T-SP1: a novel serine protease-like protein predominantly expressed in testis

Here, we describe a novel member in the group of membrane-anchored chymotrypsin (S1)-like serine proteases, namely testis serine protease 1 (T-SP1), as it is principally expressed in testis tissue. The human T-SP1 gene encompasses 28.7 kb on the short arm of chromosome 8 and consists of seven exons. Rapid amplification of cDNA ends ( RACE) experiments revealed that due to alternative splicing three different variants (T-SP1/1, -2, -3) are detectable in testis tissue displaying pronounced heterogeneity at their 3'-end. T-SP1/1 consists of an 18 amino acid signal peptide and of a 49 amino acid propeptide. The following domain with the catalytic triad of His(108), Asp(156), and Ser(250) shares sequence identities of 42% and 40% with the blood coagulation factor XI and plasma kallikrein, respectively. Only T-SP1/1 contains a hydrophobic part at the C-terminus, which provides the basis for cell membrane anchoring. Using a newly generated polyclonal anti-T-SP1 antibody, expression of the T-SP1 protein was found in the Leydig and Sertoli cells of the testis and in the epithelial cells of the ductuli efferentes. Notably, T-SP1 protein was also detectable in prostate cancer and in some ovarian cancer tissues, indicating tumor-related synthesis of T-SP1 beyond testis tissue

Wide-angle seismic transect reveals the crustal structure of(f) southern Sri Lanka

We present results derived from a seismic refraction experiment and gravity measurements about the upper mantle and crustal structure of southern Sri Lanka and the adjacent Indian Ocean. A P-wave velocity model was derived using forward modelling of the observed travel times along a 509 km long, N-S trending profile at 81°E longitude. Our results show that the continental crust below southern Sri Lanka is up to 38 km thick. A ~65 km wide transition zone, which thins seaward to ~7 km thickness, divides stretched continental from oceanic crust. The adjacent, 4.7 to 7 km thick normal oceanic crust is covered by up to 4 km thick sediments. The oceanic crust is characterized by intra-crustal reflections and displays P-wave velocity variations, especially in oceanic layer 2, along our profile. In the central part of the profile, the uppermost mantle layer is characterized by normal P-wave mantle velocities of 8.0 -8.1 km/s. At the southern end of the profile, unusual low upper mantle seismic velocities, ranging from 7.5 to 7.6 km/s only, characterize the uppermost mantle layer. These low upper mantle velocities are probably caused by serpentinized upper mantle. At even greater depths the upper mantle layer is characterized by velocities of 8.3 km/s on average. The type of margin along our profile is difficult to identify, since it is characterized by features typical for different types of margins

Gas hydrate distribution and hydrocarbon maturation north of the Knipovich Ridge, western Svalbard margin

A bottom-simulating reflector (BSR) occurs west of Svalbard in water depths exceeding 600 m, indicating that gas hydrate occurrence in marine sediments is more widespread in this region than anywhere else on the eastern North Atlantic margin. Regional BSR mapping shows the presence of hydrate and free gas in several areas, with the largest area located north of the Knipovich Ridge, a slow-spreading ridge segment of the Mid Atlantic Ridge system. Here, heat flow is high (up to 330 mW m-2), increasing towards the ridge axis. The coinciding maxima in across-margin BSR width and heat flow suggest that the Knipovich Ridge influenced methane generation in this area. This is supported by recent finds of thermogenic methane at cold seeps north of the ridge termination. To evaluate the source rock potential on the western Svalbard margin, we applied 1D petroleum system modeling at three sites. The modeling shows that temperature and burial conditions near the ridge were sufficient to produce hydrocarbons. The bulk petroleum mass produced since the Eocene is at least 5 kt and could be as high as ~0.2 Mt. Most likely, source rocks are Miocene organic-rich sediments and a potential Eocene source rock that may exist in the area if early rifting created sufficiently deep depocenters. Thermogenic methane production could thus explain the more widespread presence of gas hydrates north of the Knipovich Ridge. The presence of microbial methane on the upper continental slope and shelf indicates that the origin of methane on the Svalbard margin varies spatially

Mesenchymal stromal cell and bone marrow concentrate therapies for musculoskeletal indications: a concise review of current literature

The interest on applying mesenchymal stromal cells (MSCs) in orthopedic disorders has risen tremendously in the last years due to scientific successes in preclinical in vitro and animal model studies. In a wide range of diseases and injuries of the musculoskeletal system, MSCs are currently under evaluation, but so far have found access to clinical use only in few cases. The current assignment is to translate the acquired knowledge into clinical practice. Therefore, this review aims at presenting a synopsis of the up-to-date status of the use of MSCs and MSC related cell products in musculoskeletal indications. Clinical studies were included, whereas preclinical and animal study data not have been considered. Most studies published so far investigate the final outcome applying bone marrow derived MSCs. In fewer trials the use of adipose tissue derived MSCs and allogenic MSCs was investigated in different applications. Although the reported results are equivocal in the current literature, the vast majority of the studies shows a benefit of MSC based therapies depending on the cell sources and the indication in clinical use. In summary, the clinical use of MSCs in patients in orthopedic indications has been found to be safe. Standardized protocols and clear definitions of the mechanisms of action and the mode and timing of application as well as further coordinated research efforts will be necessary for finally adding MSC based therapies in standard operating procedures and guidelines for the clinicians treating orthopedic disorders

HIPGEN: a randomized, multicentre phase III study using intramuscular PLacenta-eXpanded stromal cells therapy for recovery following hip fracture arthroplasty : a study design

Aims The aim of the HIPGEN consortium is to develop the first cell therapy product for hip fracture patients using PLacental-eXpanded (PLX-PAD) stromal cells. Methods HIPGEN is a multicentre, multinational, randomized, double-blind, placebo-controlled trial. A total of 240 patients aged 60 to 90 years with low-energy femoral neck fractures (FNF) will be allocated to two arms and receive an intramuscular injection of either 150 × 106 PLX-PAD cells or placebo into the medial gluteal muscle after direct lateral implantation of total or hemi hip arthroplasty. Patients will be followed for two years. The primary endpoint is the Short Physical Performance Battery (SPPB) at week 26. Secondary and exploratory endpoints include morphological parameters (lean body mass), functional parameters (abduction and handgrip strength, symmetry in gait, weightbearing), all-cause mortality rate and patient-reported outcome measures (Lower Limb Measure, EuroQol five-dimension questionnaire). Immunological biomarker and in vitro studies will be performed to analyze the PLX-PAD mechanism of action. A sample size of 240 subjects was calculated providing 88% power for the detection of a 1 SPPB point treatment effect for a two-sided test with an α level of 5%. Conclusion The HIPGEN study assesses the efficacy, safety, and tolerability of intramuscular PLX-PAD administration for the treatment of muscle injury following arthroplasty for hip fracture. It is the first phase III study to investigate the effect of an allogeneic cell therapy on improved mobilization after hip fracture, an aspect which is in sore need of addressing for the improvement in standard of care treatment for patients with FNF

Individual Effector/Regulator T Cell Ratios Impact Bone Regeneration

There is increasing evidence that T lymphocytes play a key role in controlling endogenous regeneration. Regeneration appears to be impaired in case of local accumulation of CD8+ effector T cells (TEFF), impairing endogenous regeneration by increasing a primary "useful" inflammation toward a damaging level. Thus, rescuing regeneration by regulating the heightened pro-inflammatory reaction employing regulatory CD4+ T (TReg) cells could represent an immunomodulatory option to enhance healing. Hypothesis was that CD4+ TReg might counteract undesired effects of CD8+ TEFF. Using adoptive TReg transfer, bone healing was consistently improved in mice possessing an inexperienced immune system with low amounts of CD8+ TEFF. In contrast, mice with an experienced immune system (high amounts of CD8+ TEFF) showed heterogeneous bone repair with regeneration being dependent upon the individual TEFF/TReg ratio. Thus, the healing outcome can only be improved by an adoptive TReg therapy, if an unfavorable TEFF/TReg ratio can be reshaped; if the individual CD8+ TEFF percentage, which is dependent on the individual immune experience can be changed toward a favorable ratio by the TReg transfer. Remarkably, also in patients with impaired fracture healing the TEFF/TReg ratio was higher compared to uneventful healers, validating our finding in the mouse osteotomy model. Our data demonstrate for the first time the key-role of a balanced TEFF/TReg response following injury needed to reach successful regeneration using bone as a model system. Considering this strategy, novel opportunities for immunotherapy in patients, which are at risk for impaired healing by targeting TEFF cells and supporting TReg cells to enhance healing are possible

Heat stress reduces the contribution of diazotrophs to coral holobiont nitrogen cycling

Efficient nutrient cycling in the coral-algal symbiosis requires constant but limited nitrogen availability. Coral-associated diazotrophs, i.e., prokaryotes capable of fixing dinitrogen, may thus support productivity in a stable coral-algal symbiosis but could contribute to its breakdown when overstimulated. However, the effects of environmental conditions on diazotroph communities and their interaction with other members of the coral holobiont remain poorly understood. Here we assessed the effects of heat stress on diazotroph diversity and their contribution to holobiont nutrient cycling in the reef-building coral Stylophora pistillata from the central Red Sea. In a stable symbiotic state, we found that nitrogen fixation by coral-associated diazotrophs constitutes a source of nitrogen to the algal symbionts. Heat stress caused an increase in nitrogen fixation concomitant with a change in diazotroph communities. Yet, this additional fixed nitrogen was not assimilated by the coral tissue or the algal symbionts. We conclude that although diazotrophs may support coral holobiont functioning under low nitrogen availability, altered nutrient cycling during heat stress abates the dependence of the coral host and its algal symbionts on diazotroph-derived nitrogen. Consequently, the role of nitrogen fixation in the coral holobiont is strongly dependent on its nutritional status and varies dynamically with environmental conditions.Peer reviewe

Cardiac magnetic resonance findings predict increased resource utilization in elective coronary artery bypass grafting

Morbidity following CABG (coronary artery bypass grafting) is difficult to predict and leads to increased healthcare costs. We hypothesized that pre-operative CMR (cardiac magnetic resonance) findings would predict resource utilization in elective CABG. Over a 12-month period, patients requiring elective CABG were invited to undergo CMR 1 day prior to CABG. Gadolinium-enhanced CMR was performed using a trueFISP inversion recovery sequence on a 1.5 tesla scanner (Sonata; Siemens). Clinical data were collected prospectively. Admission costs were quantified based on standardized actual cost/day. Admission cost greater than the median was defined as 'increased'. Of 458 elective CABG cases, 45 (10%) underwent pre-operative CMR. Pre-operative characteristics [mean (S.D.) age, 64 (9) years, mortality (1%) and median (interquartile range) admission duration, 7 (6–8) days] were similar in patients who did or did not undergo CMR. In the patients undergoing CMR, eight (18%) and 11 (24%) patients had reduced LV (left ventricular) systolic function by CMR [LVEF (LV ejection fraction) <55%] and echocardiography respectively. LE (late enhancement) with gadolinium was detected in 17 (38%) patients. The average cost/day was $2723. The median (interquartile range) admission cost was$19059 ($10891–157917). CMR LVEF {OR (odds ratio), 0.93 [95% CI (confidence interval), 0.87–0.99]; P=0.03} and SV (stroke volume) index [OR 1.07 (95% CI, 1.00–1.14); P=0.02] predicted increased admission cost. CMR LVEF (P=0.08) and EuroScore tended to predict actual admission cost (P=0.09), but SV by CMR (P=0.16) and LV function by echocardiography (P=0.95) did not. In conclusion, in this exploratory investigation, pre-operative CMR findings predicted admission duration and increased admission cost in elective CABG surgery. The cost-effectiveness of CMR in risk stratification in elective CABG surgery merits prospective assessment

Chronology of the Fram Slide Complex offshore NW Svalbard and its implications for local and regional slope stability

Highlights • The Fram Slide Complex has been active from late Miocene to late Pleistocene. • Local processes were critical for slope stability in the Fram Strait area. • Toe erosion caused by normal faulting may have led to retrogressive failure. • Low gradient contourite drifts might smooth and stabilize submarine slopes. • Low tsunami potential from the Fram Slide Complex could increase in the future. Abstract The best known submarine landslides on the glaciated NW European continental margins are those at the front of cross-shelf troughs, where the alternation of rapidly deposited glycogenic and hemi pelagic material generates sedimentary overpressure. Here, we investigate landslides in two areas built of contourite drifts bounded seaward by a ridge-transform junction. Seismic and bathymetric data from the Fram Slide Complex are compared with the tectonically similar Vastness area ~ 120 km to the south, to analyze the influence of local and regional processes on slope stability. These processes include tectonic activity, changes of climate and oceanography, gas hydrates and fluid migration systems, slope gradient, toe erosion and style of contourite deposition. Two areas within the Fram Slide Complex underwent different phases of slope failures, whereas there is no evidence at all for major slope failures in the Vastness area. The comparison cannot reveal the distinct reason for slope failure but demonstrates the strong impact of variation in the local controls on slope stability. The different failure chronologies suggest that toe erosion, which is dependent on the throw of normal faults, and the different thickness and geometry of contourite deposits can result in a critical slope morphology and exert pronounced effects on slope stability. These results highlight the limitations of regional hazard assessments and the need for multi-disciplinary investigations, as small differences in local controlling factors led to substantially different slope failure histories