CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling

RAF kinase functions in the mitogen-activated protein kinase (MAPK) pathway to transmit growth signals to the downstream kinases MEK and ERK. Activation of RAF catalytic activity is facilitated by a regulatory complex comprising the proteins CNK (Connector enhancer of KSR), HYP (Hyphen), and KSR (Kinase Suppressor of Ras). The sterile alpha-motif (SAM) domain found in both CNK and HYP plays an essential role in complex formation. Here, we have determined the x-ray crystal structure of the SAM domain of CNK in complex with the SAM domain of HYP. The structure reveals a single-junction SAM domain dimer of 1:1 stoichiometry in which the binding mode is a variation of polymeric SAM domain interactions. Through in vitro and in vivo mutational analyses, we show that the specific mode of dimerization revealed by the crystal structure is essential for RAF signaling and facilitates the recruitment of KSR to form the CNK/HYP/KSR regulatory complex. We present two docking-site models to account for how SAM domain dimerization might influence the formation of a higher-order CNK/HYP/KSR complex.     

An audit on HIV antibody test uptake amongst GUM clinic attendees in the West Midland region

We audited the practice of offering, and the uptake of, an HIV antibody test amongst genitourinary medicine clinic patients in the West Midlands region. There were wide variations in the offering (from 14 to 100%) and uptake (18 to 64%) of the test in the different clinics within the same region.     

l -Arginine Can Enhance the Beneficial Effect of Losartan in Patients with Chronic Aortic Regurgitation and Isolated Systolic Hypertension

Information about the effects of angiotensin II receptor blocker (ARB) therapy on the hemodynamic and cardiac structure in patients with chronic aortic regurgitation (CAR) and isolated systolic hypertension (ISH) is limited. This study planned to test the hypothesis that l -arginine could further enhance the beneficial effect of an ARB, losartan, and provide a favorable effect on the natural history of CAR and ISH. Sixty patients with CAR and ISH were enrolled in a randomized, double-blind trial comparing hemodynamic and ultrasonic change in two treatment arms: losartan +  l -arginine and losartan-only treated groups. Serial echocardiographic and hemodynamic studies were evaluated before and after treatment. Both groups had a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP), left ventricular end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), LV mass index (LVMI), and LV mean wall stress after 6- and 12-month treatment ( p <0.01 in all comparisons). Both groups had a significant increase in LV ejection fraction and exercise duration after 6- and 12-month treatment ( p  < 0.01 in all comparisons). Using multivariate linear regression analysis, only losartan +  l -arginine therapy achieved a significantly lower LVESVI (38.89 ± 0.23 mL/m ² ), LVEDVI (102.3 ± 0.3 mL/m ² ), LVMI (107.6 ± 0.3 g/m ² ), SBP (123.5 ± 1.0 mm Hg), and greater exercise duration (7.38 ± 0.02 minutes) than those of the losartan-only treated groups ( p <0.01 in all comparisons). These findings suggest that early co-administrative strategy provides a beneficial approach to favorably influence the natural history of CAR.     

A humid corridor across the Sahara for the migration of early modern humans out of Africa 120,000 years ago

It is widely accepted that modern humans originated in sub-Saharan Africa approximately 150-200 thousand years ago (ka), but their route of dispersal across the currently hyperarid Sahara remains controversial. Given that the first modern humans north of the Sahara are found in the Levant approximately 120-90 ka, northward dispersal likely occurred during a humid episode in the Sahara within Marine Isotope Stage (MIS) 5e (130-117 ka). The obvious dispersal route, the Nile, may be ruled out by notable differences between archaeological finds in the Nile Valley and the Levant at the critical time. Further west, space-born radar images reveal networks of-now buried-fossil river channels that extend across the desert to the Mediterranean coast, which represent alternative dispersal corridors. These corridors would explain scattered findings at desert oases of Middle Stone Age Aterian lithic industries with bifacial and tanged points that can be linked with industries further to the east and as far north as the Mediterranean coast. Here we present geochemical data that demonstrate that water in these fossil systems derived from the south during wet episodes in general, and penetrated all of the way to the Mediterranean during MIS 5e in particular. This proves the existence of an uninterrupted freshwater corridor across a currently hyperarid region of the Sahara at a key time for early modern human migrations to the north and out of Africa.     

Lung inflation with direct injection of agarose: a technique for simultaneous molecular and morphometric measurements

The usual methods for preparing lungs for morphologic study involve the instillation of fixatives that modifyproteins and RNA such that the tissue is unsuitable for molecular studies. To develop a technique suitable for molecular studies, pieces of adult rat lungs were infiltrated with agarose, glutaraldehyde, or paraformaldehyde and the consistency of alveolar inflation was compared to lungs inflated with 10% formalin. Only direct injection with 1% agarose resulted in comparable inflation of lung tissue and preserved RNA and protein. Thus, this technique enables simultaneous molecular and morphometric analysis of the lung on small pieces of lung tissue in heterogeneous lung diseases.     

Autonomic cardiovascular responses are impaired in women with irritable bowel syndrome

GOALS: This study characterizes cardiovascular autonomic function in women with irritable bowel syndrome (IBS), using standardized techniques. BACKGROUND: Autonomic dysfunction is believed to contribute to abnormal gastrointestinal motility and visceral hypersensitivity in IBS. There is mounting evidence of generalized impairment of autonomic activity in patients with IBS. STUDY: Thirty women aged 39 years (95% C.I. 25-53 years) diagnosed with IBS, and 30 age-matched healthy women were studied. The ratio of low frequency to high frequency heart rate variability domains (LF:HF ratio) was used to represent cardiac sympathovagal activity, and orthostatic testing and sustained isometric handgrip exercise were used as sympathetic stimuli. Parasympathetic activity was represented by the expiratory to inspiratory R-R interval (E:I) ratio during deep breathing at 6 minutes. RESULTS: LF:HF responses to handgrip exercise (316%, C.I. 134% to 498% vs. 107%, C.I. 15% to 153%; P < 0.05) and orthostatic testing (648%, C.I. 520% to 904% vs. 330%, C.I. 140% to 520%; P < 0.05) were higher in IBS patients than controls, and the E:I ratio was significantly lower (1.47, C.I. 1.33-1.61 vs. 1.20, C.I. 1.14-1.26; P < 0.01). CONCLUSIONS: Autonomic cardiovascular function is impaired in IBS, manifest as attenuated cardio-vagal tone, and relative sympathetic excess during stimulated conditions.     

From the Cover: A Middle Eocene lowland humid subtropical “Shangri-La” ecosystem in central Tibet

Tibet’s ancient topography and its role in climatic and biotic evolution remain speculative due to a paucity of quantitative surface-height measurements through time and space, and sparse fossil records. However, newly discovered fossils from a present elevation of ∼4,850 m in central Tibet improve substantially our knowledge of the ancient Tibetan environment. The 70 plant fossil taxa so far recovered include the first occurrences of several modern Asian lineages and represent a Middle Eocene (∼47 Mya) humid subtropical ecosystem. The fossils not only record the diverse composition of the ancient Tibetan biota, but also allow us to constrain the Middle Eocene land surface height in central Tibet to ∼1,500 ± 900 m, and quantify the prevailing thermal and hydrological regime. This “Shangri-La”–like ecosystem experienced monsoon seasonality with a mean annual temperature of ∼19 °C, and frosts were rare. It contained few Gondwanan taxa, yet was compositionally similar to contemporaneous floras in both North America and Europe. Our discovery quantifies a key part of Tibetan Paleogene topography and climate, and highlights the importance of Tibet in regard to the origin of modern Asian plant species and the evolution of global biodiversity.

The Tibetan Plateau, once thought of as entirely the product of the India–Eurasia collision, is known to have had significant complex relief before the arrival of India early in the Paleogene (1–3). This large region, spanning ∼2.5 million km², is an amalgam of tectonic terranes that impacted Asia long before India’s arrival (4, 5), with each accretion contributing orographic heterogeneity that likely impacted climate in complex ways. During the Paleogene, the Tibetan landscape comprised a high (>4 km) Gangdese mountain range along the southern margin of the Lhasa terrane (2), against which the Himalaya would later rise (6), and a Tanghula upland on the more northerly Qiangtang terrane (7). Separating the Lhasa and Qiangtang blocks is the east–west trending Banggong-Nujiang Suture (BNS), which today hosts several sedimentary basins (e.g., Bangor, Nyima, and Lunpola) where >4 km of Cenozoic sediments have accumulated (8). Although these sediments record the climatic and biotic evolution of central Tibet, their remoteness means fossil collections have been hitherto limited. Recently, we discovered a highly diverse fossil assemblage in the Bangor Basin. These fossils characterize a luxuriant seasonally wet and warm Shangri-La forest that once occupied a deep central Tibetan valley along the BNS, and provide a unique opportunity for understanding the evolutionary history of Asian biodiversity, as well as for quantifying the paleoenvironment of central Tibet.^*Details of the topographic evolution of Tibet are still unclear despite decades of investigation (4, 5). Isotopic compositions of carbonates recovered from sediments in some parts of central Tibet have been interpreted in terms of high (>4 km) Paleogene elevations and aridity (9, 10), but those same successions have yielded isolated mammal (11), fish (12), plant (13–18), and biomarker remains (19) more indicative of a low (≤3-km) humid environment, but how low is poorly quantified. Given the complex assembly of Tibet, it is difficult to explain how a plateau might have formed so early and then remained as a surface of low relief during subsequent compression from India (20). Recent evidence from a climate model-mediated interpretation of palm fossils constrains the BNS elevation to below 2.3 km in the Late Paleogene (16), but more precise paleoelevation estimates are required. Further fossil discoveries, especially from earlier in the BNS sedimentary records, would document better the evolution of the Tibetan biota, as well as informing our understanding of the elevation and climate in an area that now occupies the center of the Tibetan Plateau.Our work shows that the BNS hosted a diverse subtropical ecosystem at ∼47 Ma, and this means the area must have been both low and humid. The diversity of the fossil flora allows us to 1) document floristic links to other parts of the Northern Hemisphere, 2) characterize the prevailing paleoclimate, and 3) quantify the elevation at which the vegetation grew. We propose that the “high and dry” central Tibet inferred from some isotope paleoaltimetry (9, 10) reflects a “phantom” elevated paleosurface (20) because fractionation over the bounding mountains allowed only isotopically light moist air to enter the valley, giving a false indication of a high elevation (21).