Organics in Space: Results from Space Exposure Platforms and Nanosatellites

A series of successful laboratory astrophysics experiments performed on International Space Station(ISS) external platforms such as EXPOSE have provided insights into the evolution of organic and biological materials in space and planetary environments. The study of the reactions, destruction, and longevity of organics in the space environment is of fundamental interest. To provide an accurate outer space environment for extended durations, exposure experiments in low Earth orbit have been conducted in the last decades in order to examine the consequences of actual space conditions including combinations of solar and cosmic radiation, space vacuum, and microgravity. The OOREOS (OrganismORganic Exposure to Orbital Stresses) nanosatellite studied in situ during the 6-month primary and 1-year extended mission the photochemical processing of selected PAHs in low Earth orbit (650 km altitude); results were autonomously telemetered to Earth. We report on the methods and flight preparation of samples for space exposure platforms and results on the stability of organic thin-films. The UV-vis degradation process of thin-films was recorded over time, which revealed intriguing and counter-intuitive photolytic kinetics that will be re-investigated on the ISS in a space environment

Hereditary sensory neuropathy type I

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma. Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease

Anthropogenic, Direct Pressures on Coastal Wetlands

Coastal wetlands, such as saltmarshes and mangroves that fringe transitional waters, deliver important ecosystem services that support human development. Coastal wetlands are complex social-ecological systems that occur at all latitudes, from polar regions to the tropics. This overview covers wetlands in five continents. The wetlands are of varying size, catchment size, human population and stages of economic development. Economic sectors and activities in and around the coastal wetlands and their catchments exert multiple, direct pressures. These pressures affect the state of the wetland environment, ecology and valuable ecosystem services. All the coastal wetlands were found to be affected in some ways, irrespective of the conservation status. The main economic sectors were agriculture, animal rearing including aquaculture, fisheries, tourism, urbanization, shipping, industrial development and mining. Specific human activities include land reclamation, damming, draining and water extraction, construction of ponds for aquaculture and salt extraction, construction of ports and marinas, dredging, discharge of effluents from urban and industrial areas and logging, in the case of mangroves, subsistence hunting and oil and gas extraction. The main pressures were loss of wetland habitat, changes in connectivity affecting hydrology and sedimentology, as well as contamination and pollution. These pressures lead to changes in environmental state, such as erosion, subsidence and hypoxia that threaten the sustainability of the wetlands. There are also changes in the state of the ecology, such as loss of saltmarsh plants and seagrasses, and mangrove trees, in tropical wetlands. Changes in the structure and function of the wetland ecosystems affect ecosystem services that are often underestimated. The loss of ecosystem services impacts human welfare as well as the regulation of climate change by coastal wetlands. These cumulative impacts and multi-stressors are further aggravated by indirect pressures, such as sea-level rise

Anthropogenic, Direct Pressures On Coastal Wetlands

Coastal wetlands, such as saltmarshes and mangroves that fringe transitional waters, deliver important ecosystem services that support human development. Coastal wetlands are complex social-ecological systems that occur at all latitudes, from polar regions to the tropics. This overview covers wetlands in five continents. The wetlands are of varying size, catchment size, human population and stages of economic development. Economic sectors and activities in and around the coastal wetlands and their catchments exert multiple, direct pressures. These pressures affect the state of the wetland environment, ecology and valuable ecosystem services. All the coastal wetlands were found to be affected in some ways, irrespective of the conservation status. The main economic sectors were agriculture, animal rearing including aquaculture, fisheries, tourism, urbanization, shipping, industrial development and mining. Specific human activities include land reclamation, damming, draining and water extraction, construction of ponds for aquaculture and salt extraction, construction of ports and marinas, dredging, discharge of effluents from urban and industrial areas and logging, in the case of mangroves, subsistence hunting and oil and gas extraction. The main pressures were loss of wetland habitat, changes in connectivity affecting hydrology and sedimentology, as well as contamination and pollution. These pressures lead to changes in environmental state, such as erosion, subsidence and hypoxia that threaten the sustainability of the wetlands. There are also changes in the state of the ecology, such as loss of saltmarsh plants and seagrasses, and mangrove trees, in tropical wetlands. Changes in the structure and function of the wetland ecosystems affect ecosystem services that are often underestimated. The loss of ecosystem services impacts human welfare as well as the regulation of climate change by coastal wetlands. These cumulative impacts and multi-stressors are further aggravated by indirect pressures, such as sea-level rise

Structural, mechanistic and regulatory studies of serine palmitoyltransferase

SLs (sphingolipids) are composed of fatty acids and a polar head group derived from l-serine. SLs are essential components of all eukaryotic and many prokaryotic membranes but S1P (sphingosine 1-phosphate) is also a potent signalling molecule. Recent efforts have sought to inventory the large and chemically complex family of SLs (LIPID MAPS Consortium). Detailed understanding of SL metabolism may lead to therapeutic agents specifically directed at SL targets. We have studied the enzymes involved in SL biosynthesis; later stages are species-specific, but all core SLs are synthesized from the condensation of l-serine and a fatty acid thioester such as palmitoyl-CoA that is catalysed by SPT (serine palmitoyltransferase). SPT is a PLP (pyridoxal 5'-phosphate)-dependent enzyme that forms 3-KDS (3-ketodihydrosphingosine) through a decarboxylative Claisen-like condensation reaction. Eukaryotic SPTs are membrane-bound multi-subunit enzymes, whereas bacterial enzymes are cytoplasmic homodimers. We use bacterial SPTs (e. g. from Sphingomonas) to probe their structure and mechanism. Mutations in human SPT cause a neuropathy [HSAN1 (hereditary sensory and autonomic neuropathy type 1)], a rare SL metabolic disease. How these mutations perturb SPT activity is subtle and bacterial SPT mimics of HSAN1 mutants affect the enzyme activity and structure of the SPT dimer. We have also explored SPT inhibition using various inhibitors (e. g. cycloserine). A number of new subunits and regulatory proteins that have a direct impact on the activity of eukaryotic SPTs have recently been discovered. Knowledge gained from bacterial SPTs sheds some light on the more complex mammalian systems. In the present paper, we review historical aspects of the area and highlight recent key developments.</p

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production

Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)–MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-κB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell–dependent IL-12 production, resulting in defective IFN-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/c-Rel–mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-κB activators, such as tumor necrosis factor-α, IL-1β, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell– and CD40L-triggered, CD40-, and NEMO/NF-κB/c-Rel–mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans

DIAPH3 predicts survival of patients with MGMT-methylated glioblastoma

BackgroundGlioblastoma is one of the most aggressive primary brain tumors, with a poor outcome despite multimodal treatment. Methylation of the MGMT promoter, which predicts the response to temozolomide, is a well-established prognostic marker for glioblastoma. However, a difference in survival can still be detected within the MGMT methylated group, with some patients exhibiting a shorter survival than others, emphasizing the need for additional predictive factors.MethodsWe analyzed DIAPH3 expression in glioblastoma samples from the cancer genome atlas (TCGA). We also retrospectively analyzed one hundred seventeen histological glioblastomas from patients operated on at Saint-Luc University Hospital between May 2013 and August 2019. We analyzed the DIAPH3 expression, explored the relationship between mRNA levels and Patient’s survival after the surgical resection. Finally, we assessed the methylation pattern of the DIAPH3 promoter using a targeted deep bisulfite sequencing approach.ResultsWe found that 36% and 1% of the TCGA glioblastoma samples exhibit copy number alterations and mutations in DIAPH3, respectively. We scrutinized the expression of DIAPH3 at single cell level and detected an overlap with MKI67 expression in glioblastoma proliferating cells, including neural progenitor-like, oligodendrocyte progenitor-like and astrocyte-like states. We quantitatively analyzed DIAPH3 expression in our cohort and uncovered a positive correlation between DIAPH3 mRNA level and patient’s survival. The effect of DIAPH3 was prominent in MGMT-methylated glioblastoma. Finally, we report that the expression of DIAPH3 is at least partially regulated by the methylation of three CpG sites in the promoter region.ConclusionWe propose that combining the DIAPH3 expression with MGMT methylation could offer a better prediction of survival and more adapted postsurgical treatment for patients with MGMT-methylated glioblastoma

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

BACKGROUND: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)