Collective Dynamics of Kinesin-1.

Motor proteins are the engines of biology, converting chemical energy to mechanical work in cells. Kinesin-1 is a motor protein that transports vesicles towards the plus end of microtubules, widely believed to be responsible for anterograde transport of synaptic vesicles in neurons. Advances in single-molecule techniques have allowed the characterization of single kinesin motors in vitro at a range of loads and ATP concentrations. Single kinesin motors are capable of processive movement along the microtubule at a maximum velocity of approximately 1 μm/s. The velocity decreases roughly linearly in response to load until reaching stall at a load of approximately 6 pN. Several theoretical models have been proposed that describe the steady-state motion of single kinesin motors. However, growing evidence suggests that kinesin functions collectively in cells, whereby several motors work in a coordinated manner to transport a vesicle. A transient description is required to describe collective dynamics, as the interactions among coupled motors induce time-varying forces on each motor. Herein a mechanistic model of kinesin is proposed that is capable of accurately describing transient and steady-state dynamics. Each domain of the protein is modeled via a mechanical potential. The mechanical potentials are related explicitly to the chemical kinetics of each motor domain. The mechanistic model was used to simulate the collective behavior of coupled kinesin motors under varying loads, cargo linker stiffnesses, and numbers of motors. To analyze the simulations of coordinated transport, several metrics were developed that are specifically tailored to characterizing the synchronization of nonlinear, nonsmooth oscillators like kinesin. The model results suggest that, in the cell, coupled motors under low loads are loosely correlated. When the load is increased, such as when the cargo encounters an obstacle like another vesicle or the cytoskeleton, motors become more correlated in response to increased loads, allowing them to produce greater forces. Increasing the number of motors involved in the transport does not appreciably increase the dimensionality of the trajectory, implying large numbers of motors are able to work collectively, even without becoming fully synchronized.Ph.D.Mechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60661/1/adhendri_1.pd

Synthesis and Preliminary Evaluation Steroidal AntiestrogenGeldanamycin Conjugates

Three novel steroidal antiestrogen-geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11β-(4-functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity

Tackling in physical education rugby: an unnecessary risk?

Since 2016, we have been strong advocates for the removal of tackling from rugby (League and Union) played in school physical education in the United Kingdom [1]. This is because (a) tackling is the leading cause of injury in rugby, (b) rugby has a level of risk that is higher than non-contact sports, (c) there is no requirement or need for tackling as part of the school physical education curriculum, and (d) many children are compelled to participate in contact rugby [2]. In response to this call, the Chief Medical Officers and the Physical Activity Expert Group commented: ‘The Committee reject the call to ban tackling, as they do not feel rugby participation poses an unacceptable risk of harm’ [3]. Yet, the notion of risk (un) acceptability is a construct that needs further discussion, which we will start here [4]

B-Cell Non-Hodgkin’s Lymphoma: viewing an aggressive neck mass in an older adult from a primary care perspective

Abstract Patients with neck masses typically present to primary care providers, but most are unfamiliar with the management of aggressively expanding neck masses. With so many varied structures in the cervical region, a rapidly growing neck mass can be a diagnostic dilemma. The broad initial differential includes infectious, inflammatory, vascular, and malignant causes. When the clinical course points to an aggressive malignancy, the location of the mass helps provide the clues to the likely etiology. Potential sites of involvement include the musculature, bone, larynx, trachea, esophagus, lymph tissue and thyroid tissue. Anterior neck masses at the level the thyroid should prompt a differential of primary thyroid lymphomas. Diffuse large B-cell lymphoma is most common, followed by mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, and small lymphocytic lymphoma. Anaplastic thyroid carcinoma should be considered as well. A history of Hashimoto’s thyroiditis should lead the clinician toward the large B-cell lymphoma.Prompt diagnosis via fine-needle aspiration biopsy is essential, because compressive symptoms and airway collapse may rapidly ensue. A correct clinical and histopathologic diagnosis is essential. Primary thyroid lymphoma can often be treated with chemoimmunotherapy and radiation has a mean overall survival of 9.0 years. Anaplastic thyroid carcinoma is often locally aggressive with advanced metastatic disease at presentation, and treatment options are more limited. Primary care physicians need to be familiar with these relatively rare etiologies for an aggressively expanding neck mass in order to recognize and rapidly coordinate diagnostic and treatment options in a timely fashion

Evidence in support of the call to ban the tackle and harmful contact in school rugby: a response to World Rugby

In a paper published in BJSM (June 2016), World Rugby employees Ross Tucker and Martin Raftery and a third coauthor Evert Verhagen took issue with the recent call to ban tackling in school rugby in the UK and Ireland. That call (to ban tackling) was supported by a systematic review published in BJSM. Tucker et al claim that: (1) the mechanisms and risk factors for injury along with the incidence and severity of injury in youth rugby union have not been thoroughly identified or understood; (2) rugby players are at no greater risk of injury than other sports people, (3) this is particularly the case for children under 15 years and (4) removing the opportunity to learn the tackle from school pupils might increase rates of injuries. They conclude that a ban ‘may be unnecessary and may also lead to unintended consequences such as an increase in the risk of injury later in participation.’ Here we aim to rebut the case by Tucker et al. We share new research that extends the findings of our original systematic review and meta-analysis. A cautionary approach requires the removal of the tackle from school rugby as the quickest and most effective method of reducing high injury rates in youth rugby, a public health priority

Analysis of atomic-clock data to constrain variations of fundamental constants

We present a new framework to study the time variation of fundamental constants in a model-independent way. Model independence implies more free parameters than assumed in previous studies. Using data from atomic clocks based on $^{87}$Sr, $^{171}$Yb$^+$ and $^{133}$Cs, we set bounds on parameters controlling the variation of the fine-structure constant, $\alpha$, and the electron-to-proton mass ratio, $\mu$. We consider variations on timescales ranging from a minute to almost a day. In addition, we use our results to derive some of the tightest limits to date on the parameter space of models of ultralight dark matter and axion-like particles

Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103)

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation

Two are better than one: The link between management systems and business performance

Little is known about the complementary performance benefits associated with facilities’ combined use of both quality management systems (QMSs) and environmental management systems (EMSs), and how these performance benefits might differ from those associated with facilities’ use of only one of these management systems (or neither). We suggest that complementarities arise because each management system fosters the development of internal capabilities that facilitates the adoption and routine operationalization of the other, while maintaining differentiated goals that enhance strategic value. We examine these relationships using a sample of 2619 manufacturing facilities operating within six OECD countries, while controlling for self‐selection issues. Our findings support the idea of complementarity, in that facilities that adopt both QMS and EMS are more associated with positive business performance than facilities that adopt either a QMS or an EMS on its own, or no management system