Early HP Research Articles

Accelerated cystogenesis by dietary protein load is dependent on, but not initiated by kidney macrophages.

Disease severity of autosomal dominant polycystic kidney disease (ADPKD) is influenced by diet. Dietary protein, a recognized cyst-accelerating factor, is catabolized into amino acids (AA) and delivered to the kidney leading to renal hypertrophy. Injury-induced hypertrophic signaling in ADPKD results in increased macrophage (MФ) activation and inflammation followed by cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately stimulating MФs to promote cyst progression. Pkd1flox/flox mice with and without Cre (CAGG-ER) were given tamoxifen to induce global gene deletion (Pkd1KO). Pkd1KO mice were fed either a low (LP; 6%), normal (NP; 18%), or high (HP; 60%) protein diet for 1 week (early) or 6 weeks (chronic). Mice were then euthanized and tissues were used for histology, immunofluorescence and various biochemical assays. One week fed kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing. Chronic dietary protein load in Pkd1KO mice increased kidney weight, number of kidney infiltrating and resident MФs, chemokines, cytokines and cystic index compared to LP diet fed mice. Accelerated cyst growth induced by chronic HP were attenuated by liposomal clodronate-mediated MФ depletion. Early HP diet fed Pkd1KO mice had larger cystic kidneys compared to NP or LP fed counterparts, but without increases in the number of kidney MФs, cytokines, or markers of tubular injury. RNA sequencing of tubular epithelial cells in HP compared to NP or LP diet group revealed increased expression of sodium-glutamine transporter Snat3, chloride channel Clcnka, and gluconeogenesis marker Pepck1, accompanied by increased excretion of urinary ammonia, a byproduct of glutamine. Early glutamine supplementation in Pkd1KO mice lead to kidney hypertrophy. Chronic dietary protein load-induced renal hypertrophy and accelerated cyst growth in Pkd1KO mice is dependent on both infiltrating and resident MФ recruitment and subsequent inflammatory response. Early cyst expansion by HP diet, however, is relient on increased delivery of glutamine to kidney epithelial cells, driving downstream metabolic changes prior to inflammatory provocation.

#4837 CLINICAL OUTCOMES OF HEMOPERFUSION WITH MG350 AMONG RT-PCR-CONFIRMED SEVERE AND CRITICAL COVID-19 PATIENTS IN A TERTIARY HOSPITAL IN LA UNION

Abstract Background and Aims Hemoperfusion (HP) refers to the circulation of anticoagulated blood through an extracorporeal circuit with a disposable, adsorbent-containing cartridge. Earlier studies showed that HP stabilizes the plasma levels of cytokines in sepsis and septic shock. Case reports demonstrated the benefit of HP among COVID-19 patients with severe and critical illness but local data on the outcome of HP in COVID is still lacking. This study aimed to determine the clinical outcomes of HP with MG 350 cartridge among RT-PCR confirmed severe and critical COVID-19 patients admitted in a tertiary hospital in La Union in terms of the trend of clinical parameters before and after HP, mean duration of ventilatory support, mean duration of hospital stay and patient's disposition. Method This is a descriptive, correlational, retrospective cohort single-center study that reviewed the in-patient medical records of 89 RT-PCR confirmed severe and critical COVID-19 patients who underwent at least two HP treatments. We determined their clinical profile and described the trend of clinical parameters before and after HP. Outcome of HP in terms of mean duration of ventilatory support, mean duration of hospital stay and patient's disposition were determined. The possible significant influence of HP to the clinical profile and outcomes as well as clinical parameters to outcomes were also correlated. Results There was a significant decrease in the levels of inflammatory markers such as C-Reactive Protein (CRP), D-dimer, ferritin and Lactate dehydrogenase (LDH) as well as improved respiratory and perfusion parameters such as oxygen saturation and Partial pressure of Oxygen (PaO2) after HP. Patients with higher oxygen saturation, PaO2 and lower fraction of inspired oxygen (FiO2) had shorter duration of ventilatory support. Increased FiO2, CRP, D-dimer, ferritin, white blood cell (WBC) count and Neutrophil Lymphocyte Ratio (NLR) are highly correlated with increased mortality. Early hemoperfusion correlated with shorter duration of ventilatory support, shorter hospital stay and decreased mortality. Interestingly, those with higher oxygen saturation, Pao2, ferritin and procalcitonin correlated with longer duration of hospital stay after HP. Patients with critical illness and late HP had longer duration of ventilatory support. Patients with bilateral infiltrates on chest X-ray and those on mechanical ventilator had longer duration of hospital stay. Increased COVID severity and decreased mean arterial pressure (MAP) had higher likelihood of death even after HP. Conclusion Hemoperfusion significantly decreased the level of inflammatory markers thereby lowering the risk for cytokine storm for COVID-19 patients. Early HP is recommended as it is correlated with shorter duration of ventilatory support, shorter hospital stay and decreased mortality.

P–T–t–D records of Early Palaeozoic Andean‐type shortening of a hot active margin: The Dunhuang block in NW China

AbstractHigh‐pressure (HP) granulites form either in the domain of the subducted plate during continental collision or in supra‐subduction systems where the thermally softened upper plate is shortened and thickened. Such a discrepancy in tectonic setting can be evaluated by metamorphic pressure–temperature–time‐deformation (P–T–t–D) paths. In the current study, P–T–t–D paths of Early Palaeozoic HP granulite facies rocks, in the form of metabasic lenses enclosed in migmatitic metapelite, from the Dunhuang block, NW China, are investigated in order to constrain the nature of the HP rocks and shed light on the geodynamic evolution of a modern hot orogenic system in an active margin setting. The rocks show a polyphase evolution characterized by (1) relics of horizontal or gently dipping fabric (S1) preserved in cores of granulite lenses and in garnet porphyroblasts, (2) a N‐S trending sub‐vertical fabric (S2) preserved in low‐strain domains and (3) upright folds (F3) associated with a ubiquitous steep E‐W striking axial planar foliation (S3). Garnet in the granulites preserves relics of a prograde mineral assemblage M1a equilibrated at ~11.5 kbar and ~770–780°C, whereas the matrix granulite assemblage (M1b) from the S1 fabric attained peak pressure at ~13.5 kbar and ~850°C. The granulites were overprinted at ~8–11 kbar and ~850–900°C during crustal melting (M2) followed by partial re‐equilibration (M3) at ~8 kbar and ~625°C. A garnet Lu–Hf age of 421.6 ± 1.2 Ma dates metamorphism M1, while a garnet Sm–Nd age of 385.3 ± 4.0 Ma reflects M3 cooling of the granulites. The mineral assemblage, M1, of the host migmatitic metapelite formed at ~9–12.5 kbar and ~760–810°C, partial melting and migmatization (M2) occurred at ~7 kbar and ~760°C and re‐equilibration (M3) at ~5–6 kbar and ~675°C. A garnet Lu–Hf age of 409.7 ± 2.3 Ma dates thermal climax (M2) and a garnet Sm–Nd age of 356 ± 11 Ma constrains M3 for the migmatitic metapelites. The timing of this late phase is also bracketed by an emplacement age of syntectonic granite dated at c. 360 Ma. Decoupling of M1 and M2 P–T evolutions between the mafic granulites and migmatitic metapelites indicates their different positions in the crustal column, while the shared pressure–temperature (P–T) evolution M3 suggests formation of a mélange‐like association during the late stages of orogeny. The high‐pressure event D1‐M1 is interpreted as a result of Late Silurian–Early Devonian moderate crustal thickening of a thermally softened and thinned pre‐orogenic crust. The high‐temperature (HT) re‐equilibration D2‐M2 is interpreted as a result of Mid‐Devonian shortening of the previously thickened crust, possibly due to ‘Andean‐type’ underthrusting. The D3‐M3 event reflects Late Devonian supra‐subduction shortening and continuous erosion of the sub‐crustal lithosphere. This tectono‐metamorphic sequence of events is explained by polyphased Andean‐type deformation of a ‘Cascadia‐type’ active margin, which corresponds to a supra‐subduction tectonic switching paradigm.

40Ar behaviour and exhumation dynamics in a subduction channel from multi-scale 40Ar/39Ar systematics in phengite

The behaviour of the phengite 40Ar/39Ar system has been explored at different scales on Sifnos and Syros, two key islands of the Upper Cycladic Blueschist system (UCB). These islands expose well-preserved eclogites and blueschists that were exhumed via extensional collapse of the Aegean subduction/accretionary wedge during the Eocene and Miocene. Both islands record the switch from convergence to extension via a nappe-scale thermal-kinematic reworking marked by a sharp (~2 km thick) metamorphic transition from preserved high-pressure low-temperature (HP/LT) eclogites and blueschists at the top of the stack (peak P-T conditions of 22 ± 2 kbar and 550 ± 25 °C), to retrogressed greenschists at the base (overprinted at P-T conditions of 12–10 kbar and 500-450 °C). Extensive mapping of regional- to grain-scale 40Ar/39Ar age variations along this gradient reveals that phengite ages consistently decrease from 51 Ma down to 18 Ma towards the base of the stack, in parallel with progressive strain localization during exhumation and reworking by the regional greenschist ductile overprint. Homogeneous grain-scale Ar distributions are recorded in the poorly deformed topmost HP samples as Eocene (51–37 Ma) plateau ages and homogeneous in situ UV ablation ages, and by Miocene (20–18 Ma) plateaus in the intensely deformed basal greenschist samples. The homogeneous eclogite and blueschist ages are interpreted to record protracted crystallization in the subduction channel between 51 and 37 Ma, while the homogeneous basal ages likely record complete resetting and/or neocrystallization at 20–18 Ma. All intermediate samples across the metamorphic transition display variably complex age spectra and discordant in situ ages. Sub-grain scale Ar disequilibrium is ubiquitous in the form of within-sample and within-grain variations, with in situ (≪1 mm) variations locally encompassing almost the entire age span recorded regionally (up to 26 Myr). These variations occur mostly independent of microstructures and overlapping textural relationships. We interpret the bulk downward younging and associated internal discordance as the result of competing mechanisms of 40Ar retention and partial resetting operating during the regional greenschist thermo-kinematic overprint at the sub-crystal level. Grain-scale variations in solid-state Ar retention properties, fluid-phase dissolution/precipitation creep, and shear localization resulted in a mosaic of subdomains composed of partially reset to fully preserved relics of early HP clasts coexisting with neo-crystallized domains formed during metamorphic re-equilibration. This domain-like Ar behaviour operated largely below the spatial resolution of the UV probe (<50 μm), irrespective of phengite compositional variations, indicating that structural and thermal-kinetic crystallographic processes driving 40Ar and stoichiometric recombinations in phengite are coupled at a more elementary level, possibly the K-interlayer proper. A major outcome of this study is that it is clearly not possible to properly interpret 40Ar/39Ar phengite ages from HP/LT settings without integrating the information at all scales, from the crystal proper to the regional relationships. On Syros and Sifnos, the interplay between thermal-induced volume diffusion and strain localization is temporally and spatially related to the exhumation dynamics at the scale of the UCB, but these appear locally decoupled at the microscale. Such a complex behaviour is likely to be prevalent in other HP/LT successions exhumed elsewhere.

The pressure–temperature–time–deformation history of the Beni Mzala unit (Upper Sebtides, Rif belt, Morocco): Refining the Alpine tectono‐metamorphic evolution of the Alboran Domain of the western Mediterranean

AbstractThe structural and thermal relaxation overprint associated with the Neogene Alboran rifting have obscured the early Alpine tectono‐metamorphic evolution of the Alboran Domain, representing the metamorphic core of the Betic–Rif orogen of the western Mediterranean region. This study focuses on the Beni Mzala unit, forming the lower and deeper structural level of the Alpine metamorphic nappe stack (Upper Sebtides) in the Moroccan Rif. Meso‐ and micro‐scale structural investigations are carried out on high‐P aluminum silicate (Ky‐bearing)‐quartz segregations that occur as boudins within the main retrogressive syn‐greenschist foliation (S2/D2) and assumed to preserve the early M1 HP metamorphism associated with the Alpine orogenic construction in the Alboran Domain. These boudins host an early crenulated high‐P foliation (S1, D1/M1) made of quartz–kyanite–white mica–rutile. A large spread in white mica composition is documented, with the highest Si content per formula unit (up to 3.18 apfu) preserved along the S1 foliation and the lower Si content observed in the white mica marking the S2 retrogressive foliation (D2/M2) and the rim of S1 mica. Microtextural evidence documents post‐tectonic andalusite growth and static recrystallization of the quartz microlithons. Inverse (Zr‐in‐Rt thermometry) and forward modelling thermobarometry are integrated with Ar–Ar white mica geochronology to define the peak and exhumation pressure–temperature–time (P–T–t) path of the Beni Mzala unit. Minimum thermo‐baric estimates for the M1 event are ~1.4 GPa and 600°C, corresponding to a metamorphic gradient of ~11°/km, consistent with subduction zone metamorphism. Exhumation is constrained by re‐equilibration of the white mica composition (from high to low celadonite) between c. 29 and 22 Ma, during a nearly isothermal retrogressive path, with final equilibration at high‐T/low‐P conditions within the andalusite stability field (~0.2–0.3 GPa and 500°C). A minimum late Oligocene age is proposed for the Alpine D1 tectono‐metamorphic stage in the Rif, suggesting as feasible the previously proposed Eocene timing for the subduction‐zone metamorphism of the Alboran Domain. Conclusive evidence is provided to link the early Miocene tectono‐metamorphic event to a late thermal perturbation that affected the Alboran Domain at shallow crustal conditions, post‐dating the almost complete exhumation of the deep roots of the Alpine belt in the western Mediterranean.

АКТИВНЫЕ ФОРМЫ КИСЛОРОДА КАК ТРИГГЕРЫ ИНФАРКТ-ЛИМИТИРУЮЩЕГО ЭФФЕКТА РАННЕГО ГИПОКСИЧЕСКОГО ПРЕКОНДИЦИОНИРОВАНИЯ МИОКАРДА КРЫСЫ

It is believed that reactive oxygen species (ROS) are involved in the performance of this adaptive hepatoprotective effect phenomenon. However, the role of ROS in the signaling mechanism of the early hypoxic preconditioning (early HP) and the contribution of individual types of oxygen radicals in the infarct-limiting effect of early HP remains uncertain to the end. Objective was to investigate the role of various types of reactive oxygen species in the signaling mechanism of the infarct-limiting effect of early hypoxic preconditioning. We investigated the role of reactive oxygen species in the signaling mechanism of early HP in vivo. Adaptation of animals was conducted with 6 transient hypoxia-reoxygenation sessions before prolonged ischemia (45 min) and reperfusion (120 min). Low molecular weight antioxidants were administered 15 minutes prior to the HP. We found out that pretreatment with the nonselective antioxidant indirect action of N-(2-mercaptopropionyl)-glycine and "trap" of hydroxyl radicals 1,3-dimethylthiourea completely eliminated the infarct-limiting effect of adaptation. Administration of antioxidants tempol and trolox, as well as the use of N-(2-mercaptopropionyl)-glycine after HP had no effect on the protective effect of adaptation. Consequently, reactive oxygen species, including hydroxyl radical, operate as the trigger function in the signaling mechanism of early HP.

Early Cretaceous extensional reworking of the Triassic HP–UHP metamorphic orogen in Eastern China

Corresponding to the Early Mesozoic continental subduction between the North China Block (NCB) and the South China Block (SCB), the Tongbaishan–Hong'an–Dabieshan–Sulu massifs are famous for their HP–UHP metamorphism. More than 50% of the HP–UHP Orogenic Belt was significantly reworked by Early Cretaceous extensional tectonics. This Early Cretaceous event with a fast cooling period, at 130–120Ma, superimposed on the Early Mesozoic HP–UHP orogenic belt and intensively changed the architecture of this orogen. Each individual segment documents different Early Cretaceous extensional structures, namely the central Tongbaishan domain is a metamorphic core complex (MCC) represented by an A-type non-cylindrical antiform; the central Dabieshan domain is a typical Cordilleran-type migmatite-cored MCC; the Southern Sulu UHP domain is a “wedge-shaped” structure exhumed by a simple detachment fault. These late stage extensional structures expose the previous HP–UHP orogenic belt as fragments along the NCB–SCB boundary. The geodynamic setting of this Early Cretaceous extensional tectonics along the HP–UHP orogen is a part of a 1000km-scale crustal extension belt that is widespread in eastern Eurasia continent from Trans-Baikal to the central part of SCB. Convective erosion or delamination of the mantle lithosphere might be considered as a possible mechanism for mantle removal.

Maternal high-protein diet during pregnancy, but not during suckling, induced altered expression of an increasing number of hepatic genes in adult mouse offspring.

Indirect effects of a high-protein maternal diet are not well understood. In this study, we analyzed short-term and sustainable effects of a prenatal versus early postnatal maternal high-protein diet on growth and hepatic gene expression in mouse offspring. Dams were exposed to an isoenergetic high-protein (HP, 40 % w/w) diet during pregnancy or lactation. Growth and hepatic expression profiles of male offspring were evaluated directly after weaning and 150 days after birth. Offspring from two dietary groups, high-protein diet during pregnancy and control diet during lactation (HPC), and control diet during pregnancy and high-protein diet during lactation (CHP), were compared with offspring (CC) from control-fed dams. Maternal CHP treatment was associated with sustained offspring growth retardation, but decreased numbers of affected hepatic genes in adults compared to weanlings. In contrast, offspring of the HPC group did not show persistent effects on growth parameters, but the number of affected hepatic genes was even increased at adult age. In both dietary groups, however, only a small subset of genes was affected in weanlings as well as in adults. We conclude that (1) prenatal and early postnatal maternal HP diet caused persistent, but (2) different effects and partially complementary trends on growth characteristics and on the hepatic transcriptome and associated pathways and that (3) only a small number of genes and associated upstream regulators might be involved in passing early diet-induced imprints to adulthood.

Effect of rhubarb as the main composition of sequential treatment in patients with acute paraquat poisoning: a prospective clinical research

To observe the effect of rhubarb as the main composition in the therapy for patients with acute paraquat poisoning (AP). A prospective randomized controlled trial was conducted. 128 patients with APP admitted to Harrison International Peace Hospital from March 2011 to December 2013 were randomly divided into western medicine control group (n = 64) and western medicine and traditional Chinese medicine (TCM) combination group (n = 64). All the patients were treated with repeated gastric lavage and oral kaolin. The patients in western medicine control group were given 20% mannitol and (or) magnesium sulfate for catharsis, early ( within 8 hours of admission ) hemoperfusion HP), and also given the routine combined therapy. In TCM combination group, in addition to the above treatment patients were given oral paraquat poisoning detoxification prescription No.1 every 2 hours for catharsis, which was composed of rhubarb 10 g, glauber salt 12 g, agrimony 12 g, and licorice 6 g. When green stool disappeared, detoxification therapy was changed to No. 2 compound once a day for 14 days, which was consisted of rhubarb 10 g, ginseng 6 g, agrimony 15 g, rhizoma chuanxiong 10 g, licorice 6 g. The poison volume, first dose of oral drug, time for the first HP, time of the first defecation, the time of last green stool, decontamination time, white blood cell count ( WBC ), C-reactive protein ( CRP ), arterial blood gas analysis, blood lactic acid ( Lac ), liver and kidney functions, myocardial enzyme spectrum, chest CT, adverse reaction, days of hospitalization, and mortality rate were observed in both groups. The levels of paraquat in plasma and urine were determined before treatment and 12 hours after poisoning in both groups. Sixty days after discharge, chest CT was taken for observation of pulmonary fibrosis. There were no significant differences in the poison volume, ingestion time and the time for the first HP between the two groups. Compared with western medicine control group, the first defecation time (hours: 3.94 ± 1.14 vs. 6.17 ± 1.52), the last time of green stool (hours: 36.90 ± 4.10 vs. 51.6 3 ± 4.91), and poison clean-up time from plasma (hours: 19.48 ± 3.63 vs. 23.84 ± 3.29) in combination with TCM group were significantly earlier (all P < 0.01). WBC, CRP, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) levels were gradually increased after admission in combination with TCM group, and they peaked on 5th day [WBC ( × 10⁹/L) : 15.35 ± 2.17 vs. 17.47 ± 2.09, CRP (mg/L): 32.62 ± 2.76 vs. 39.51 ± 2.45, ALT (U/L): 270.88 ± 11.06 vs. 334.67 ± 7.85, BUN (mmol/L): 13.29 ± 1.90 vs. 17.63 ± 1.42, SCr (μmol/L): 203.54 ± 18.40 vs. 251.53 ± 14.38, all P < 0.05 ], and then they declined; Lac after admission was gradually increased, and peaked at 7 days (mmol/L: 3.53 ± 0.21 vs. 3.82 ± 0.14, P < 0.05 ), and then it was decreased. Myocardial enzyme spectrum was increased after admission, and peaked on 3rd day [creatine kinase (CK, U/L): 192.09 ± 16.26 vs. 216.20 ± 11.96, creatine kinase isoenzyme enzyme ( K-MB, U/L): 39.03 ± 3.75 vs. 47.22 ± 5.84, both P < 0.05 ), and then they declined gradually. Arterial partial pressure of oxygen (PaO₂) and base excess (E) were gradually decreased after admission, down to trough on the 7th day after admission [PaO₂(mmHg, 1 mmHg = 0.133 kPa): 87.04 ± 2.37 vs. 84.93 ± 2.44, BE (mmol/L): -7.31 ± 2.31 vs. -9.18 ± 2.49, both P < 0.05 ], and then they were increased. At 12 hours after poisoning, paraquat contents in plasma and urine in combination with TCM group were significantly lower than those of the western medicine control group [plasma (ng/L): 0.83 ± 0.08 vs. 0.96 ± 0.10, urine (ng/L): 0.88 ± 0.09 vs. 0.97 ± 011, both P < 0.05]. The injury to lung tissue was significantly improved in combination with TCM group compared with that in the western medicine control group, and no serious adverse reactions was found, and the hospital stay time (days: 20.46 ± 6.07 vs. 29.73 ± 9.16) was significantly shortened (P < 0.01), and the mortality rate [ 35.9% (23/64) vs. 45.3% (29/64) ] was significantly lowered compared with western medicine control group (P < 0.05). In the combination with TCM group pulmonary fibrosis was lighter than that in the western medicine control group during the 60-day follow-up. The sequential treatment of No. 1 and No. 2 detoxification of APP, using rhubarb as the main drug, can effectively eliminate paraquat, reduce absorption of the toxin, prevent the development of multiple organ dysfunction syndrome (MODS) induced by the toxin, shorten the hospital stay days, and improve the prognosis of APP.

The optimal timing of hemoperfusion component in combined hemodialysis–hemoperfusion treatment for uremic toxins removal

The combination of hemodialysis–hemoperfusion (HDHP) has been proved to be superior to hemodialysis (HD) in eliminating uremic toxins. There are two methods of combination of HD and HP: the HP regime is utilized during the first two-hour an early HP conducted HDHP (EHDHP) or the last two-hour late HP conducted HDHP (LHDHP) of 4 h regular HD session. The present study was to compare these two methods in uremic toxins removal. Twenty adult chronic HD patients were enrolled in this self-control method study. The patients were randomized to receive one session of EHDHP or LHDHP. Two weeks later, the dialysis modalities were switched. The reduction ratio (RR) of targeted uremic toxins for each session was assessed. Both EHDHP and LHDHP showed a significant removal of small water-soluble solutes, middle-sized toxins and cytokines as well (p < 0.05). There were no significant differences between two methods in RR of small water-soluble solutes, like urea and creatinine. For middle-sized molecules and cytokines, such as PTH, β2-M, IL-1, IL-6, and TNF-α, the RR was markedly increased in LHDHP than that in EHDHP (p < 0.05). LHDHP showed no more intradialytic events than EHDHP. The combination of HD and HP in the last two hours in one hemodialysis session had more effect on eliminating middle-sized toxins and cytokines.

Functional insights into the innovative Early Howiesons Poort technology at Diepkloof Rock Shelter (Western Cape, South Africa)

The Howiesons Poort (‘HP’) is characterized by a set of technological innovations that mark a rupture in the Southern African Middle Stone Age. However perspectives regarding its origin and emergence remain speculative. The recent identification of an Early HP phase at Diepkloof Rock Shelter provides the opportunity to characterize the initial stage of this technology and to discuss various mechanisms behind its innovative characteristics.This study provides a technological characterization of the Early HP lithic industry of Diepkloof that focuses on micro-wear analysis. These results suggest that the Early HP contained the full spectrum of innovations found in later expressions of the HP in terms of raw material provisioning strategies and techno-typological rules. Use-wear analyses support the suggestion that a wide range of activities were performed on site and show that geometric backed tools (predominantly composed of truncated forms) were 1) not devoted to specific tasks and 2) used predominantly as knives, not as projectiles. The innovative driver at the origin of the HP is likely not related to the adoption of new hunting weapons but to a novel way of conceiving and hafting tools, based on standardized and interchangeable products. The rapid adoption of this new hafting technique may explain the sudden appearance of the HP technological system in the archaeological record.

Tectonic evolution of a composite collision orogen: An overview on the Qinling–Tongbai–Hong'an–Dabie–Sulu orogenic belt in central China

The formation of collisional orogens is a prominent feature in convergent plate margins. It is generally a complex process involving multistage tectonism of compression and extension due to continental subduction and collision. The Paleozoic convergence between the South China Block (SCB) and the North China Block (NCB) is associated with a series of tectonic processes such as oceanic subduction, terrane accretion and continental collision, resulting in the Qinling–Tongbai–Hong'an–Dabie–Sulu orogenic belt. While the arc–continent collision orogeny is significant during the Paleozoic in the Qinling–Tongbai–Hong'an orogens of central China, the continent–continent collision orogeny is prominent during the early Mesozoic in the Dabie–Sulu orogens of east-central China. This article presents an overview of regional geology, geochronology and geochemistry for the composite orogenic belt. The Qinling–Tongbai–Hong'an orogens exhibit the early Paleozoic HP–UHP metamorphism, the Carboniferous HP metamorphism and the Paleozoic arc-type magmatism, but the three tectonothermal events are absent in the Dabie–Sulu orogens. The Triassic UHP metamorphism is prominent in the Dabie–Sulu orogens, but it is absent in the Qinling–Tongbai orogens. The Hong'an orogen records both the HP and UHP metamorphism of Triassic age, and collided continental margins contain both the juvenile and ancient crustal rocks. So do in the Qinling and Tongbai orogens. In contrast, only ancient crustal rocks were involved in the UHP metamorphism in the Dabie–Sulu orogenic belt, without involvement of the juvenile arc crust. On the other hand, the deformed and low-grade metamorphosed accretionary wedge was developed on the passive continental margin during subduction in the late Permian to early Triassic along the northern margin of the Dabie–Sulu orogenic belt, and it was developed on the passive oceanic margin during subduction in the early Paleozoic along the northern margin of the Qinling orogen.Three episodes of arc–continent collision are suggested to occur during the Paleozoic continental convergence between the SCB and NCB. The first episode of arc–continent collision is caused by northward subduction of the North Qinling unit beneath the Erlangping unit, resulting in UHP metamorphism at ca. 480–490Ma and the accretion of the North Qinling unit to the NCB. The second episode of arc–continent collision is caused by northward subduction of the Prototethyan oceanic crust beneath an Andes-type continental arc, leading to granulite-facies metamorphism at ca. 420–430Ma and the accretion of the Shangdan arc terrane to the NCB and reworking of the North Qinling, Erlangping and Kuanping units. The third episode of arc–continent collision is caused by northward subduction of the Paleotethyan oceanic crust, resulting in the HP eclogite-facies metamorphism at ca. 310Ma in the Hong'an orogen and low-P metamorphism in the Qinling–Tongbai orogens as well as crustal accretion to the NCB. The closure of backarc basins is also associated with the arc–continent collision processes, with the possible cause for granulite-facies metamorphism. The massive continental subduction of the SCB beneath the NCB took place in the Triassic with the final continent–continent collision and UHP metamorphism at ca. 225–240Ma. Therefore, the Qinling–Tongbai–Hong'an–Dabie–Sulu orogenic belt records the development of plate tectonics from oceanic subduction and arc-type magmatism to arc–continent and continent–continent collision.

The making of Gondwana: Discovery of 650 Ma HP granulites from the North Lhasa, Tibet

The Lhasa terrane has been traditionally considered as the northern boundary of the Indian continent. Here we report the discovery of high-pressure granulites occurring as blocks within the Paleozoic sedimentary rocks of the North Lhasa terrane. The mafic HP granulite is composed of garnet, clinopyroxene, plagioclase, rutile and quartz, whereas the pelitic HP granulite has an assemblage of garnet, kyanite, biotite, muscovite, plagioclase and quartz. The mafic rocks show whole-rock compositional features of MORB. Our thermobarometric computations yield P–T conditions of ca. 1.7–1.8GPa and 690–730°C, corresponding to metamorphism under eclogite-facies, with a peak metamorphic gradient of ∼14°C/km, typical of collision-zone metamorphism. In situ zircon U–Pb dating places the timing of the early HP metamorphism at ca. 650Ma, with the late amphibolite-facies retrogression lasting up to ca. 480Ma. Our study reports the first evidence for Late Neoproterozoic HP metamorphism from Tibet, suggesting that the North Lhasa terrane might have been derived from the northern segment of the East African Orogen formed during the assembly of crustal blocks within the Eastern and Western Gondwana.

Postconditioning by mild hypoxic exposures reduces rat brain injury caused by severe hypoxia

A potent neuroprotective effect of ischemic postconditioning has previously been described using cerebral artery occlusion but this is not a practical therapeutic option. The present study has been performed to determine whether postconditioning by mild episodes of hypobaric hypoxia (hypoxic postconditioning, HP) can reduce post-hypoxic brain injury in rats. Male Wistar rats were submitted to severe hypobaric hypoxia (180Torr, 3h) followed by HP (360Torr, 2h, 3 trials spaced at 24h) starting either 3h (early HP) or 24h (delayed HP) after severe hypoxia. The structural and functional brain injury was assessed by a complex of histological techniques, behavioral methods, and by testing the functions of the hypothalamic–pituitary–adrenal axis (HPA). It was found that early and delayed HP considerably attenuated post-hypoxic injury, reducing pyknosis, hyperchromatosis, and interstitial brain edema, as well as the rates of neuronal loss in hippocampus and neocortex. Delayed HP produced prominent anxiolytic effect on rat behavior, preventing development of post-hypoxic anxiety. Both modes of HP had beneficial effect on the functioning of HPA, but only delayed HP normalized completely the baseline HPA activity and its reactivity to stress. The results obtained demonstrate that postconditioning by using repetitive episodes of mild hypobaric hypoxia may provide a powerful neuroprotective procedure that can be easily adopted for clinical practice and recommended as a research tool for identification of endogenous mechanisms involved in post-ischemic neuroprotection.

EMP-monazite age controls on P-T paths of garnet metapelites in the Variscan inverted metamorphic sequence of La Sioule, French Massif Central

AbstractIn the La Sioule region (northern French Massif Central), a Variscan inverted metamorphic sequence is made up by high-grade Upper Gneiss (UGU) and Lower Gneiss Units (LGU) which overlie amphibolite-facies micaschists of a Parautochthonous Unit (PAU). Growth-zoned garnets crystallized in gneisses and micaschists and display different Mg-Fe-Mn-Ca evolution trends in the metamorphic units. Microstructurally-controlled geothermobarometry based on cation exchange and net transfer reactions was used to reconstruct syndeformational prograde P-T paths. The P-T paths do not pass eclogite-facies conditions. Different metamorphic peak temperatures confirm the individual character of the evolution in each of the units. EMP-monazite dating (CHIME method) was used to evaluate the age of the P-T-evolution in the garnet-bearing samples. Monazite ages compiled from numerous matrix grains range between 327 and 343 Ma in single samples. Unimodal distributions of ages signalize only slightly younger (320–330 Ma) monazites in the UGU as in the LGU and PAU (330–340 Ma). The inverted metamorphic stratigraphy can be explained by contractional crustal tectonics. In a northern structural domain this involved a top-to-WNW shearing followed by a first thrusting event at the end of garnet growth in UGU and PAU. In a southern domain, the nappe pile was overprinted by a second event with top-to-SE shearing at low pressures. The bulk of monazites should postdate garnet crystallization and the first thrusting event observed in UGU and PAU. At best the ~340 Ma monazites in the LGU to the south may have crystallized during the second tectonic event. The bulk monazite crystallization appears to be related to a Late-Visean thermal event when the three units were already juxtaposed in a nappe pile. In consequence, metapelite garnet and monazite crystallization in the La Sioule series belong to a Late Devonian – Early Carboniferous prograde-retrograde metamorphism. This metamorphic evolution appears as a second metamorphic cycle subsequent to the Silurian – Early Devonian HP and HT events within the complex frame of the Variscan orogeny in the French Massif Central.

SHRIMP U–Pb dating, trace elements and the Lu–Hf isotope system of coesite-bearing zircon from amphibolite in the SW Sulu UHP terrane, eastern China

In this study, we link mineral inclusion data, trace element analyses, U–Pb age and Hf isotope composition obtained from distinct zircon domains of complex zircon to unravel the origin and multi-stage metamorphic evolution of amphibolites from the Sulu ultrahigh-pressure (UHP) terrane, eastern China. Zircon grains separated from amphibolites from the CCSD-MH drill hole (G12) and Niushan outcrop (G13) were subdivided into two main types based on cathodoluminescence (CL) and Laser Raman spectroscopy: big dusty zircons with inherited cores and UHP metamorphic rims and small clear zircons. Weakly zoned, grey-white luminescent inherited cores preserve mineral inclusions of Cpx+Pl+Ap±Qtz indicative of a mafic igneous protolith. Dark grey luminescent overgrowth rims contain the coesite eclogite-facies mineral inclusion assemblage Coe+Grt+Omp+Phe+Ap, and formed at T=732–839°C and P=3.0–4.0GPa. In contrast, white luminescent small clear zircons preserve mineral inclusions formed during retrograde HP quartz eclogite to LP amphibolite-facies metamorphism (T=612–698°C and P=0.70–1.05GPa). Inherited zircons from both samples yield SHRIMP 206Pb/238U ages of 695–520Ma with an upper intercept age of 800±31Ma. The UHP rims yield consistent Triassic ages around 236–225 and 239–225Ma for G12 and G13 with weighted means of 229±3 and 231±3Ma, respectively. Small clear zircons from both samples give 206Pb/238U ages around 219–210Ma with a weighted mean of 214±3Ma, interpreted as the age of retrograde quartz eclogite-facies metamorphism. Matrix amphibole from both samples indicate Ar–Ar ages of 209±0.7 and 207±0.7Ma, respectively, probably dating late amphibolite-facies retrogression. The data suggest subduction of Neoproterozoic mafic igneous rocks to UHP conditions in Middle Triassic (∼230Ma) times and subsequent exhumation to an early HP (∼214Ma) and a late LP stage (∼208Ma) over a period of ∼16 and 6Myr, respectively. Thus, early exhumation from a mantle depth of 120–100km to about 60km occurred at an average rate of 0.3cm/y, while subsequent exhumation to a middle crustal level took place at approximately 0.54cm/y. These exhumation rates are considerably slower than those obtained for UHP rocks in the Dora Maira and Kokchetav massifs (2–3cm/y).Based on similar P–T estimates and trace element and Hf isotope compositions, Sulu amphibolites can be identified as retrograde UHP eclogites. The εHf(800) of +8 implies a significant input from the depleted mantle to the Sulu–Dabie terrane during the middle Neoproterozoic. Overgrown rims are characterized by a distinct trace element composition with low Lu/Hf and Th/U and significantly higher 176Hf/177Hf ratios than inherited cores, consistent with formation during/after garnet (re-)crystallization and fractionation of the Lu–Hf system during UHP metamorphism. The combined dataset suggests homogenization of the 176Hf/177Hf ratio within the metamorphic mineral assemblage and during protolith formation. Observed variations are explained by mixing of material from both domains during laser ablation, e.g., due to partial recrystallization of inherited cores.

Extensional v. contractional origin for the southern Menderes shear zone, SW Turkey: tectonic and metamorphic implications

The southern Menderes Massif in southwest Turkey consists mainly of orthogneisses and overlying Palaeozoic–Middle Paleocene schists and marbles. The contact between the two distinct rock types is almost everywhere structural, herein named the southern Menderes shear zone: a S-facing, high-angle ductile shear zone that separates metamorphic rocks of differing grade. Although there is a consensus that the shear zone was associated with top-to-the-S–SSW shearing and is of Tertiary age, its origin and nature have been highly debated over the last decade. Some claim the contact is a thrust fault, while others have argued for an extensional shear zone. Integration of field and microstructural data (the identification of different fabrics, associated kinematics and overprinting relationships) with fission-track thermochronology and the P–T paths of the rocks above and below the shear zone, supports the conclusion that the southern Menderes shear zone is an extensional shear zone and not a thrust. The data are consistent with a model that the exhumation and cooling of the southern Menderes Massif occurred after a period of extensional deformation. Pervasive top-to-the-N–NNE high-temperature–medium-pressure ductile shear structures (D2 deformation) overprint an early HP event (D1 deformation). The subsequent top-to-the-S–SSW greenschist shear band foliation (D3 deformation) developed mostly around the orthogniess–schist contact and forms the most characteristic features of the massif. The top-to-the-N–NNE structures are attributed to the main Alpine constructional deformation that developed during back-thrusting of the Lycian nappes during the latest Palaeogene collision between the Sakarya continent and the Anatolide-Tauride platform across the Neotethyan Ocean. The top-to-the-S–SSW structures are interpreted to be the result of the exhumation of the massif during the activity of the southern Menderes shear zone. The presence of these two distinct fabrics with differing kinematics suggests that the southern Menderes shear zone operated as a top-to-the-N–NNE thrust fault during early Alpine contractional deformation but was later reactivated with an opposite sense of movement (top-to-the-S–SSW) during subsequent Oligocene–Miocene extensional collapse.

U–Pb isotopic studies of eclogites and their host gneisses in the Xitieshan area of the North Qaidam mountains, western China: New evidence for an early Paleozoic HP–UHP metamorphic belt

Using both TIMS and SHRIMP methods, U–Pb isotopic dating was carried out on zircons from eclogites and their host gneisses in the Xitieshan area of the north Qaidam mountains, western China. Zircons from both eclogites and retrograded eclogites with metamorphic characteristics gave ages of 485–500 Ma, representing the age of eclogite facies metamorphism. Euhedral zircons from the eclogites, which show a magmatic character (Th/U>1), yielded ages of 750–800 Ma, which are believed to represent the magmatic crystallization age of the protlith. TIMS dating of zircons from granitic gneiss enclosing retrograded eclogite gave an upper intercept age of 952±13 Ma and a lower intercept age of 478±44 Ma. The former probably represents the magmatic crystallization age of the granitic protolith, and the latter is in agreement with the age of metamorphic zircons from the eclogite within the margin of error. This implies that the eclogites and their enclosing gneisses in Xitieshan area as a whole underwent HP–UHP metamorphism during an early Paleozoic orogeny to form one part of the north Qaidam HP–UHP metamorphic belt. These results also suggest an ‘in situ’ rather than ‘tectonic'relationship between the eclogites and their host gneisses.

Les « Porphyroı̈des » de Bretagne méridionale : une unité de HP–BT dans la chaı̂ne hercynienne

Abstract The so-called ‘Porphyroides’ Unit of South Brittany is located below units marked by an early HP–LT event (blueschists from the Ile de Groix) and above units marked by Upper Carboniferous HT metamorphism. P – T estimates in the Porphyroides (at Belle-Ile-en-Mer), using the phengite–chlorite thermobarometer, indicate pressures around 8 kbar and temperatures of 350–400 °C. These new estimates suggest that the early tectonic history of the ‘Porphyroides’ should be linked to that of the overlying Blueschists, and imply a much larger areal extension of the HP–LT domain in this part of the Hercynian Belt. To cite this article: F. Le Hebel et al., C. R. Geoscience 334 (2002) 205–211.

Stringently purified human hematopoietic progenitors/stem cells: analysis of cellular/molecular mechanisms underlying early hematopoiesis.

Analysis of the cellular/molecular basis of the early steps of hematopoietic proliferation and differentiation is hindered by the rarity of hematopoietic progenitors and stem cells (HP/HSC). The intensive efforts devoted to the development of purification methods for early HP and HSC, although initially largely unsuccessful, have recently provided a high level of HP/HSC yield and/or recovery. The methodology developed by our group, recently improved, provides not only virtually complete purification, but also abundant recovery of early HP/HSC such as colony forming units granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM), burst forming units erythroid (BFU-E), CFU granulocyte/macrophage (CFU-GM)/CFU blast cells (CFU-B), and long-term culture initiating cells (LTC-IC) from adult peripheral and cord blood (CB). We have also developed a serum-free liquid suspension culture for unilineage erythroid (E), granulocytic (G) or monocytic (M) differentiation of stringently purified HP/HSC. These culture systems allow sequential collection and cellular/molecular analysis of discrete populations of hematopoietic cells at a homogenous stage of differentiation specifically along a unilineage pathway. These experimental tools have been utilized to investigate cellular/molecular mechanisms underlying early hematopoiesis. The transcription factor (TF) GATA-1 is considered to be the "master" gene of erythropoiesis. In highly purified HP/HSC undergoing E or GM differentiation, GATA-1 expression is characterized initially by proliferation-dependent activation and at later stages by sustained expression in the E pathway and suppression in the GM pathway. Hypothetically, similar on/off switches of lineage-restricted TF may underlie the binary fate decisions of early HP differentiation. The expression and modulation of hematopoietic growth factor receptors (HGFR) in early hematopoiesis have been extensively analyzed. The results suggest a model of transactivation cascade for HGFR such as interleukin 6 receptor (IL-6R), IL-3R, GM colony stimulating factor receptor (GM-CSFR), and erythropoietin receptor (EpR), whereby each HGF upmodulates the R(s) for distal-acting HGF(s). Finally, we have investigated the effect of HGF on reactivation of hemoglobin F (HbF) in clonogenic or liquid suspension serum-free culture of purified adult HP. The results suggest that c-kit ligand (KL) plays a key role in the reactivation of HbF synthesis in adult life, and IL-3/GM-CSF potentiate this effect at low KL level. The KL-induced HbF reactivation is seemingly related to an enhanced proliferation of early E progenitors in their differentiation pathway.