogens

The Cenozoic Himalaya-Tibet orogen is generally regarded as the archetypal continental collision zone and is often used as an analogue for interpreting ancient orogenic events. However, given the wide diversity observed in present-day collisional mountain belts, the extent to which such inferences can be made remains debated. In this Review, we compare the metamorphic and magmatic record of the Himalaya-Tibet orogen to four ancient orogens — the Palaeozoic Caledonian orogen, the Meso-Neoproterozoic Grenville and Sveconorwegian orogens, and the Palaeoproterozoic Trans-Hudson orogen — to establish the controls on the underlying dynamics and the nature of the resulting rock record. The similarities in rock records, and, thus, thermal conditions, are interpreted to result from comparable foreland strengths, resulting in similar maximum crustal thicknesses. Apparent differences in the records are mainly attributed to variation in exposed structural level rather than fundamentally different tectonic processes. We, therefore, suggest that foreland rheology is a critical factor in determining the effectiveness of orogen comparisons. Future research is required to investigate the causes and consequences of lateral variability in mountain belts, in particular, focussing on the record of orogens smaller than those considered here, and to understand if and why mountain building processes have varied through Earth history