The occurence and effects of short paths in scale-free geometric random graphs

We investigate a large class of geometric random graphs defined on a Poisson point process in Euclidean space, where each vertex carries an independent random mark. On this vertex set edges are established at random, such that the class is only determined by upper and lower bounds on the connection probabilities between finitely many pairs of vertices, which depend crucially on the marks and the spatial distance of each pair of vertices. This class includes different geometric random graphs emerging from real-world network models, such as a version of spatial preferential attachment (where marks can be understood as birth times), and continuum percolation, such as the soft Boolean model, as well as a whole range of further graph models with scale-free degree distribution and edges between distant vertices. For this class of geometric random graphs we study the occurence of short paths leading to ultrasmallness of the graphs, i.e. that the graph distance of a pair of distant vertices grows at most of doubly logarithmic order in the spatial distance of the pair. We give a sharp criterion for the absence of ultrasmallness of the graphs and in the ultrasmall regime establish a limit theorem for the chemical distance of two very distant vertices. Unlike in non-spatial scale-free network models and spatially embedded random graphs such as scale-free percolation the boundary of the ultrasmall regime and the limit theorem depend not only on the power-law exponent of the degree distribution but also on the rate of decay of the probability of an edge connecting two vertices with typical marks in terms of their Euclidean distance. Furthermore, we study the effect of the short paths in the ultrasmall regime on the survival of the contact process on geometric random graphs in this class. We show that the non-extinction probability is positive for any positive choice of the infection rate and give precise asymptotics for it when the infection rate decays to zero. On finite spatial restrictions of the graphs we show that the extinction time is of exponential order of the size of the graphs

Citizen Science Based Monitoring of Greylag goose (Anser anser) in Bavaria (Germany): Combining Count Data and Bag Data to Estimate Long-Term Trends between 1988/89 and 2010/11

Introduction, Material and Methods: Numbers of large grazing bird (geese, swans, cranes) have increased all over Europe, but monitoring these species, e.g. for management purposes, can be time consuming and costly. In Bavaria, sedentary Greylag geese (Anser anser) are monitored during the winter by two different citizen-based monitoring schemes: the International Waterbird Census [IWC] and hunting bag statistics. We compared the results of both schemes for the seasons 1988/89 to 2010/11 by analysing annual indices calculated using the software TRends and Indices for Monitoring Data-TRIM. Results and Discussion: We identified similar, highly significant rates of increase in both data sets for the entire region of Bavaria (IWC 14% [13-15%], bag 13% [12-14%]). Furthermore, in all of the seven Bavarian regions, trends in annual indices of both data sets correlated significantly. The quality of both datasets as indicators of abundances in Greylag geese populations in Bavaria was not undermined by either weaknesses typically associated with citizen based monitoring or problems generally assumed for IWC and bag data. We also show that bag data are, under the German system of collecting bag statistics, a reliable indicator of species' distribution, especially for detecting newly colonized areas. Therefore, wildlife managers may want to consider bag data from citizen science led monitoring programmes as evidence supporting the decision making processes. We also discuss requirements for any bag monitoring schemes being established to monitor trends in species' distribution and abundance

Interdisciplinary Decision Making in Hemorrhagic Stroke Based on CT Imaging—Differences Between Neurologists and Neurosurgeons Regarding Estimation of Patients' Symptoms, Glasgow Coma Scale, and National Institutes of Health Stroke Scale

Background and Purpose: Acute intracerebral hemorrhage (ICH) requires rapid decision making toward neurosurgery or conservative neurological stroke unit treatment. In a previous study, we found overestimation of clinical symptoms when clinicians rely mainly on cerebral computed tomography (cCT) analysis. The current study investigates differences between neurologists and neurosurgeons estimating specific scores and clinical symptoms. Methods: Overall, 14 neurologists and 15 neurosurgeons provided clinical estimates and National Institutes of Health Stroke Scale (NIHSS) as well as Glasgow Coma Scale (GCS) based on cCT images and basic information of 50 patients with hypertensive and lobar ICH. Subgroup analyses were performed for the different professions (neurologists vs. neurosurgeons) and bleeding subtypes (typical location vs. atypical). The differences between the actual GCS and NIHSS scores and the cCT-imaging-based estimated scores were depicted as Bland-Altman plots and negative and positive predictive value (NPV and PPV) for prediction of clinical relevant items. Delta NIHSS points (Delta GCS points) were calculated as the difference between actual and rated NIHSS (GCS) including 95% confidence interval (CI). Results: Mean Delta GCS points for neurosurgeons was 1.16 (95% CI: -2.67-4.98); for neurologists, 0.99 (95% CI: -2.58-4.55), p = 0.308; mean Delta NIHSS points for neurosurgeons was -2.95 (95% CI: -12.71-6.82); for neurologists, -0.33 (95% CI: -9.60-8.94), p < 0.001. NPV and PPV for stroke symptoms were low, with large differences between different symptoms, bleeding subtypes, and professions. Both professions had more problems in proper rating of specific clinic-neurological symptoms than rating scores. Conclusion: Our results stress the need for joint decision making based on detailed neurological examination and neuroimaging findings also in telemedicine

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy : a randomised, open-label, phase 3 trial

Background: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. Methods: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged >= 55 to <= 90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2.5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 mu g once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. Findings: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2.6% (95% CI 2.2 to 3.0) in the romosozumab group and -0.6% (-1.0 to -0.2) in the teriparatide group; difference 3.2% (95% CI 2.7 to 3.8; p<0.0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. Interpretation: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density.

Funder: NIHR Cambridge BRC; Id: http://dx.doi.org/10.13039/501100018956Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a -0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (-4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).This research was funded by Amgen and supported by the NIHR Cambridge BRC. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study

BACKGROUND: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. METHODS: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. RESULTS: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. CONCLUSION: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data

Optical Control of Metabotropic Glutamate Receptors

G-protein coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype-specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto-chemical engineering native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized “LimGluRs”. The light-agonized “LimGluR2”, on which we focused, is fast, bistable, and supports multiple rounds of on/off switching. Light gates two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. The light-antagonized “LimGluR2block” can be used to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalize the optical control to two additional family members: mGluR3 and 6. The system works in rodent brain slice and in zebrafish in vivo, where we find that mGluR2 modulates the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Synthetic receptors for the differentiation of phosphorylated peptides and synthesis and use of tetrahydrofuran amino acids

In the first part of the work a combination of bis(Zn(II)-cyclen) triazine metal complex binding sites with guanidinium moieties or Zn(II)-NTA complexes leads to artificial receptors for the differentiation of phosphorylated peptides which contain either a histidine side chain or a glutamic acid side chain as a second binding site. General methods for the synthesis of such bidentate receptors consisting either of two bis(Zn(II)-cyclen) triazine complexes or of one bis(Zn(II)-cyclen) triazine complex and a guanidinium moiety were developed and several receptors varying in length were synthesized. These complexes in combination with previously prepared complexes consisting of a bis(Zn(II)-cyclen) triazine complex in combination with a Zn(II)-NTA complex were tested in a fluorescence polarization assay against the peptide-protein interaction of different peptides and their corresponding proteins STAT1, STAT3 and GST-Lck. All receptors were found to be active showing an influence on the peptide-protein binding at receptor concentrations of 200 - 600 uM. Unfortunately, it was also found that the incorporation of a second binding site into the receptors did not alter the activity of the compounds significantly. In addition, the synthesized complexes were used to determine their binding affinities towards the fluorescently labeled peptides 5/6-Carboxyfluorescein-Gly-pSer-Ala-Ala-His-Val-NH2 and 5/6-Carboxyfluorescein-Gly-pSer-Ala-Ala-Glu-Val-NH2. The right combination of binding moieties leads to nanomolar peptide binding affinities in aqueous media at physiological pH. To the best of our knowledge these are the highest affinities of phosphopeptide binding by artificial receptors reported so far. Depending on the second functional group (His or Glu/Asp) beside the phosphate ester, selectivities of up to three orders of magnitude of the binding constant are observed. Although the bidentate receptors did not show the supposed increased activity in the STAT assay, their remarkably high binding affinities and also selectivities to certain peptide sequences could make them a versatile tool for the inhibition of peptide-protein interactions. Therefore further effort should be undertaken to test the receptors in other biologically relevant systems. In the second part the unnatural Calpha-tetrasubstituted tetrahydrofuran alpha-amino acid (TAA) was used for the synthesis of 13 new peptides based on an alternated sequence of the S- or R-configured alpha-amino acid valine and the TAA. Homo- and heterochiral stereoisomers with up to eight residues in length were systematically synthesized in good yields and high purity by solution phase chemistry. X-ray crystallography, NMR- and CD-measurements showed that all homochiral peptides, even the tetrapeptides, form helical structures in the solid state and in solution. The handedness of the helix is determined by the use of S-amino acids for right-handed or R-amino acids for left-handed peptide helices. The stable and predictable secondary structure of the new peptides makes them suitable for applications as scaffolds and peptidomimetics. Additional moieties e.g. dyes, can be introduced by metal catalyzed functionalization of the brominated arene substituent. In addition the TAA was used in CuI-catalyzed N-arylation which proceed in moderate to good yields with a variety of amines allowing to introduce aliphatic aldehydes and different functional group containing amines into the side chain of the protected TAA. An intramolecular Cu(I)-catalyzed N-arylation reaction was used for the synthesis of the 17-membered macrocycle compounds, but the obtained yield was low. Pd(0)-catalyzed O-arylations gave higher yields for the macrocylization of non-natural tripeptides containing the TAA: A 15-membered macrocycle was obtained in good yield using Pd(OAc)2 and a sterically demanding ligand. The examples illustrate that copper(I)-catalyzed N-arylations and palladium(0)-catalyzed O-arylations give access to side chain modified derivatives of the unnatural amino acid TAA and macrocyclic peptidomimetics