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Before regulation, the White Nile contributed 83% of the low water flow to the main Nile and was responsible for maintaining the Nile as a perennial river during times of drought in Ethiopia. Two key unresolved questions relating to the White Nile are: (a) When did the White Nile first join the main Nile? (b) What type of sediment did the White Nile contribute to the main Nile? The answer to the first question has important implications for our understanding of hydro–climatic and tectonic events in the Ugandan Lake Plateau. The answer to the second question is essential for correctly interpreting the sedimentary record preserved in the Nile deep sea fan in the eastern Mediterranean. Our work has shown for the first time that the White Nile has been transporting smectite–rich sediments from the time of its probable inception over 240 ka ago and possibly since about 400 ka. Our analysis of the heavy mineral assemblages in White Nile alluvial sediments provides strong support for a source in the Lake Plateau region of Uganda. The White Nile was flowing from Uganda by at least 240 ka and very likely from about 400 ka.

Penetrating traumatic injuries can present a challenging scenario due to the potential for multisystem involvement requiring swift collaboration between surgical specialities. We present the case of a 66-year-old female who was stabbed in the right posterior chest. CT revealed a diaphragmatic injury, liver laceration involving segments 6/7 with active bleeding, and a posterior superior mesenteric artery (SMA) to anterior inferior vena cava (IVC) fistula. Due to the proximity of the SMA injury to a replaced right hepatic artery origin, the fistulous connection with the suprarenal IVC, and suspected pancreatic and duodenal injuries, a hybrid rather than a purely endovascular approach was taken. A large compliant occlusion balloon was placed percutaneously in the hepatic IVC. Subsequent trauma laparotomy and right medial visceral rotation identified SMA and SMV injuries, which were repaired with temporary supracoeliac aortic clamping. Further kocherisation of the duodenum revealed a 10 cm longitudinal IVC laceration causing sudden large volume venous haemorrhage. This was repaired after control was gained with supracoeliac aortic clamping, infrarenal IVC vessel loop and balloon inflation. An abdominal VAC dressing was applied. Before transfer to ICU, however, 1L of blood was noted in the VAC cannister and a relook laparotomy demonstrated more than 1L of intrabdominal fresh blood. Bleeding vessels around the uncinate process were ligated. After 48 hours, a relook laparotomy revealed no significant bleeding, and the abdomen was closed. A post-operative MRCP demonstrated pancreatic divisum and likely laceration of the aberrant ventral duct. A subsequent peripancreatic collection was managed conservatively.

Dental caries and periodontal disease are very common chronic diseases closely linked to inadequate removal of dental plaque. Powered toothbrushes are viewed as more effective at removing plaque; however, the conflicting evidence and considerable unexplained heterogeneity in their clinical outcomes does not corroborate the relative merits of powered tooth brushing. To explain the heterogeneity of brushing patterns with powered toothbrushes, we conducted a observational study of tooth brushing practices of 12 participants in their naturalistic setting. Integrated brush sensors and a digital data collection platform allowed unobtrusive and accurate capture of habitual brushing patterns. Annotated brushing data from 10 sessions per participant was chosen for scrutiny of brushing patterns. Analysis of brushing patterns from the total 120 sessions revealed substantial between- and within-participant variability in brushing patterns and efficiency. Most participants (91.67%) brushed for less than the generally prescribed two minutes; individual participants were also inconsistent in brushing duration across sessions. The time devoted to brushing different dental regions was also quite unequal. Participants generally brushed their buccal tooth surfaces more than twice as long as the occlusal (2.18 times longer (95% CI 1.42, 3.35; p < 0.001)) and lingual surfaces (2.22 times longer (95% CI 1.62, 3.10; p < 0.001); the lingual surfaces of the maxillary molars were often neglected (p < 0.001). Participants also varied in the epochs of excessive brushing pressure and the regions to which they were applied. In general, the occlusal surfaces were more likely to be brushed with excessive pressure (95% CI 0.10, 0.98; p = 0.015). Our study reveals that users of powered toothbrushes vary substantially in their use of the toothbrushes and diverge from recommended brushing practices. The inconsistent brushing patterns, between and within individuals, can affect effective plaque removal. Our findings underscore the limited uptake of generic oral self-care recommendations and emphasize the need for personalized brushing recommendations that derive from the objective sensor data provided by powered toothbrushes.

SOS is a key activator of the small GTPase Ras. In cells, SOS-Ras signaling is thought to be initiated predominantly by membrane recruitment of SOS via the adaptor Grb2 and balanced by rapidly reversible Grb2-SOS binding kinetics. However, SOS has multiple protein and lipid interactions that provide linkage to the membrane. In reconstituted-membrane experiments, these Grb2-independent interactions were sufficient to retain human SOS on the membrane for many minutes, during which a single SOS molecule could processively activate thousands of Ras molecules. These observations raised questions concerning how receptors maintain control of SOS in cells and how membrane-recruited SOS is ultimately released. We addressed these questions in quantitative assays of reconstituted SOS-deficient chicken B-cell signaling systems combined with single-molecule measurements in supported membranes. These studies revealed an essentially one-way trafficking process in which membrane-recruited SOS remains trapped on the membrane and continuously activates Ras until being actively removed via endocytosis.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner.

We introduce a novel approach to analyse and assess the structural framework of ore deposits that fully integrates 3D implicit modelling in data-rich environments with field observations. We apply this approach to the early Palaeozoic Navachab gold deposit which is located in the Damara orogenic belt, Namibia. Compared to traditional modelling methods, 3D implicit modelling reduces user-based modelling bias by generating open or closed surfaces from geochemical, lithological or structural data without manual digitisation and linkage of sections or level plans. Instead, a mathematically defined spatial interpolation is used to generate 3D models that show trends and patterns that are embedded in large drillhole datasets. In our 3D implicit model of the Navachab gold deposit, distinctive high-grade mineralisation trends were identified and directly related to structures observed in the field. The 3D implicit model and field data suggest that auriferous semi-massive sulphide ore shoots formed near the inflection line of the steep limb of a regional scale dome, where shear strain reached peak values during fold amplification. This setting generated efficient conduits and traps for hydrothermal fluids and associated mineralisation that led to the formation of the main ore shoots in the deposit. Both bedding-parallel and highly discordant sets of auriferous quartz-sulphide veins are interpreted to have formed during the later lock-up stage of the regional scale dome. Additionally, pegmatite dykes crosscut and remobilise gold mineralisation at the deposit scale and appear to be related to a younger joint set. We propose that kilometre-scale active folding is an important deformation mechanism that influences the spatial distribution and orientation of mineralisation in ore deposits by forming structures (traps and pathways for fluids) at different preferred sites and orientations. We also propose that areas that experience high shear strain, located along the inflection lines of folds can act as preferred sites for syn-deformational hydrothermal mineralisation and should be targeted for regional scale exploration in fold and thrust belts. Our research also suggests that examination of existing drillhole datasets using 3D implicit modelling is a powerful tool for spatial analysis of mineralisation patterns. When combined with fieldwork, this approach has the potential to improve structural understanding of a variety of ore deposits.

T cell receptor (TCR) stimulation activates diverse kinase pathways, which include the mitogen-activated protein kinases (MAPKs) ERK and p38, the phosphoinositide 3-kinases (PI3Ks), and the kinase mTOR. Although TCR stimulation activates the p38 pathway through a "classical" MAPK cascade that is mediated by the adaptor protein LAT, it also stimulates an "alternative" pathway in which p38 is activated by the kinase ZAP70. Here, we used dual-parameter, phosphoflow cytometry and in silico computation to investigate how both classical and alternative p38 pathways contribute to T cell activation. We found that basal ZAP70 activation in resting T cell lines reduced the threshold ("primed") TCR-stimulated activation of the classical p38 pathway. Classical p38 signals were reduced after T cell- specific deletion of the guanine nucleotide exchange factors Sos1 and Sos2, which are essential LAT signalosome components. As a consequence of Sos1/2 deficiency, production of the cytokine IL-2 was impaired, differentiation into regulatory T cells was reduced, and the autoimmune disease EAE was exacerbated in mice. These data suggest that the classical and alternative p38 activation pathways exist to generate immune balance.

This case report describes a noncontact traffic accident involving a motor scooter and a tractor-trailer with a focus on the wind-drag effect. We used load cells to measure the drag force acting on a substantially similar motor scooter when a substantially similar tractor-trailer passes by it, taking into consideration various speeds of the tractor-trailer and distances between the two vehicles. A three-dimensional steady-state flow analysis was also performed by using the CFX program for computational fluid dynamics to examine the streamlines and the pressure distribution around the tractor-trailer at various speeds. From the experiment, for a separation distance of 1.0 m (3.28 ft) and a speed of 90 km/h (55.9 mph), the maximum resultant drag force is 124.5 N (28 lb); this constitutes a degree of force that could abruptly disrupt the stability in maneuvering by an operator who is unaware of the approaching tractor-trailer. In addition, a single equation that relates the tractor-trailer speed to the drag force that acts on the motor scooter was derived on the basis of the Reynolds number (Re) and the wind-drag coefficient (C(d)): C(d) = 1.298 × 10(-7) Re.

Summary Background. Hyaluronan (HA), a major extracellular matrix component in epidermis, has been found to accumulate in the epidermis after disruption of the epidermal barrier; however, the precise mechanisms underlying this process are not yet clear. Alterations in the epidermal calcium gradient are an important signal for permeability-barrier homeostasis. Thus, we hypothesized that epidermal calcium-ions might regulate HA expression. Aim. To investigate whether changes in the epidermal calcium gradient and subsequent induction of cytokines regulate HA, HA synthase (HAS) and HA receptor (CD44) expression in mouse epidermis, and to clarify the mechanisms of HA induction. Methods. Sonophoresis of 1.5 mmol/L Ca2+-containing gel or Ca2+-free gel was performed to manipulate the epidermal Ca2+ content without disrupting the permeability barrier. We also manipulated the Ca2+ gradient by tape-stripping with or without 2 h immersion in 1.2 mmol/L Ca2+-containing solutions. Next we inhibited cytokine activity using tumour necrosis factor (TNF)-α or interleukin (IL)-1 inhibitors before sonophoresis. Six hours after each treatment, the expression of HA, HAS and CD44 were analysed using reverse transcription PCR and immunohistochemical stains. Results. Sonophoresis of Ca2+-free gel significantly increased HA, HAS3 and CD44 expression in epidermis and in tape-stripped skin. However, the inhibition of Ca2+ decrease in the upper epidermis by sonophoresis of Ca2+-containing gel or immersion of barrier-disrupted skin into a Ca2+-containing solution attenuated these inductions. Specific inhibitors of TNF-α and IL-1 specific inhibitors also abolished the sonophoresis-induced expression of HA, HAS3 and CD44. Conclusions. These results suggest that modulations in epidermal calcium regulate HA and CD44 expression directly or via induction of cytokines.

Divergent hypotheses exist to explain how signaling by the B cell receptor (BCR) is initiated after antigen binding and how it is qualitatively altered in anergic B cells to selectively uncouple from nuclear factor κB and c-Jun N-terminal kinase pathways while continuing to activate extracellular signal–regulated kinase and calcium–nuclear factor of activated T cell pathways. Here we find that BCRs on anergic cells are endocytosed at a very enhanced rate upon binding antigen, resulting in a large steady-state pool of intracellularly sequestered receptors that appear to be continuously cycling between surface and intracellular compartments. This endocytic mechanism is exquisitely sensitive to the lowering of plasma membrane cholesterol by methyl-β-cyclodextrin, and, when blocked in this way, the sequestered BCRs return to the cell surface and RelA nuclear accumulation is stimulated. In contrast, when plasma membrane cholesterol is lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by rapid receptor internalization.

Interpreted either as a folded igneous sheet or a basin-shaped intrusion, the origin of the Palaeoproterozoic Sudbury Igneous Complex (SIC), Ontario, Canada, has been debated by geologists for over a century. Most recent proposals view the SIC to have been emplaced as a horizontal impact melt and subsequently folded after solidification. This requires the SIC to have folded from an originally horizontal sheet, to the present basinal geometry, with dips of 30° in the North Range and 70° in the East Range. The fold scenario would require the sharply curved juncture between the North and East Ranges (North Lobe) to be deformed in the solid-state due to folding. In order to test the fold model, the rock fabric was investigated in the East and North Ranges and the North Lobe of SIC at 256 sites with the aid of anisotropy of magnetic susceptibility (AMS). A sampling transect through an undeformed portion of the SIC in the western North Range reveals that the gabbro-norite exhibits SIC contact-parallel magnetic foliation and down-dip magnetic lineation, both of which, respectively, correlate to an igneous foliation and lineation. The granophyre, in contrast, features spatially consistent magnetic lineation that is oriented orthogonal to the SIC contact. This magnetic lineation can be correlated to a mineral fabric characterised by aligned acicular crystals of plagioclase, and is interpreted to be a wall-orthogonal crystallisation texture. The East and North Ranges in the eastern SIC reveal similar patterns of AMS fabrics. The magnetic lineation of the granophyre is orthogonal to the basal contact of the SIC in the East and North Ranges, and in the fold-like North Lobe between the two ranges. An axial-planar magnetic foliation is developed in the granophyre as the North Lobe is approached, but the magnetic lineation is nevertheless contact-orthogonal and well-defined. This AMS fabric is interpreted to be a combination of an original igneous contact-orthogonal lineation and a foliation resulting from tectonic overprint. The preservation of the contact-orthogonal magnetic lineation implies low levels of tectonic overprint. Conservative shortening strains estimated from AMS numerical modelling suggest

The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells.

Thymocytes convert graded T cell receptor (TCR) signals into positive selection or deletion, and activation of extracellular signal-related kinase (ERK), p38, and Jun N-terminal protein kinase (JNK) mitogen-activated protein kinases (MAPKs) has been postulated to play a discriminatory role. Two families of Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP, activate Ras and the downstream RAF-MEK-ERK pathway. The pathways leading to lymphocyte p38 and JNK activation are less well defined. We previously described how RasGRP alone induces analog Ras-ERK activation while SOS and RasGRP cooperate to establish bimodal ERK activation. Here we employed computational modeling and biochemical experiments with model cell lines and thymocytes to show that TCR-induced ERK activation grows exponentially in thymocytes and that a W729E allosteric pocket mutant, SOS1, can only reconstitute analog ERK signaling. In agreement with RasGRP allosterically priming SOS, exponential ERK activation is severely decreased by pharmacological or genetic perturbation of the phospholipase Cγ (PLCγ)-diacylglycerol-RasGRP1 pathway. In contrast, p38 activation is not sharply thresholded and requires high-level TCR signal input. Rac and p38 activation depends on SOS1 expression but not allosteric activation. Based on computational predictions and experiments exploring whether SOS functions as a RacGEF or adaptor in Rac-p38 activation, we established that the presence of SOS1, but not its enzymatic activity, is critical for p38 activation.

Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper-responsive to a variety of laboratory stress conditions.This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS-constipation and 21 IBS-diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject's results were synchronized to the first onset of stage 2 sleep.Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS.This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS.

Histone deacetylases (HDACs) are associated with the development and progression of cancer, but it is not known which of the HDAC isoforms play important roles in breast cancer metastasis. This study identified the specific HDAC isoforms that are necessary for invasion and/or migration in human breast cancer cell lines. MDA-MB-231 cells were significantly more invasive and expressed higher levels of matrix metalloproteinase-9 (MMP-9) compared to MCF-7 cells. We compared the expression of HDAC isoforms between MCF-7 and MDA-MB-231 cells and found greater expression of HDAC4, 6 and 8 in MDA-MB-231 cells by RT-PCR and Western blot analyses. In addition, apicidin, a histone deacetylase inhibitor, was shown to attenuate the invasion, migration and MMP-9 expression in MDA-MB-231 cells. Using specific siRNAs directed against HDAC1, 4, 6 and 8, we show that inhibition of HDAC1, 6 and 8, but not HDAC4, are responsible for invasion and MMP-9 expression in MDA-MB-231 cells. We analyzed the invasiveness of MCF-7 cells overexpressing HDAC1, 4, 6 or 8 and found that overexpression of HDAC1, 6 or 8 increased invasion and MMP-9 expression. By developing HDAC isoforms as potential biomarkers for breast cancer metastasis, the present study can be extended to developing therapies for breast cancer invasion.

The north-south trending Permo-Triassic Sydney Basin (southern sector of the Sydney-Bowen Basin) is unique compared to many documented retro-arc foreland basins, in that considerable basin-fill was derived from a cratonic source as well as a coeval fold belt source. Quantitative analysis of up-sequence changes in sandstone petrography and palaeoflow directions, together with time-rock stratigraphy of the fluvial basin-fill, indicate two spatially and temporally separated depositional episodes of longitudinal fluvial dispersal systems. A longitudinal drainage-net similar in geometry to the modern Ganga River system (reduced to 60% original size) explains many of the palaeoflow patterns and cross-basinal petrofacies variation recorded in the basin-fill. The Late Permian to Early Triassic rocks reveal a basin-wide southerly directed fluvial drainage system, contemporaneous with east-west shortening recorded in the New England Fold Belt. In contrast, the Middle Triassic strata reveal a change to an easterly directed fluvial system, correlated to a shift in orogenic load to a NW-SE orientation in the fold belt northeast of the basin. The detailed petrofacies variation in the deposits of the second longitudinal fluvial dispersal system reveals vertical jumps in petrofacies compositions, with uniform compositions between jumps. The petrological jumps are interpreted as the result of minor fault adjustments in the fold belt, resulting in changing rates of sediment supply to the foreland basin. Uninterrupted erosion of the same terrain most likely caused the compositional uniformity between jumps. The identification of similar longitudinal fluvial systems, with transverse variation in detrital composition, is likely to help resolve the tectonic history of foreland fold belts elsewhere.