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Practitioners and academics alike have argued that a firm’s interest in its short-term capital market valuation (short-termism) is harmful to the firm’s long-term profit. Their argument is intuitive—when a firm exhibits short-termism, its decision making will cater to the short term at the expense of the long term. Some practitioners claim that the adverse effects of increased short-termism become particularly acute in competitive markets. However, there is little academic research that examines the compound effect of short-termism and competition on a firm’s operational choices and long-term profit. In this paper, we provide a rigorous analytical model to examine how short-termism and competition can interact to induce a firm to distort its capacity investment and affect its long-term profit. We model a firm that has private information about its market demand, which can be either high or low and is captured by the firm’s type. Signaling this private information can influence both the investor’s valuation and the competitor’s entry decision. We find that operational distortion can emerge not only when short-termism is large, but also when it is small. In fact, when short-termism is sufficiently small, both firm types will distort their operational decision by underinvesting in a pooling outcome. We show, however, that the impact of short-termism on a firm’s long-term profit is not monotonically negative, and a certain level of short-termism can be beneficial to a firm’s long-term profit. The positive impact of incremental short-termism is robust to alternative modeling assumptions, including the form of competition and the investor’s risk profile. This paper was accepted by Victor Martínez-de-Albéniz, operations management.

Problem definition: Operational disruptions can impact a firm’s risk, which manifests in a host of operational issues, including a higher holding cost for inventory, a higher financing cost for capacity expansion, and a higher perception of the firm’s risk among its supply chain partners. Academic/practical relevance: Although disruptions have been studied extensively in the operations management literature, the emphasis has been on mitigating the deleterious impact on the firm’s production potential rather than its risk. We examine whether implementing and credibly attesting to having effective internal control systems will meaningfully influence the impact of operational disruptions on the firm’s risk and market valuation. Methodology: We exploit a 2004 regulatory change that required certain firms to attest to having control systems in place. Our triple-difference regression specification takes advantage of a regulatory anomaly that excluded a well-defined set of firms from complying with the control system requirement. Results: We find that firms that were obligated to comply with this regulatory requirement experienced a materially smaller increase in their risk and a smaller decrease in their market value in the aftermath of an operational disruption. Firms that were not obligated to comply with this requirement did not experience such benefits in the aftermath of a disruption and instead, experienced a larger increase in their risk. Managerial implications: Fostering a better understanding of whether credible control systems can reduce the impact of disruptions on the firm’s risk and value is important as it identifies a broader set of mitigation strategies available to operations managers. This can help managers achieve a better fit between their risk mitigation initiatives and their objectives and budget constraints.

Companies that experience a disruption in their supply chain often face a difficult decision—either accept the information that they have regarding the duration of the disruption, or invest in collecting better information. This choice is not clear since better information may not be attainable, and if it is attainable, it may not improve operational decision‐making. In light of this dilemma, we collaborate with a multinational division of a Fortune 500 manufacturing firm to develop stochastic linear programming models that quantify the value of disruption duration information. Our models allow us to examine characteristics of the disrupted part that may be associated with the value of better information. We focus on characteristics that are knowable at the outset of the disruption, as those can help the firm decide whether to invest in collecting better information. Using our research partner's supply chain and production data, we find that the value of information can vary materially—from

Muscle contraction is regulated by the movement of end-to-end-linked troponin−tropomyosin complexes over the thin filament surface, which uncovers or blocks myosin binding sites along F-actin. The N-terminal half of troponin T (TnT), TNT1, independently promotes tropomyosin-based, steric inhibition of acto-myosin associations, in vitro. Recent structural models additionally suggest TNT1 may restrain the uniform, regulatory translocation of tropomyosin. Therefore, TnT potentially contributes to striated muscle relaxation; however, the in vivo functional relevance and molecular basis of this noncanonical role remain unclear. Impaired relaxation is a hallmark of hypertrophic and restrictive cardiomyopathies (HCM and RCM). Investigating the effects of cardiomyopathy-causing mutations could help clarify TNT1’s enigmatic inhibitory property. We tested the hypothesis that coupling of TNT1 with tropomyosin’s end-to-end overlap region helps anchor tropomyosin to an inhibitory position on F-actin, where it deters myosin binding at rest, and that, correspondingly, cross-bridge cycling is defectively suppressed under diastolic/low Ca(2+) conditions in the presence of HCM/RCM lesions. The impact of TNT1 mutations on Drosophila cardiac performance, rat myofibrillar and cardiomyocyte properties, and human TNT1’s propensity to inhibit myosin-driven, F-actin−tropomyosin motility were evaluated. Our data collectively demonstrate that removing conserved, charged residues in TNT1’s tropomyosin-binding domain impairs TnT’s contribution to inhibitory tropomyosin positioning and relaxation. Thus, TNT1 may modulate acto-myosin activity by optimizing F-actin−tropomyosin interfacial contacts and by binding to actin, which restrict tropomyosin’s movement to activating configurations. HCM/RCM mutations, therefore, highlight TNT1’s essential role in contractile regulation by diminishing its tropomyosin-anchoring effects, potentially serving as the initial trigger of pathology in our animal models and humans.

Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction., The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation is located near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here the authors assessed M305L actin in vivo, in vitro, and in silico to characterize emergent pathological properties and define the mechanistic basis of disease.

Objective Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function. Recent studies have demonstrated that the acetylation of cardiac myofibril proteins accelerates relaxation and that cTnI is acetylated in the heart. These findings highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to changes in myofilament, myofibril, and/or cellular mechanics. The objective of this study was to determine the effects of mimicking acetylation at a single site of cTnI (lysine-132; K132) on myofilament, myofibril, and cellular mechanics and elucidate its influence on molecular function. Methods To determine if pseudo-acetylation of cTnI at 132 modulates thin filament regulation of the acto-myosin interaction, we reconstituted thin filaments containing WT or K132Q (to mimic acetylation) cTnI and assessed in vitro motility. To test if mimicking acetylation at K132 alters cellular relaxation, adult rat ventricular cardiomyocytes were infected with adenoviral constructs expressing either cTnI K132Q or K132 replaced with arginine (K132R; to prevent acetylation) and cell shortening and isolated myofibril mechanics were measured. Finally, to confirm that changes in cell shortening and myofibril mechanics were directly due to pseudo-acetylation of cTnI at K132, we exchanged troponin containing WT or K132Q cTnI into isolated myofibrils and measured myofibril mechanical properties. Results Reconstituted thin filaments containing K132Q cTnI exhibited decreased calcium sensitivity compared to thin filaments reconstituted with WT cTnI. Cardiomyocytes expressing K132Q cTnI had faster relengthening and myofibrils isolated from these cells had faster relaxation along with decreased calcium sensitivity compared to cardiomyocytes expressing WT or K132R cTnI. Myofibrils exchanged with K132Q cTnI ex vivo demonstrated faster relaxation and decreased calcium sensitivity. Conclusions Our results indicate for the first time that mimicking acetylation of a specific cTnI lysine accelerates myofilament, myofibril, and myocyte relaxation. This work underscores the importance of understanding how acetylation of specific sarcomeric proteins affects cardiac homeostasis and disease and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

The Klamath Mountains province and adjacent Franciscan subduction complex (northern California–southern Oregon) together contain a world-class archive of subduction-related growth and stabilization of continental lithosphere. These key elements of the North American Cordillera expanded significantly from Middle Jurassic to Early Cretaceous time, apparently by a combination of tectonic accretion and continental arc– plus rift-related magmatic additions. The purpose of this field trip is twofold: to showcase the rock record of continental growth in this region and to discuss unresolved regional geologic problems. The latter include: (1) the extent to which Mesozoic orogenesis (e.g., Siskiyou and Nevadan events plus the onset of Franciscan accretion) was driven by collision of continental or oceanic fragments versus changes in plate motion, (2) whether growth involved “accordion tectonics” whereby marginal basins (and associated fringing arcs) repeatedly opened and closed or was driven by the accretion of significant volumes of material exotic to North America, and (3) the origin of the Condrey Mountain schist, a composite low-grade unit occupying an enigmatic structural window in the central Klamaths—at odds with the east-dipping thrust sheet regional structural “rule.” Respectively, we assert that (1) if collision drove orogenesis, the requisite exotic materials are missing (we cannot rule out the possibility that such materials were removed via subduction and/or strike slip faulting); (2) opening and closure of the Josephine ophiolite-floored and Galice Formation–filled basin demonstrably occurred adjacent to North America; and (3) the inner Condrey Mountain schist domain is equivalent to the oldest clastic Franciscan subunit (the South Fork Mountain schist) and therefore represents trench assemblages underplated >100 km inboard of the subduction margin, presumably during a previously unrecognized phase of shallow-angle subduction. In aggregate, these relations suggest that the Klamath Mountains and adjacent Franciscan complex represent telescoped arc and forearc upper plate domains of a dynamic Mesozoic subduction zone, wherein the downgoing oceanic plate took a variety of trajectories into the mantle. We speculate that the downgoing plate contained alternating tracts of smooth and dense versus rough and buoyant lithosphere—the former gliding into the mantle (facilitating slab rollback and upper plate extension) and the latter enhancing basal traction (driving upper plate compression and slab-shallowing). Modern snapshots of similarly complex convergent settings are abundant in the western Pacific Ocean, with subduction of the Australian plate beneath New Guinea and adjacent island groups providing perhaps the best analog.

In many practical settings, human decision-makers can review the recommendations that a decision support model generates and either approve or override the recommendation. Overrides can be rare when the decision support model is well-tuned to its task. However, the human decision-maker is still burdened with reviewing a potentially large number of recommendations. In this paper, we examine whether a machine learning (ML) prediction model can address this inefficiency. We develop a set of ML models in conjunction with our research partner, a large materials handling equipment manufacturer, and employ the models using our partner's procurement ordering process. This process covers 535,168 orders at suppliers over four years for 36 decision-makers (planners). Using only features that are available at the time a system makes a recommendation, our proposed set of ML models predict (1) whether or not the decision-maker will modify the recommendation and (2) whether such a modification will improve or impair the performance of the system. Our analysis is complicated by the fact that some of the planners have few observations in our training data, leading to poor predictions for those planner-level models. We address this by augmenting our planner-level models with cluster-level models. The latter draws inferences from the predicted behavior of clusters of planners with similar behavior. Using our ML models, we identify a material portion of the order recommendations that can be automated with little, or even a positive, impact on performance. Using our results to automate orders, the firm can (1) free the decision-makers' time for other value-added activities and (2) improve the system's performance.

Recent proteomics studies of vertebrate striated muscle have identified lysine acetylation at several sites on actin. Acetylation is a reversible post-translational modification that neutralizes lysine's positive charge. Positively charged residues on actin, particularly Lys(326) and Lys(328), are predicted to form critical electrostatic interactions with tropomyosin (Tpm) that promote its binding to filamentous (F)-actin and bias Tpm to an azimuthal location where it impedes myosin attachment. The troponin (Tn) complex also influences Tpm's position along F-actin as a function of Ca(2+) to regulate exposure of myosin-binding sites and, thus, myosin cross-bridge recruitment and force production. Interestingly, Lys(326) and Lys(328) are among the documented acetylated residues. Using an acetic anhydride-based labeling approach, we showed that excessive, nonspecific actin acetylation did not disrupt characteristic F-actin–Tpm binding. However, it significantly reduced Tpm-mediated inhibition of myosin attachment, as reflected by increased F-actin–Tpm motility that persisted in the presence of Tn and submaximal Ca(2+). Furthermore, decreasing the extent of chemical acetylation, to presumptively target highly reactive Lys(326) and Lys(328), also resulted in less inhibited F-actin–Tpm, implying that modifying only these residues influences Tpm's location and, potentially, thin filament regulation. To unequivocally determine the residue-specific consequences of acetylation on Tn–Tpm–based regulation of actomyosin activity, we assessed the effects of K326Q and K328Q acetyl (Ac)-mimetic actin on Ca(2+)-dependent, in vitro motility parameters of reconstituted thin filaments (RTFs). Incorporation of K328Q actin significantly enhanced Ca(2+) sensitivity of RTF activation relative to control. Together, our findings suggest that actin acetylation, especially Lys(328), modulates muscle contraction via disrupting inhibitory Tpm positioning.

High impact / low probability supply chain disruptions represent a major challenge for firms. Such disruptions represent a classic bottleneck shifting problem. When the firm can backlog some portion of its unmet customer orders, its disruption exposure is driven by (i) lost demand in the disruption period due to part constraints and (ii) lost demand in the recovery period due to capacity constraints. Although holding inventory has been shown to mitigate a firm's disruption exposure, it is considered costly to do so. We address this complication by showing that the firm's disruption exposure is decreasing at a decreasing rate with the inventory quantity of the disrupted part. More surprisingly, the firm's disruption exposure is decreasing at a decreasing rate with the inventory quantity of non-disrupted parts. We exploit these findings to further show that the firm can materially reduce its disruption exposure across all parts by holding a small amount of incremental inventory of selected parts. Using these insights and the detailed supply chain and operational data from our research partner, a large manufacturer of material handling equipment, we show how targeted changes to the firm's inventory policies across many parts can achieve a significant reduction in its disruption exposure, at no cost. This "strategic pool" of parts serves as a means for the firm to effectively store its otherwise unused disruption period production capacity.

Purpose This outcome analysis presents 88 consecutive shoulders presenting with irreparable rotator cuff tears that we treated with arthroscopic superior capsular reconstruction (SCR) using an acellular dermal allograft. We also present the concept of superior capsular distance to quantitatively measure the decreased distance present upon restoration of superior capsular integrity. Methods A retrospective review was conducted of patients treated with arthroscopic SCR with a minimum 12-month follow-up. Outcome analysis was performed via an internet-based outcome-tracking system to evaluate visual analog scale (VAS) and American Shoulder and Elbow Surgeons (ASES) scores. Radiographic analysis of anteroposterior radiographs analyzed acromiohumeral interval and superior capsular distance. Digital dynamometric strength and functional range of motion assessments were also obtained. The main inclusion criteria for patients in this analysis was all patients who underwent superior capsular reconstruction during the time period of this report. Results Eighty-six patients with an average age of 59.4 years presented with massive rotator cuff tears (Cofield >5 cm). Outcome data revealed improvement in VAS (4.0-1.5), and ASES (52-82) scores at 1 year ( P = .005). Radiographic analysis showed increase in acromiohumeral interval (mean 7.1 mm preoperatively to mean 9.7 mm at 1 year) ( P = .049) and superior capsular distance (mean 52.9 mm preoperatively to mean 46.2 mm at 1 year) ( P = .011). Strength improved significantly (forward flexion/abduction/external rotation of 4.8/4.1/7.7 lb preoperatively to 9.8/9.2/12.3 lb at 1 year) as well as range of motion (forward flexion/abduction of 120°/103° preoperatively to 160°/159° at 1 year) ( P = .044/ P = .007/ P = .02). At follow-up, 90% of patients were satisfied. Conclusions This analysis reveals that arthroscopic SCR with acellular dermal allograft has been successful in decreasing pain and improving function in this patient subset. Radiographic analysis has also shown a consistent and lasting decrease in superior capsular distance and increase in acromiohumeral interval, indicating maintenance of superior capsular stability. Level of Evidence Level IV, retrospective case series.

BackgroundMost patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.MethodsPatients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.ResultsFor randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients ConclusionsSeviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.Trial registration numberNCT01546571.

Elementary students engage with marbles to understand how it move when placed and released at different angles. Students also observe and record information on how the marble behaves on different surfaces.

Intellectual property (IP) protections have affected drug development and are considered one of the most important assets of any corporate entity or research organization. The four main types of IP rights are patents, trademarks, copyrights, and trade secrets. IP affects everything from the choice of brand name to stock valuation. Patents are a quid pro quo “right to exclude” which encourage innovation by providing financial incentives for research and development (R&D) activities. The three requirements for patenting are usefulness, novelty, and nonobviousness. Patent protection allows authorities to take active measure to prevent counterfeit versions of medications. Additionally, few of the new medications for diseases such as AIDS that have caused deaths to plummet would have come into existence without patent incentives and the prospect of a return on investment provided by that incentive.

Objective: Cardiac troponin I (cTnI) is an essential regulator of cardiac contractility and relaxation. Mutations within key regions of this regulator lead to cardiomyopathies. Further, post-translational modification of cTnI through phosphorylation impacts myofibril relaxation and calcium sensitivity. Recent studies have also demonstrated that myofibril proteins are acetylated leading to faster relaxation. These studies highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to mechanical changes in the myofibril. The objective of this study was to determine if acetylation at a single site of cTnI (lysine-132; K132) is sufficient to alter myofibril protein mechanics. Methods: Adult rat ventricular cardiomyocytes infected with adenoviral constructs expressing either cTnI K132 replaced with glutamine (K132Q; to mimic acetylation) or K132 replaced with arginine (K132R; to prevent acetylation) were subjected to cell contractility and isolated myofibril mechanic measurements. Additionally, skinned myofibrils were exchanged with troponin containing wildtype (WT) or K132Q cTnI and mechanics assessed. Finally, dynamics of reconstituted thin filaments containing WT or K132Q cTnI were assessed by in vitro motility assay. Results: Cardiomyocytes expressing cTnI K132Q relaxed faster and had decreased calcium sensitivity compared to WT cTnI at the whole cell and myofibril level. Relaxation or calcium sensitivity did not differ between cardiomyocytes infected with WT cTnI and cTnI K132R. Myofibrils with cTnI K132Q exchanged ex vivo demonstrate faster relaxation and decreased calcium sensitivity as well as decreased motility. Conclusions: Our results indicate for the first time that acetylation at a specific cTnI lysine can alter myofibril relaxation and calcium sensitivity. This work underscores the importance of understanding how acetylation affects specific sarcomeric proteins in the context of cardiac disease, and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

1 The Role of International Assessments in Understanding Teacher Quality -- 2 A Review of the Literature on Teacher Effectiveness and Student Outcomes -- 3 Teacher Variables, and Modeling the Relationships Between Teacher Characteristics, Teacher Behaviors, and Student -- 4 Measuring Teacher Effectiveness Across Time: What Does TIMSS Reveal About Education System Level Trends? -- 5 Teacher Quality and Mean Student Outcomes: A Multi-model Approach -- 6 Relationships Between Instructional Alignment, Time, Instructional Quality, Teacher Quality, and Student Mathematics Achievement -- 7 Teacher Effectiveness and Educational Equity -- 8 What Does the TIMSS Tell Us About Teacher Effectiveness? -- Appendix A: Detailed Country-Level Means for Key Variables -- Appendix B: Detailed Regression Estimates for the Single-level, Multilevel, and Classroom-mean Models. This open access book examines the interrelationship of national policy, teacher effectiveness, and student outcomes with a specific emphasis on educational equity. Using data from the IEA’s Trends in International Mathematics and Science Study (TIMSS) conducted between 1995 and 2015, it investigates grade four and grade eight data to assess trends in key teacher characteristics (experience, education, preparedness, and professional development) and teacher behaviors (instructional time and instructional content), and how these relate to student outcomes. Taking advantage of national curriculum data collected by TIMSS to assess changes in curricular strategy across countries and how these may be related to changes in teacher and student factors, the study focuses on the distributional impact of curriculum and instruction on students, paying particular attention to overall inequalities and variations in socioeconomic status at the student and country level, and how such factors have altered over time. Multiple methods, including regression and fixed effects analyses, and structural equation modelling, establish the evolution of these associations over time.

Striated muscle contraction is regulated by Ca(2+)-dependent modulation of myosin cross-bridge binding to F-actin by the thin filament troponin (Tn)-tropomyosin (Tm) complex. In the absence of Ca(2+), Tn binds to actin and constrains Tm to an azimuthal location where it sterically occludes myosin binding sites along the thin filament surface. This limits force production and promotes muscle relaxation. In addition to Tn-actin interactions, inhibitory Tm positioning requires associations between other thin filament constituents. For example, the actin “A-triad”, composed of residues K326, K328, and R147, forms numerous, highly favorable electrostatic contacts with Tm that are critical for establishing its inhibitory azimuthal binding position. Here, we review recent findings, including the identification and interrogation of modifications within and proximal to the A-triad that are associated with disease and/or altered muscle behavior, which highlight the surface feature’s role in F-actin-Tm interactions and contractile regulation.

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca(2+)](i) in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca(2+)-activated force (F(max)) and increased the [Ca(2+)](i) required for 50% of F(max) (Ca(50)) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.—Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle.

We offer a new network perspective on one of the central topics in operations management—the bullwhip effect (BWE). The topic has both practical and scholarly implications. We start with an observation: the variability of orders placed to suppliers is larger than the variability of sales to customers for most firms, yet the aggregate demand variability felt by suppliers upstream does not amplify commensurably. We hypothesize that changes to the supplier’s customer base can smooth out its aggregate demand. We test the hypothesis with a data set that tracks the evolution of supply relationships over time. We show that the effect of customer base management extends beyond the statistical benefits of aggregation. In particular, both the formation and the dissolution of customer-supplier relationships are associated with the smoothing of the aggregate demand experienced by suppliers. This provides fresh insight into how firms may leverage their customer-supplier relationships to mitigate the impact of the BWE. This paper was accepted by Jay Swaminathan, operations management.

Over the past two decades, a discrepancy has emerged between two different techniques for measuring the proton's electromagnetic form factors. Unpolarized electron-proton cross section measurements paint a picture of the proton's internal structure that is incompatible with measurements from polarization transfer experiments. The leading hypothesis is that the discrepancy is caused by a typically neglected radiative correction, hard two-photon exchange (TPE), which would affect the two measurement techniques in different ways. There is no model independent way to calculate hard TPE, but it can be measured experimentally by looking for an asymmetry between the positron-proton and electron-proton elastic cross sections. Three recent experiments have attempted to quantify this asymmetry, and, just last month, the third of these, called OLYMPUS, released its results (arXiv:1611.04685). The OLYMPUS experiment collected data in 2012 at DESY, alternating between 2 GeV electron and positron beams, directed through a hydrogen gas target. The scattered lepton and recoiling proton were detected in coincidence with a large acceptance toroidal spectrometer. The relative luminosity between the two beam species was monitored with three independent systems, and the results comprise 3 inverse fb of integrated luminosity, exceeding by a factor of three the other two TPE experiments combined. In this talk, the case for the TPE hypothesis will be presented, the OLYMPUS experiment will be described, and the results of all three experiments will be compared.

Tropomyosin is an elongated α-helical coiled coil that binds to seven consecutive actin subunits along the long-pitch helix of actin filaments. Once bound, tropomyosin polymerizes end-to-end and both stabilizes F-actin and regulates access of various actin-binding proteins including myosin in muscle and nonmuscle cells. Single tropomyosin molecules bind weakly to F-actin with millimolar Kd , whereas the end-to-end linked tropomyosin associates with about a 1000-fold greater affinity. Despite years of study, the assembly mechanism of tropomyosin onto actin filaments remains unclear. In this study, we used total internal reflection fluorescence microscopy to directly monitor the cooperative binding of fluorescently labeled tropomyosin molecules to phalloidin-stabilized actin filaments. We find that tropomyosin molecules assemble from multiple growth sites after random low-affinity binding of single molecules to actin. As the length of the tropomyosin chain increases, the probability of detachment decreases, which leads to further chain growth. Tropomyosin chain extension is linearly dependent on the concentration of tropomyosin, occurring at approximately 100 monomers/(μM*s). The random tropomyosin binding to F-actin leads to discontinuous end-to-end association where gaps in the chain continuity smaller than the required seven sequential actin monomers are available. Direct observation of tropomyosin detachment revealed the number of gaps in actin-bound tropomyosin, the time course of gap annealing, and the eventual filament saturation process.

Autologous hematopoietic cell transplantation (Auto-HCT) is commonly an in-patient procedure. However, Auto-HCT is increasingly being offered on an outpatient basis. To better characterize the safety of outpatient Auto-HCT, we compared the outcome of 230 patients who underwent Auto-HCT on an in-patient vs outpatient basis for myeloma or lymphoma within a single transplant program. All outpatient transplants occurred in a cancer center day hospital. Hematopoietic recovery occurred earlier in the outpatient cohort, with median time to neutrophil recovery of 10 vs 11 days (P

This research investigates how information asymmetry between the firm and its investors can influence supply chain disruptions. In such settings, these actors may be induced to take steps which exacerbate rather than ameliorate both the likelihood and impact of disruptions. By better understanding these mechanisms, managers and investors alike are better armed to avoid the costly consequences.

SUMMARY Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder., In Brief Viswanathan et al. demonstrate that the conserved actin A-triad, composed of K326, K328, and R147, normally biases tropomyosin to a position that impedes actomyosin associations along resting striated muscle thin filaments. The proximally located actin A295S hypertrophic cardiomyopathy mutation distorts A-triad-tropomyosin associations, which promotes contractile disinhibition, hypercontraction, and disease pathogenesis.