Tree rings reveal the transient risk of extinction hidden inside climate envelope forecasts.

Given the importance of climate in shaping species' geographic distributions, climate change poses an existential threat to biodiversity. Climate envelope modeling, the predominant approach used to quantify this threat, presumes that individuals in populations respond to climate variability and change according to species-level responses inferred from spatial occurrence data-such that individuals at the cool edge of a species' distribution should benefit from warming (the "leading edge"), whereas individuals at the warm edge should suffer (the "trailing edge"). Using 1,558 tree-ring time series of an aridland pine (Pinus edulis) collected at 977 locations across the species' distribution, we found that trees everywhere grow less in warmer-than-average and drier-than-average years. Ubiquitous negative temperature sensitivity indicates that individuals across the entire distribution should suffer with warming-the entire distribution is a trailing edge. Species-level responses to spatial climate variation are opposite in sign to individual-scale responses to time-varying climate for approximately half the species' distribution with respect to temperature and the majority of the species' distribution with respect to precipitation. These findings, added to evidence from the literature for scale-dependent climate responses in hundreds of species, suggest that correlative, equilibrium-based range forecasts may fail to accurately represent how individuals in populations will be impacted by changing climate. A scale-dependent view of the impact of climate change on biodiversity highlights the transient risk of extinction hidden inside climate envelope forecasts and the importance of evolution in rescuing species from extinction whenever local climate variability and change exceeds individual-scale climate tolerances.

Generalized additive models to analyze nonlinear trends in biomedical longitudinal data using R: Beyond repeated measures ANOVA and linear mixed models.

In biomedical research, the outcome of longitudinal studies has been traditionally analyzed using the repeated measures analysis of variance (rm-ANOVA) or more recently, linear mixed models (LMEMs). Although LMEMs are less restrictive than rm-ANOVA as they can work with unbalanced data and non-constant correlation between observations, both methodologies assume a linear trend in the measured response. It is common in biomedical research that the true trend response is nonlinear and in these cases the linearity assumption of rm-ANOVA and LMEMs can lead to biased estimates and unreliable inference. In contrast, GAMs relax the linearity assumption of rm-ANOVA and LMEMs and allow the data to determine the fit of the model while also permitting incomplete observations and different correlation structures. Therefore, GAMs present an excellent choice to analyze longitudinal data with non-linear trends in the context of biomedical research. This paper summarizes the limitations of rm-ANOVA and LMEMs and uses simulated data to visually show how both methods produce biased estimates when used on data with non-linear trends. We present the basic theory of GAMs and using reported trends of oxygen saturation in tumors, we simulate example longitudinal data (2 treatment groups, 10 subjects per group, 5 repeated measures for each group) to demonstrate their implementation in R. We also show that GAMs are able to produce estimates with non-linear trends even when incomplete observations exist (with 40% of the simulated observations missing). To make this work reproducible, the code and data used in this paper are available at: https://github.com/aimundo/GAMs-biomedical-research.

Past and future global transformation of terrestrial ecosystems under climate change.

Impacts of global climate change on terrestrial ecosystems are imperfectly constrained by ecosystem models and direct observations. Pervasive ecosystem transformations occurred in response to warming and associated climatic changes during the last glacial-to-interglacial transition, which was comparable in magnitude to warming projected for the next century under high-emission scenarios. We reviewed 594 published paleoecological records to examine compositional and structural changes in terrestrial vegetation since the last glacial period and to project the magnitudes of ecosystem transformations under alternative future emission scenarios. Our results indicate that terrestrial ecosystems are highly sensitive to temperature change and suggest that, without major reductions in greenhouse gas emissions to the atmosphere, terrestrial ecosystems worldwide are at risk of major transformation, with accompanying disruption of ecosystem services and impacts on biodiversity.

Noninvasive 40-Hz light flicker to recruit microglia and reduce amyloid beta load.

Microglia, the primary immune cells of the brain, play a key role in pathological and normal brain function. Growing efforts aim to reveal how these cells may be harnessed to treat both neurodegenerative diseases such as Alzheimer's and developmental disorders such as schizophrenia and autism. We recently showed that using noninvasive exposure to 40-Hz white-light (4,000 K) flicker to drive 40-Hz neural activity transforms microglia into an engulfing state and reduces amyloid beta, a peptide thought to initiate neurotoxic events in Alzheimer's disease (AD). This article describes how to construct an LED-based light-flicker apparatus, expose animals to 40-Hz flicker and control conditions, and perform downstream assays to study the effects of these stimuli. Light flicker is simple, faster to implement, and noninvasive, as compared with driving 40-Hz activity using optogenetics; however, it does not target specific cell types, as is achievable with optogenetics. This noninvasive approach to driving 40-Hz neural activity should enable further research into the interactions between neural activity, molecular pathology, and the brain's immune system. Construction of the light-flicker system requires ~1 d and some electronics experience or available guidance. The flicker manipulation and assessment can be completed in a few days, depending on the experimental design.

Immunoengineering nerve repair.

Injuries to the peripheral nervous system are major sources of disability and often result in painful neuropathies or the impairment of muscle movement and/or normal sensations. For gaps smaller than 10 mm in rodents, nearly normal functional recovery can be achieved; for longer gaps, however, there are challenges that have remained insurmountable. The current clinical gold standard used to bridge long, nonhealing nerve gaps, the autologous nerve graft (autograft), has several drawbacks. Despite best efforts, engineering an alternative "nerve bridge" for peripheral nerve repair remains elusive; hence, there is a compelling need to design new approaches that match or exceed the performance of autografts across critically sized nerve gaps. Here an immunomodulatory approach to stimulating nerve repair in a nerve-guidance scaffold was used to explore the regenerative effect of reparative monocyte recruitment. Early modulation of the immune environment at the injury site via fractalkine delivery resulted in a dramatic increase in regeneration as evident from histological and electrophysiological analyses. This study suggests that biasing the infiltrating inflammatory/immune cellular milieu after injury toward a proregenerative population creates a permissive environment for repair. This approach is a shift from the current modes of clinical and laboratory methods for nerve repair, which potentially opens an alternative paradigm to stimulate endogenous peripheral nerve repair.

The basis function approach for modeling autocorrelation in ecological data.

Analyzing ecological data often requires modeling the autocorrelation created by spatial and temporal processes. Many seemingly disparate statistical methods used to account for autocorrelation can be expressed as regression models that include basis functions. Basis functions also enable ecologists to modify a wide range of existing ecological models in order to account for autocorrelation, which can improve inference and predictive accuracy. Furthermore, understanding the properties of basis functions is essential for evaluating the fit of spatial or time-series models, detecting a hidden form of collinearity, and analyzing large data sets. We present important concepts and properties related to basis functions and illustrate several tools and techniques ecologists can use when modeling autocorrelation in ecological data.

A regenerative microchannel device for recording multiple single-unit action potentials in awake, ambulatory animals.

Despite significant advances in robotics, commercially advanced prosthetics provide only a small fraction of the functionality of the amputated limb that they are meant to replace. Peripheral nerve interfacing could provide a rich controlling link between the body and these advanced prosthetics in order to increase their overall utility. Here, we report on the development of a fully integrated regenerative microchannel interface with 30 microelectrodes and signal extraction capabilities enabling evaluation in an awake and ambulatory rat animal model. In vitro functional testing validated the capability of the microelectrodes to record neural signals similar in size and nature to those that occur in vivo. In vitro dorsal root ganglia cultures revealed striking cytocompatibility of the microchannel interface. Finally, in vivo, the microchannel interface was successfully used to record a multitude of single-unit action potentials through 63% of the integrated microelectrodes at the early time point of 3 weeks. This marks a significant advance in microchannel interfacing, demonstrating the capability of microchannels to be used for peripheral nerve interfacing.

Avanti lipid tools: connecting lipids, technology, and cell biology.

Lipid research is challenging owing to the complexity and diversity of the lipidome. Here we review a set of experimental tools developed for the seasoned lipid researcher, as well as, those who are new to the field of lipid research. Novel tools for probing protein-lipid interactions, applications for lipid binding antibodies, enhanced systems for the cellular delivery of lipids, improved visualization of lipid membranes using gold-labeled lipids, and advances in mass spectrometric analysis techniques will be discussed. Because lipid mediators are known to participate in a host of signal transduction and trafficking pathways within the cell, a comprehensive lipid toolbox that aids the science of lipidomics research is essential to better understand the molecular mechanisms of interactions between cellular components. This article is part of a Special Issue entitled Tools to study lipid functions.

Evidence-based treatment of hamstring tears.

Hamstring tears are exceedingly common in a variety of athletic populations and contribute to a significant amount of morbidity and time lost from sport. Many modifiable and nonmodifiable risk factors have been identified with hamstring injury. There is strong evidence that Nordic hamstring exercises can decrease the risk of hamstring injury, limited evidence that sports specific anaerobic interval training and isokinetic strengthening can reduce injury rates, and limited evidence that daily static stretching after injury can increase recovery rate. The majority of medical, surgical, and rehabilitative intervention studies have limitations based on the total number of hamstring injuries included in a given study, reliance on retrospective cohort studies, and conclusions based on case series that limit the utility of the information. Most do not provide a level of evidence greater than expert opinion.

Obturator neuropathy.

Obturator neuropathy is a difficult clinical problem to evaluate. One possible cause of pain is due to fascial entrapment of the nerve. Symptoms include medial thigh or groin pain, weakness with leg adduction, and sensory loss in the medial thigh of the affected side. Radiographic imaging provides limited diagnostic help. MRI may detect atrophy in the adductors of the leg. However, it is unable to detect any abnormality of the nerve or in the fibro-osseus tunnel. The best test for diagnosis is by electromyography (EMG) and can be confirmed by a local nerve block. Pharmacologic management of pain and physical therapy can be helpful in the acute phase of injury. Surgical decompression of the nerve should be considered for lesions documented by EMG or local nerve block, for those with predisposing risk factors (prior surgery, pelvic trauma, or hematoma) and with prolonged or severe lesions.

Ice reduces edema. A study of microvascular permeability in rats.

BACKGROUND: Ice is applied following a soft-tissue injury on the basis of clinical information. This study investigates the relationship between ice therapy (cryotherapy) and edema by determining microvascular permeability before and after contusion with and without ice therapy and provides data supporting a reduction in edema following cryotherapy. METHODS: A dorsal microvascular chamber was created in rats to allow the direct examination of microvascular parameters in intact, pre-established microvascular beds of the cutaneous maximus muscle in conscious rats. The rats received a contusion or sham contusion and were treated with cryotherapy or were not treated. Microvascular permeability (edema) was assessed by measuring fluorescent-labeled albumin in the interstitial fluid before and after contusion. RESULTS: Microvascular permeability following contusion was significantly increased in the group that received the contusion without cryotherapy compared with that in the group that received the sham contusion without cryotherapy (control) (p < 0.001). When ice was applied fifteen minutes after the contusion for twenty minutes, microvascular permeability (edema) decreased significantly (p < 0.001) compared with that in the group that did not receive cryotherapy after contusion. Permeability was increased in the group that received cryotherapy following the contusion compared with that in the control group (p = 0.012), although the increase was not as great as that between the group that received the contusion without cryotherapy and the control group. Sham contusion with cryotherapy significantly reduced microvascular permeability compared with that in the control group (p = 0.004). Sham contusion without cryotherapy did not cause a significant change in the microvascular permeability of postcapillary venules after 300 minutes compared with baseline measurements. CONCLUSIONS: The application of ice significantly decreased microvascular permeability following striated muscle contusion. The results of this study demonstrated that microvascular permeability is increased following a contusion coincident with significant leukocyte-endothelial interactions. However, microvascular permeability was significantly reduced following cryotherapy, a treatment demonstrated to reduce the number of rolling and adherent leukocytes. This association suggests that the reduction in edema in injured skeletal muscle following cryotherapy may be due to a reduction in leukocyte-endothelial interactions.