Research Summary
Supervised machine learning (ML) methods are a powerful toolkit for discovering robust patterns in quantitative data. The patterns identified by ML could be used for exploratory ...inductive or abductive research, or for post hoc analysis of regression results to detect patterns that may have gone unnoticed. However, ML models should not be treated as the result of a deductive causal test. To demonstrate the application of ML for pattern discovery, we implement ML algorithms to study employee turnover at a large technology company. We interpret the relationships between variables using partial dependence plots, which uncover surprising nonlinear and interdependent patterns between variables that may have gone unnoticed using traditional methods. To guide readers evaluating ML for pattern discovery, we provide guidance for evaluating model performance, highlight human decisions in the process, and warn of common misinterpretation pitfalls. The Supporting Information section provides code and data to implement the algorithms demonstrated in this article.
Managerial Summary
Supervised machine learning (ML) methods are a powerful toolkit that might help managers and researchers discover interesting patterns in large and complex data. We demonstrate this by using several ML algorithms to investigate the drivers of employee turnover at a large technology company. We evaluate the performance of the models, and use visual tools to interpret the patterns revealed. These patterns can be useful in understanding turnover, but we caution not to confuse correlation with causation. These methods should be viewed as “exploratory” and not conclusive proof of relationships in the data. Our guidance can be helpful for managers evaluating analysis conducted by data scientists in their organizations.
Pre-mRNA splicing is regulated by developmental and environmental cues, but little is known about how specific signals are transduced in mammalian cells to regulate this critical gene expression ...step. Here, we report massive reprogramming of alternative splicing in response to EGF signaling. By blocking individual branches in EGF signaling, we found that Akt activation plays a major role, while other branches, such as the JAK/STAT and ERK pathways, make minor contributions to EGF-induced splicing. Activated Akt next branches to SR protein-specific kinases, rather than mTOR, by inducing SRPK autophosphorylation that switches the splicing kinases from Hsp70- to Hsp90-containing complexes. This leads to enhanced SRPK nuclear translocation and SR protein phosphorylation. These findings reveal a major signal transduction pathway for regulated splicing and place SRPKs in a central position in the pathway, consistent with their reputed roles in a large number of human cancers.
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► SR kinases are a major branch in the EGF pathway to regulate alternative splicing ► Activated Akt induces SRPK1autophosphorylation ► Activated SRPK1 translocates to the nucleus in an Hsp90-dependent manner ► Induced SR protein hyperphosphorylation leads to widespread changes in splicing
Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the ...acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury-during the chronic phase-we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be 'unlocked' by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.
Two simplifying hypotheses have been proposed for whole‐plant respiration. One links respiration to photosynthesis; the other to biomass. Using a first‐principles carbon balance model with a ...prescribed live woody biomass turnover, applied at a forest research site where multidecadal measurements are available for comparison, we show that if turnover is fast the accumulation of respiring biomass is low and respiration depends primarily on photosynthesis; while if turnover is slow the accumulation of respiring biomass is high and respiration depends primarily on biomass. But the first scenario is inconsistent with evidence for substantial carry‐over of fixed carbon between years, while the second implies far too great an increase in respiration during stand development—leading to depleted carbohydrate reserves and an unrealistically high mortality risk. These two mutually incompatible hypotheses are thus both incorrect. Respiration is not linearly related either to photosynthesis or to biomass, but it is more strongly controlled by recent photosynthates (and reserve availability) than by total biomass.
Metabolism, reserves and size all drive forest C‐balance.
Climate change is likely to alter wildfire regimes, but the magnitude and timing of potential climate-driven changes in regional fire regimes are not well understood. We considered how the ...occurrence, size, and spatial location of large fires might respond to climate projections in the Greater Yellowstone ecosystem (GYE) (Wyoming), a large wildland ecosystem dominated by conifer forests and characterized by infrequent, high-severity fire. We developed a suite of statistical models that related monthly climate data (1972–1999) to the occurrence and size of fires >200 ha in the northern Rocky Mountains; these models were cross-validated and then used with downscaled (∼12 km × 12 km) climate projections from three global climate models to predict fire occurrence and area burned in the GYE through 2099. All models predicted substantial increases in fire by midcentury, with fire rotation (the time to burn an area equal to the landscape area) reduced to <30 y from the historical 100–300 y for most of the GYE. Years without large fires were common historically but are expected to become rare as annual area burned and the frequency of regionally synchronous fires increase. Our findings suggest a shift to novel fire–climate–vegetation relationships in Greater Yellowstone by midcentury because fire frequency and extent would be inconsistent with persistence of the current suite of conifer species. The predicted new fire regime would transform the flora, fauna, and ecosystem processes in this landscape and may indicate similar changes for other subalpine forests.
Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
The authors sought to understand the ...presentation and clinical course of ICI-associated myocarditis.
After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
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Objectives
The National Institutes of Health, led by the National Heart, Lung, and Blood Institute, organized a working group of experts to discuss the problem of weight regain after weight loss. A ...number of experts in integrative physiology and behavioral psychology were convened with the goal of merging their perspectives regarding the barriers to scientific progress and the development of novel ways to improve long‐term outcomes in obesity therapeutics. The specific objectives of this working group were to: (1) identify the challenges that make maintaining a reduced weight so difficult; (2) review strategies that have been used to improve success in previous studies; and (3) recommend novel solutions that could be examined in future studies of long‐term weight control.
Results
Specific barriers to successful weight loss maintenance include poor adherence to behavioral regimens and physiological adaptations that promote weight regain. A better understanding of how these behavioral and physiological barriers are related, how they vary between individuals, and how they can be overcome will lead to the development of novel strategies with improved outcomes.
Conclusions
Greater collaboration and cross‐talk between physiological and behavioral researchers is needed to advance the science and develop better strategies for weight loss maintenance.
There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker ...of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.
This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.
This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.
Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).
GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
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