Mapping the Linguistic Landscapes of Mesopotamia

Though Ancient Near Eastern Studies has increasingly paidattention to language contact and areal linguistics in recentyears, there have so far been but few systematic attempts atplacing the relevant languages on a map. The essay provides asurvey of maps of the languages of the Ancient Near East fromthe first areal maps in the 19th century to the artefact mapsin recent publications. The different visual grammars used inthe cartography of these ancient languages also imply widelyvarying narratives of linguistic geography. The recent move to-wards artefact mapping shifts the discussion away from staticinterpretations of language as a strong correlate of ethnicity to-wards an interpretation of language as a public expression oflinguistic identity within the landscapes of Mesopotamia

Assessing periodicity of periodic leg movements during sleep

Periodic leg movements (PLM) during sleep consist of involuntary periodic movements of the lower extremities. The debated functional relevance of PLM during sleep is based on correlation of clinical parameters with the PLM index (PLMI). However, periodicity in movements may not be reflected best by the PLMI. Here, an approach novel to the field of sleep research is used to reveal intrinsic periodicity in inter movement intervals (IMI) in patients with PLM

IVIg dose increase in multifocal motor neuropathy: a prospective six month follow-up

In this prospective, non-randomized 6-month observational study we evaluated the efficacy of intravenous immunoglobulin (IVIg) dose increase in patients with multifocal motor neuropathy (MMN). Diagnosis according to AAEM criteria, repetitive IVIg treatment for at least one year, persistent paresis and conduction block, stable symptoms and findings for at least six months were inclusion criteria. Nine patients (7 men) were identified and approved to standardized increase of IVIg dose. Patients were monitored using clinical scores and electrophysiological studies. Dose was increased from a baseline of 0.5 g/kg per month [mean, range: 0.1-1.1], given at variable intervals [4-12 weeks] to 1.2 g/kg per month given over 3 consecutive days planned for 6 cycles. If the patients' motor function did not improve after two cycles they entered step two: Dose was increased to 2 g/kg per month given over 5 consecutive days. The increased dose was maintained for 6 months. Assessments were performed by the same investigator, not involved in the patient's management, at baseline, after 2 and after 6 months. Following dose increase, motor function significantly improved in 6 patients (p = 0.014), 2 patients entered step two, 1 patient withdrew due to absent efficacy. Higher doses of IVIg caused more side effects, however, transient and rarely severe (p = 0.014). IVIg dose increase may improve motor functions in patients with stable MMN on long-term IVIg therapy independent of baseline dose. Improvement of motor function was associated with shorter disease duration (p = 0.008), but not with degree of muscle atrophy (p = 0.483). The treatment strategy to try to find the lowest effective dose and the longest tolerated interval might lead to underdosing in the long-term in many patients

How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?

Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme

Structural characterization of vanadium oxide catalysts supported on nanostructured silica SBA-15 using X-ray absorption spectroscopy

The local structure of vanadium oxide supported on nanostructured SiO2 (VxOy/SBA-15) was investigated by in situ X-ray absorption spectroscopy (XAS). Because the number of potential parameters in XAS data analysis often exceeds the number of "independent" parameters, evaluating the reliability and significance of a particular fitting procedure is mandatory. The number of independent parameters (Nyquist) may not be sufficient. Hence, in addition to the number of independent parameters, a novel approach to evaluate the significance of structural fitting parameters in XAS data analysis is introduced. Three samples with different V loadings (i.e. 2.7 wt %, 5.4 wt %, and 10.8 wt %) were employed. Thermal treatment in air at 623 K resulted in characteristic structural changes of the V oxide species. Independent of the V loading, the local structure around V centers in dehydrated VxOy/SBA-15 corresponded to an ordered arrangement of adjacent V2O7 units. Moreover, the V2O7 units were found to persist under selective oxidation reaction conditions

A conserved regulatory program drives emergence of the lateral plate mesoderm

Cardiovascular cell lineages emerge with kidney, smooth muscle, and limb skeleton progenitors from the lateral plate mesoderm (LPM). How the LPM emerges during development and how it has evolved to form key lineages of the vertebrate body plan remain unknown. Here, we captured LPM formation by transgenic in toto imaging and lineage tracing using the first pan-LPM enhancer element from the zebrafish gene draculin (drl). drl LPM enhancer-based reporters are specifically active in LPM-corresponding territories of several chordate species, uncovering a universal LPM-specific gene program. Distinct from other mesoderm, we identified EomesA, FoxH1, and MixL1 with BMP/Nodal-controlled Smad activity as minimally required factors to drive drl-marked LPM formation. Altogether, our work provides a developmental and mechanistic framework for LPM emergence and the in vitro differentiation of cardiovascular cell types. Our findings suggest that the LPM may represent an ancient cell fate domain that predates ancestral vertebrates

Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition

Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in TNBC patients, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cells lines. Results: Cyclin E overexpression (1) is enriched in TNBCs with high recurrence rates, (2) sensitizes TNBC cell lines and PDX models to AZD1775, (3) leads to CDK2-dependent activation of DNA replication stress pathways and (4) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions: Cyclin E is a potential biomarker of response (1) for AZD1775 as monotherapy in cyclin E high TNBC tumors and (2) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E low TNBC tumors

Fluorescence Nanoscopy in Whole Cells by Asynchronous Localization of Photoswitching Emitters

We demonstrate nanoscale resolution in far-field fluorescence microscopy using reversible photoswitching and localization of individual fluorophores at comparatively fast recording speeds and from the interior of intact cells. These advancements have become possible by asynchronously recording the photon bursts of individual molecular switching cycles. We present images from the microtubular network of an intact mammalian cell with a resolution of 40 nm

Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery

Survival of glioblastoma patients has been linked to the completeness of surgical resection. Available data, however, were generated with adjuvant radiotherapy. Data confirming that extensive cytoreduction remains beneficial to patients treated with the current standard, concomitant temozolomide radiochemotherapy, are limited. We therefore analyzed the efficacy of radiochemotherapy for patients with little or no residual tumor after surgery. In this prospective, non-interventional multicenter cohort study, entry criteria were histological diagnosis of glioblastoma, small enhancing or no residual tumor on post-operative MRI, and intended temozolomide radiochemotherapy. The primary study objective was progression-free survival; secondary study objectives were survival and toxicity. Furthermore, the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was investigated in a subgroup of patients. One-hundred and eighty patients were enrolled. Fourteen were excluded by patient request or failure to initiate radiochemotherapy. Twenty-three patients had non-evaluable post-operative imaging. Thus, 143 patients qualified for analysis, with 107 patients having residual tumor diameters ≤1.5 cm. Median follow-up was 24.0 months. Median survival or patients without residual enhancing tumor exceeded the follow-up period. Median survival was 16.9 months for 32 patients with residual tumor diameters >0 to ≤1.5 cm (95% CI: 13.3–20.5, p = 0.039), and 13.9 months (10.3–17.5, overall p < 0.001) for 36 patients with residual tumor diameters >1.5 cm. Patient age at diagnosis and extent of resection were independently associated with survival. Patients with MGMT promoter methylated tumors and complete resection made the best prognosis. Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation