The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations ...of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.
The aim of this study was to assess the incidence and pattern of cervical lymph node (LN) metastases in carcinomas of the upper aerodigestive tract in relation to primary tumor (PT) invasion of the ...equivalents of pharyngeal arches (PhA) and occipital and cervical somites (OCS) in adults.
The pretherapeutic computed tomography scans and clinical findings in 729 patients with histologically proven carcinoma of the upper aerodigestive tract (112 nasopharyngeal, 289 oropharyngeal, 252 laryngo-hypopharyngeal, and 76 oral cavity carcinomas, with LN involvement in 70% of the total) were analyzed in relation to PT invasion of equivalents of PhA and OCS. Tumors were recorded according to the infiltration of these equivalents. The metastatic involvement of the different cervical LN groups was analyzed and correlated to the pattern of PT invasion of equivalents of PhA and OCS by the chi-square test.
The findings show that the pattern of cervical LN involvement depends on the location and extension of the PT and its invasion of equivalents of the PhA and OCS. Jugular LN metastases were found in tumors invading the equivalents of PhA 2-6. Submandibular LN metastases were evident in tumors invading tissues arising from the first PhA and the tongue. Retropharyngeal, spinal accessory and transversa colli LN metastases were found in tumors invading tissues arising from OCS. The frequency of LN metastases in the different LN chains decreased in the cranio-caudal direction. Each neck hemisphere showed separate lymphatic drainage.
Analysis of PT extension in relation to PhA and OCS equivalents allows patterns of LN involvement to be predicted.
In cranial sutural samples derived from five children with premature cranial suture fusion we have performed immunostaining for the urokinase plasminogen activator (uPA) and urokinase receptor ...(uPAR). We have found a strong reactivity for cell- or matrix-bound uPA and uPAR in the sutural connective tissue and associated with the osteoblasts and osteocytes lining the calvarial bone. The sutural tissue itself showed a banding with different intensity of urokinase and uPAR staining concerning connective tissue. It is proposed that the components of the plasminogen activating system are involved in tissue turnover of sutural tissue and in sutural growth.
Granulocyte colony-stimulating factor (G-CSF) has been used for over 20 years to obtain peripheral blood stem cells from healthy donors for allogeneic stem cell transplantation. Concerns have been ...raised about a potentially increased cancer incidence in donors after donation, especially regarding haematological malignancies. In a prospective Swedish national cohort study, we studied the cancer incidence after donation in 1082 Swedish peripheral blood stem cell donors, donating between 1998 and 2014. The primary objective was to evaluate if the cancer incidence increased for donors treated with G-CSF. With a median follow-up time of 9.8 years, the incidence of haematological malignancies was 0.85 cases per 1000 person-years, and did not significantly differ from the incidence in age-, sex- and residence-matched population controls (hazard ratio 1.70, 95% confidence interval (CI) 0.79-3.64, p value 0.17), bone marrow donors or non-donating siblings. The total cancer incidence for peripheral blood stem cell donors was 6.0 cases per 1000 person-years, equal to the incidence in matched population controls (hazard ratio 1.03, 95% CI 0.78-1.36, p value 0.85), bone marrow donors or non-donating siblings. In this study of healthy peripheral blood stem cell donors, the cancer incidence was not increased after treatment with G-CSF.
During storage in the silk gland, the N-terminal domain (NT) of spider silk proteins (spidroins) keeps the aggregation-prone repetitive region in solution at extreme concentrations. We observe that ...NTs from different spidroins have co-evolved with their respective repeat region, and now use an NT that is distantly related to previously used NTs, for efficient recombinant production of the amyloid-β peptide (Aβ) implicated in Alzheimer's disease. A designed variant of NT from Nephila clavipes flagelliform spidroin, which in nature allows production and storage of β-hairpin repeat segments, gives exceptionally high yields of different human Aβ variants as a solubility tag. This tool enables efficient production of target peptides also in minimal medium and gives up to 10 times more isotope-labeled monomeric Aβ peptides per liter bacterial culture than previously reported.
Abstract
Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ...ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters
e.g
., at the blood-brain barrier (BBB). The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.
A major surface circulation feature of the Arctic Ocean is the Transpolar Drift (TPD), a current that transports river‐influenced shelf water from the Laptev and East Siberian Seas toward the center ...of the basin and Fram Strait. In 2015, the international GEOTRACES program included a high‐resolution pan‐Arctic survey of carbon, nutrients, and a suite of trace elements and isotopes (TEIs). The cruises bisected the TPD at two locations in the central basin, which were defined by maxima in meteoric water and dissolved organic carbon concentrations that spanned 600 km horizontally and ~25–50 m vertically. Dissolved TEIs such as Fe, Co, Ni, Cu, Hg, Nd, and Th, which are generally particle‐reactive but can be complexed by organic matter, were observed at concentrations much higher than expected for the open ocean setting. Other trace element concentrations such as Al, V, Ga, and Pb were lower than expected due to scavenging over the productive East Siberian and Laptev shelf seas. Using a combination of radionuclide tracers and ice drift modeling, the transport rate for the core of the TPD was estimated at 0.9 ± 0.4 Sv (106 m3 s−1). This rate was used to derive the mass flux for TEIs that were enriched in the TPD, revealing the importance of lateral transport in supplying materials beneath the ice to the central Arctic Ocean and potentially to the North Atlantic Ocean via Fram Strait. Continued intensification of the Arctic hydrologic cycle and permafrost degradation will likely lead to an increase in the flux of TEIs into the Arctic Ocean.
Plain Language Summary
A major feature of the Arctic Ocean circulation is the Transpolar Drift (TPD), a surface current that carries ice and continental shelf‐derived materials from Siberia across the North Pole to the North Atlantic Ocean. In 2015, an international team of oceanographers conducted a survey of trace elements in the Arctic Ocean, traversing the TPD. Near the North Pole, they observed much higher concentrations of trace elements in surface waters than in regions on either side of the current. These trace elements originated from land, and their journey across the Arctic Ocean is made possible by chemical reactions with dissolved organic matter that originates mainly in Arctic rivers. This study reveals the importance of rivers and shelf processes combined with strong ocean currents in supplying trace elements to the central Arctic Ocean and onward to the Atlantic. These trace element inputs are expected to increase as a result of permafrost thawing and increased river runoff in the Arctic, which is warming at a rate much faster than anywhere else on Earth. Since many of the trace elements are essential building blocks for ocean life, these processes could lead to significant changes in the marine ecosystems and fisheries of the Arctic Ocean.
Key Points
The Transpolar Drift is a source of shelf‐ and river‐derived elements to the central Arctic Ocean
The TPD is rich in dissolved organic matter (DOM), which facilitates long‐range transport of trace metals that form complexes with DOM
Margin trace element fluxes may increase with future Arctic warming due to DOM release from permafrost thaw and increasing river discharge
Alzheimer‘s disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ...ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
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