Biological mechanisms of aging predict age‐related disease co‐occurrence in patients

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age‐related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co‐occurrence of age‐related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non‐random associations between age‐related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age‐related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age‐related diseases. Mechanisms of aging hence contribute both together and individually to age‐related disease co‐occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity.     

Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Hereditary degeneration of photoreceptors has been linked to over-activation of Ca²⁺-permeable channels, excessive Ca²⁺-influx, and downstream activation of Ca²⁺-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca²⁺-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca²⁺-influx, most probably by blocking the pore of Ca²⁺-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca²⁺ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca²⁺-independent degenerative mechanisms.Subject terms: Cell death in the nervous system, Ion channels in the nervous system, Molecular neuroscience     

Mapping bone cell distributions to assess ontogenetic origin of primate midfacial form

Midfacial reduction in primates has been explained as a byproduct of other growth patterns, especially the convergent orbits. This is at once an evolutionary and developmental explanation for relatively short snouts in most modern primates. Here, we use histological sections of perinatal nonhuman primates (tamarin, tarsier, loris) to investigate how orbital morphology emerges during ontogeny in selected primates compared to another euarchontan (Tupaia glis). We annotated serial histological sections for location of osteoclasts or osteoblasts, and used these to create three‐dimensional “modeling maps” showing perinatal growth patterns of the facial skeleton. In addition, in one specimen we transferred annotations from histological sections to CT slices, to create a rotatable 3D volume that shows orbital modeling. Our findings suggest that growth in the competing orbital and neurocranial functional matrices differs among species, influencing modeling patterns. Distinctions among species are observed in the frontal bone, at a shared interface between the endocranial fossa and the orbit. The medial orbital wall is extensively resorptive in primates, whereas the medial orbit is generally depositional in Tupaia. As hypothesized, the orbital soft tissues encroach on available interorbital space. However, eye size cannot, by itself, explain the extent of reduction of the olfactory recess. In Loris, the posterior portion of medial orbit differed from the other primates. It showed evidence of outward drift where the olfactory bulb increased in cross‐sectional area. We suggest the olfactory bulbs are significant to orbit position in strepsirrhines, influencing an expanded interorbital breadth at early stages of development. Am J Phys Anthropol 154:424–435, 2014. © 2014 Wiley Periodicals, Inc.     

Cerebral Hemodynamic Changes of Mild Traumatic Brain Injury at the Acute Stage

Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation.     

Response of wheat canopy CO2 and water gas-exchange to soil water content under ambient and elevated CO2

The nature of the interaction between drought and elevated CO₂ partial pressure (pC_a) is critically important for the effects of global change on crops. Some crop models assume that the relative responses of transpiration and photosynthesis to soil water deficit are unaltered by elevated pC_a, while others predict decreased sensitivity to drought at elevated pC_a. These assumptions were tested by measuring canopy photosynthesis and transpiration in spring wheat (cv. Minaret) stands grown in boxes with 100 L rooting volume. Plants were grown under controlled environments with constant light (300 µmol m^?2 s^?1) at ambient (36 Pa) or elevated (68 Pa) pC_a and were well watered throughout growth or had a controlled decline in soil water starting at ear emergence. Drought decreased final aboveground biomass (?15%) and grain yield (?19%) while elevated pC_a increased biomass (+24%) and grain yield (+29%) and there was no significant interaction. Elevated pC_a increased canopy photosynthesis by 15% on average for both water regimes and increased dark respiration per unit ground area in well‐watered plants, but not drought‐grown ones. Canopy transpiration and photosynthesis were decreased in drought‐grown plants relative to well‐watered plants after about 20–25 days from the start of the drought. Elevated pC_a decreased transpiration only slightly during drought, but canopy photosynthesis continued to be stimulated so that net growth per unit water transpired increased by 21%. The effect of drought on canopy photosynthesis was not the consequence of a loss of photosynthetic capacity initially, as photosynthesis continued to be stimulated proportionately by a fixed increase in irradiance. Drought began to decrease canopy transpiration below a relative plant‐available soil water content of 0.6 and canopy photosynthesis and growth below 0.4. The shape of these responses were unaffected by pC_a, supporting the simple assumption used in some models that they are independent of pC_a.     

Integrating microbial ecology into ecosystem models: challenges and priorities

Microbial communities can potentially mediate feedbacks between global change and ecosystem function, owing to their sensitivity to environmental change and their control over critical biogeochemical processes. Numerous ecosystem models have been developed to predict global change effects, but most do not consider microbial mechanisms in detail. In this idea paper, we examine the extent to which incorporation of microbial ecology into ecosystem models improves predictions of carbon (C) dynamics under warming, changes in precipitation regime, and anthropogenic nitrogen (N) enrichment. We focus on three cases in which this approach might be especially valuable: temporal dynamics in microbial responses to environmental change, variation in ecological function within microbial communities, and N effects on microbial activity. Four microbially-based models have addressed these scenarios. In each case, predictions of the microbial-based models differ—sometimes substantially—from comparable conventional models. However, validation and parameterization of model performance is challenging. We recommend that the development of microbial-based models must occur in conjunction with the development of theoretical frameworks that predict the temporal responses of microbial communities, the phylogenetic distribution of microbial functions, and the response of microbes to N enrichment.     

Protective Ventilation of Preterm Lambs Exposed to Acute Chorioamnionitis Does Not Reduce Ventilation-Induced Lung or Brain Injury

Background

The onset of mechanical ventilation is a critical time for the initiation of cerebral white matter (WM) injury in preterm neonates, particularly if they are inadvertently exposed to high tidal volumes (V_T) in the delivery room. Protective ventilation strategies at birth reduce ventilation-induced lung and brain inflammation and injury, however its efficacy in a compromised newborn is not known. Chorioamnionitis is a common antecedent of preterm birth, and increases the risk and severity of WM injury. We investigated the effects of high V_T ventilation, after chorioamnionitis, on preterm lung and WM inflammation and injury, and whether a protective ventilation strategy could mitigate the response.

Methods

Pregnant ewes (n = 18) received intra-amniotic lipopolysaccharide (LPS) 2 days before delivery, instrumentation and ventilation at 127±1 days gestation. Lambs were either immediately euthanased and used as unventilated controls (LPS_UVC; n = 6), or were ventilated using an injurious high V_T strategy (LPS_INJ; n = 5) or a protective ventilation strategy (LPS_PROT; n = 7) for a total of 90 min. Mean arterial pressure, heart rate and cerebral haemodynamics and oxygenation were measured continuously. Lungs and brains underwent molecular and histological assessment of inflammation and injury.

Results

LPS_INJ lambs had poorer oxygenation than LPS_PROT lambs. Ventilation requirements and cardiopulmonary and systemic haemodynamics were not different between ventilation strategies. Compared to unventilated lambs, LPS_INJ and LPS_PROT lambs had increases in pro-inflammatory cytokine expression within the lungs and brain, and increased astrogliosis (p<0.02) and cell death (p<0.05) in the WM, which were equivalent in magnitude between groups.

Conclusions

Ventilation after acute chorioamnionitis, irrespective of strategy used, increases haemodynamic instability and lung and cerebral inflammation and injury. Mechanical ventilation is a potential contributor to WM injury in infants exposed to chorioamnionitis.