Quantitative modeling of synthetic gene transfer

modeling of synthetic gene transfe

Global excitability and network structure in the human brain

We utilize a model of Wilson-Cowan oscillators to investigate structure-function relationships in the human brain by means of simulations of the spontaneous dynamics of brain networks generated through human connectome data. This allows us to establish relationships between the global excitability of such networks and global structural network quantities for connectomes of two different sizes for a number of individual subjects. We compare the qualitative behavior of such correlations between biological networks and shuffled networks, the latter generated by shuffling the pairwise connectivities of the former while preserving their distribution. Our results point towards a remarkable propensity of the brain's to achieve a trade-off between low network wiring cost and strong functionality, and highlight the unique capacity of brain network topologies to exhibit a strong transition from an inactive state to a globally excited one.Comment: 12 pages, 10 figure

Network analysis of the human structural connectome including the brainstem: a new perspective on consciousness

The underlying anatomical structure is fundamental to the study of brain networks and is likely to play a key role in the generation of conscious experience. We conduct a computational and graph-theoretical study of the human structural connectome incorporating a variety of subcortical structures including the brainstem, which is typically not considered in similar studies. Our computational scheme involves the use of Python DIPY and Nibabel libraries to develop an averaged structural connectome comprised of 100 healthy adult subjects. We then compute degree, eigenvector, and betweenness centralities to identify several highly connected structures and find that the brainstem ranks highest across all examined metrics. Our results highlight the importance of including the brainstem in structural network analyses. We suggest that structural network-based methods can inform theories of consciousness, such as global workspace theory (GWT), integrated information theory (IIT), and the thalamocortical loop theory.Comment: 23 pages, 5 figure

Machine learning using Multi-Modal Data Predicts the Production of Selective Laser Sintered 3D Printed Drug Products

Three-dimensional (3D) printing is drastically redefining medicine production, offering digital precision and personalized design opportunities. One emerging 3D printing technology is selective laser sintering (SLS), which is garnering attention for its high precision, and compatibility with a wide range of pharmaceutical materials, including low-solubility compounds. However, the full potential of SLS for medicines is yet to be realized, requiring expertise and considerable time-consuming and resource-intensive trial-and-error research. Machine learning (ML), a subset of artificial intelligence, is an in silico tool that is accomplishing remarkable breakthroughs in several sectors for its ability to make highly accurate predictions. Therefore, the present study harnessed ML to predict the printability of SLS formulations. Using a dataset of 170 formulations from 78 materials, ML models were developed from inputs that included the formulation composition and characterization data retrieved from Fourier-transformed infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Multiple ML models were explored, including supervised and unsupervised approaches. The results revealed that ML can achieve high accuracies, by using the formulation composition leading to a maximum F1 score of 81.9%. Using the FT-IR, XRPD and DSC data as inputs resulted in an F1 score of 84.2%, 81.3%, and 80.1%, respectively. A subsequent ML pipeline was built to combine the predictions from FT-IR, XRPD and DSC into one consensus model, where the F1 score was found to further increase to 88.9%. Therefore, it was determined for the first time that ML predictions of 3D printability benefit from multi-modal data, combining numeric, spectral, thermogram and diffraction data. The study lays the groundwork for leveraging existing characterization data for developing high-performing computational models to accelerate developments

Multiparity and Breast Cancer Risk Factor among Women in Burkina Faso

The relative lack of information on breast cancer etiology in Burkina Faso led us to undertake the present work to highlight risk factors. This prospective study was conducted using a questionnaire between January 2015 and February 2016 on women admitted to Yalgado OUEDRAOGO hospital, for consultation or supervision. The characteristics of multiparous breast cancer patients (n = 44) were compared with their non-multiparous counterparts (n = 36). The study found that increased risk of breast cancer among non-multiparous cases was related to body mass index (BMI) (p <0.001), age at menopause (p <0.004) and use of oral contraception (p <0.021) while abortion (p <0.002) was a risk factor among multiparous cases. These results suggest that even if multiparity is associated with a decreased risk in some women, avoidance of abortion during reproductive life should be recommended. The results provide preliminary information, which now need to be supplemented by survey of a larger sample in the national territory.Peer reviewe

Contact-controlled amoeboid motility induces dynamic cell trapping in 3D-microstructured surfaces.

On flat substrates, several cell types exhibit amoeboid migration, which is characterized by restless stochastic successions of pseudopod protrusions. The orientation and frequency of new membrane protrusions characterize efficient search modes, which can respond to external chemical stimuli as observed during chemotaxis in amoebae. To quantify the influence of mechanical stimuli induced by surface topography on the migration modes of the amoeboid model organism Dictyostelium discoideum, we apply high resolution motion analysis in microfabricated pillar arrays of defined density and geometry. Cell motion is analyzed by a two-state motility-model, distinguishing directed cellular runs from phases of isotropic migration that are characterized by randomly oriented cellular protrusions. Cells lacking myosin II or cells deprived of microtubules show significantly different behavior concerning migration velocities and migrational angle distribution, without pronounced attraction to pillars. We conclude that microtubules enhance cellular ability to react with external 3D structures. Our experiments on wild-type cells show that the switching from randomly formed pseudopods to a stabilized leading pseudopod is triggered by contact with surface structures. These alternating processes guide cells according to the available surface in their 3D environment, which we observed dynamically and in steady-state situations. As a consequence, cells perform "home-runs" in low-density pillar arrays, crawling from pillar to pillar, with a characteristic dwell time of 75 s. At the boundary between a flat surface and a 3D structured substrate, cells preferentially localize in contact with micropillars, due to the additionally available surface in the microstructured arrays. Such responses of cell motility to microstructures might open new possibilities for cell sorting in surface structured arrays

The impact of Oncotype DX testing on adjuvant chemotherapy decision making in 1–3 node positive breast cancer

Background: Oncotype DX testing has reduced the use of adjuvant chemotherapy in node-negative early breast cancer but less is known about its impact in node positive patients. Aim: This study aimed to investigate the impact of Oncotype DX gene assay testing on the decision to offer adjuvant chemotherapy in oestrogen positive, human epidermal growth factor receptor 2 negative, 1–3 lymph node positive patients. Methods: Retrospective review of all node positive patients who underwent Oncotype DX testing at a single centre. Clinicopathological data, as well as estimated survival benefit data (from the PREDICT tool), was evaluated by a multidisciplinary group of surgeons and oncologists. Treatment decisions based on clinicopathological data were compared to recurrence scores (RS). A cut off RS > 30 was used to offer adjuvant chemotherapy. Results: The 69 patients were identified, of which 9 (13%) had an RS > 30 and assigned a high-genomic risk of recurrence. The 32 patients (46.4%) were offered adjuvant chemotherapy. Overall based on the use of the RS, the decision to offer adjuvant chemotherapy changed in 36% of patients, and ultimately 24 patients (34.7%) would have been spared chemotherapy. Conclusion: Using clinicopathological data alone to make decisions regarding adjuvant chemotherapy in node positive breast cancer leads to overtreatment. Additional information on tumour biology as assessed by the Oncotype DX RS helps to select those patients who will benefit from adjuvant chemotherapy and spare patients from unnecessary chemotherapy

Long-Term Teduglutide for the Treatment of Patients With Intestinal Failure Associated With Short Bowel Syndrome

OBJECTIVES: In the pivotal 24-week, phase III, placebo-controlled trial, teduglutide significantly reduced parenteral support (PS) requirements in patients with short bowel syndrome (SBS). STEPS-2 was a 2-year, open-label extension of that study designed to evaluate long-term safety and efficacy of teduglutide. METHODS: Enrolled patients had completed 24 weeks of either teduglutide (TED/TED) or placebo (PBO/TED) in the initial placebo-controlled study or qualified for that study, but were not treated (NT/TED) because of full enrollment. Patients received subcutaneous teduglutide 0.05 mg/kg/day for up to 24 months (NT/TED and PBO/TED) or up to 30 months (TED/TED). Clinical response was defined as 20–100% reduction from baseline in weekly PS volume; baseline was considered the beginning of teduglutide treatment in the initial placebo-controlled study (TED/TED) or STEPS-2 (NT/TED and PBO/TED). Descriptive statistics summarized changes in efficacy and safety variables. RESULTS: Of 88 enrolled patients, 65 (74%) completed STEPS-2. The most common treatment-emergent adverse events were abdominal pain (34%), catheter sepsis (28%), and decreased weight (25%). Mean weight, body mass index, and serum albumin remained stable. In patients who completed the study, clinical response was achieved in 28/30 (93%) TED/TED, 16/29 (55%) PBO/TED, and 4/6 (67%) NT/TED patients. Mean PS volume reductions from baseline were 7.6 (66%), 3.1 (28%), and 4.0 (39%) l/week in the TED/TED, PBO/TED, and NT/TED groups, respectively. Thirteen patients achieved full enteral autonomy. CONCLUSIONS: In patients with SBS, long-term teduglutide treatment resulted in sustained, continued reductions in PS requirements. Overall health and nutritional status was maintained despite PS reductions