Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined ...how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.
•Repeated acute resolving inflammation leads to excessive tissue damage•IL-6 regulates profibrotic IFN-γ-secreting T cells•IFN-γ increases detrimental STAT1 signaling in stromal tissue•STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis
The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in ...some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.
The future of zoonotic risk prediction Carlson, Colin J.; Farrell, Maxwell J.; Grange, Zoe ...
Philosophical transactions - Royal Society. Biological sciences,
11/2021, Letnik:
376, Številka:
1837
Journal Article
Recenzirano
Odprti dostop
In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that ...might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges?
This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.
ObjectivesTo compare the food, nutrient and ‘family meal’ intakes of infants following baby-led weaning (BLW) with those of infants following a more traditional spoon-feeding (TSF) approach to ...complementary feeding.Study design and participantsCross-sectional study of dietary intake and feeding behaviours in 51 age-matched and sex-matched infants (n=25 BLW, 26 TSF) 6–8 months of age.MethodsParents completed a questionnaire, and weighed diet records (WDRs) on 1–3 non-consecutive days, to investigate food and nutrient intakes, the extent to which infants were self-fed or parent-fed, and infant involvement in ‘family meals’.ResultsBLW infants were more likely than TSF infants to have fed themselves all or most of their food when starting complementary feeding (67% vs 8%, p<0.001). Although there was no statistically significant difference in the large number of infants consuming foods thought to pose a choking risk during the WDR (78% vs 58%, p=0.172), the CI was wide, so we cannot rule out increased odds with BLW (OR, 95% CI: 2.57, 0.63 to 10.44). No difference was observed in energy intake, but BLW infants appeared to consume more total (48% vs 42% energy, p<0.001) and saturated (22% vs 18% energy, p<0.001) fat, and less iron (1.6 vs 3.6 mg, p<0.001), zinc (3.0 vs 3.7 mg, p=0.001) and vitamin B12 (0.2 vs 0.5 μg, p<0.001) than TSF infants. BLW infants were more likely to eat with their family at lunch and at the evening meal (both p≤0.020).ConclusionsInfants following BLW had similar energy intakes to those following TSF and were eating family meals more regularly, but appeared to have higher intakes of fat and saturated fat, and lower intakes of iron, zinc and vitamin B12. A high proportion of both groups were offered foods thought to pose a choking risk.
The pathogenic fungus
enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which ...nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized
and
via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of
is via both dectin-1 and dectin-2,
uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (
) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis.
Avian nests are fundamental structures in avian reproduction and face strong selective forces. Climatic conditions are likely to have shaped the evolution of specific nest traits, but evidence is ...scarce at a macroevolutionary level. The Thraupidae family (commonly known as tanagers) is an ideal clade to understand the link between nest architecture and climate because it presents wide variation in nest traits. To understand whether climatic variables have played a role in the diversification of nest traits among species in this family, we measured nests from 49 species using museum collections. We observed that dome‐nesting species are present in dryer and hotter environments, in line with previous findings suggesting that domed nests are a specialisation for arid conditions. We also found evidence that nests with thicker walls are present in locations with lower precipitation and that solar radiation can influence the shape of domed nests; birds tend to build shorter and narrower domes in areas with high levels of solar radiation. Open nest architecture is also potentially influenced by wind speed, with longer and deeper nests in areas characterised by strong winds. Our results support the hypothesis that different climatic variables can drive the evolution of specific aspects of nest architecture and contribute to the diversity of nest shapes we currently observe. However, climatic variables account only for a small fraction of the observed structural variation, leaving a significant portion still unexplained.
Bird nests play a crucial role in the survival and fitness of eggs, nestlings, and incubating parents, but the role of climate variables on the evolution and diversity of avian nest traits is still largely unknown. Previous studies have focused on (i) single species and few environmental variables or (ii) multiple species and general nest morphology. In our study, we explore the relationship between several climatic variables and specific nest traits in a family of birds, Thraupidae (commonly known as tanagers). Thraupidae represents an ideal clade for our study as species belonging to this family vary considerably in their nest architecture. We found evidence that nests with thicker walls are present in locations with lower precipitation and that solar radiation can influence the shape of domed nests; birds tend to build shorter and narrower nests in areas with high levels of solar radiation. Open nest architecture is also potentially influenced by wind speed, with longer and deeper nests in areas characterized by strong winds.
OBJECTIVESTo compare characteristics and needs of inpatients with neurologic disease to those with cancer referred for palliative care (PC) consultation.
METHODSThis prospective cohort study used ...data collected by the Palliative Care Quality Network from January 2013 until December 2016. We compared demographics, reasons for consultation, discharge disposition, Palliative Performance Scale (PPS) score, and outcomes of care among patients with a primary diagnosis of neurologic disease vs cancer.
RESULTSThe most common reason for PC consultation in all patients was assistance with goals of care and advanced care planning. PC consultation was less often requested for pain and symptom management in patients with neurologic disease compared to patients with cancer (13.7% vs 43%, odds ratio 0.3) and more often for assistance with transition to comfort measures only and withdrawal of life-sustaining treatment (19.1% vs 7.1%, odds ratio 1.3). Patients with cancer had higher PPS scores (42.1% vs 23.4%) and were more likely to be discharged home from the hospital, while patients with neurologic disease were more likely to die in hospital.
CONCLUSIONSPatients with neurologic disease as a reason for PC consultation are more in need of end-of-life care planning and more likely to die in the hospital than those with cancer, suggesting that targeted approaches may best address the needs of each patient population. Our results can direct further research and education in neuropalliative care.
Abstract
Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system’s cortical targets, and ...reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using 18FFluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.
Cardiorespiratory exercise is known to modulate motor cortical plasticity in young adults, but the influence of ageing on this relationship is unknown. Here, we compared the effects of a single ...session of cardiorespiratory exercise on motor cortical plasticity in young and older adults. We acquired measures of cortical excitatory and inhibitory activity of the primary motor cortex using transcranial magnetic stimulation (TMS) from 20 young (mean ± SD = 25.30 ± 4.00 years, 14 females) and 20 older (mean ± SD = 64.10 ± 6.50 years, 11 females) healthy adults. Single‐ and paired‐pulse TMS measurements were collected before and after a 20 min bout of high‐intensity interval cycling exercise or an equivalent period of rest, and again after intermittent theta burst stimulation (iTBS). In both young (P = 0.027, Cohen's d = 0.87) and older adults (P = 0.006, Cohen's d = 0.85), there was an increase in glutamatergic excitation and a reduction in GABAergic inhibition from pre‐ to postexercise. However, in contrast to younger adults, older adults showed an attenuated plasticity response to iTBS following exercise (P = 0.011, Cohen's d = 0.85). These results demonstrate an age‐dependent decline in cortical plasticity and indicate that a preceding bout of high‐intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults. Our findings align with the hypothesis that the capacity for cortical plasticity is altered in older age.
Key points
Exercise enhances motor cortical plasticity in young adults, but how ageing influences this effect is unknown.
Here, we compared primary motor cortical plasticity responses in young and older adults before and after a bout of high‐intensity interval exercise and again after a plasticity‐inducing protocol, intermittent theta burst stimulation.
In both young and older adults, exercise led to an increase in glutamatergic excitation and a reduction in GABAergic inhibition.
Our key result was that older adults showed an attenuated plasticity response to theta burst stimulation following exercise, relative to younger adults.
Our findings demonstrate an age‐dependent decline in exercise‐enhanced cortical plasticity and indicate that a preceding bout of high‐intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults.
figure legend We compared the effects of a single session of cardiorespiratory exercise on motor cortical plasticity in young and older adults. Excitatory (E) and inhibitory (I) cortical activity was measured using paired‐pulse transcranial magnetic stimulation (TMS), before and after a bout of high‐intensity interval exercise. Repeated TMS measurements were taken after a plasticity‐inducing protocol, intermittent theta burst stimulation (iTBS). Our two key results were as follows: (i) exercise modulated motor cortical activity in older adults in a similar manner as in young adults; and (ii) the exercise‐enhanced response to iTBS was attenuated in older adults. These results suggest that there is an age‐dependent decline in exercise‐enhanced plasticity within the motor cortex.
Regular exercise benefits learning and memory in older adults, but the neural mechanisms mediating these effects remain unclear. Evidence in young adults indicates that acute exercise creates a ...favourable environment for synaptic plasticity by enhancing cortical disinhibition. As such, we investigated whether plasticity‐related disinhibition mediated the relationship between cardiorespiratory fitness and memory function in healthy older adults (n = 16, mean age = 66.06). Participants completed a graded maximal exercise test and assessments of visual and verbal memory, followed by two counterbalanced sessions involving 20 min of either high‐intensity interval training exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired‐pulse transcranial magnetic stimulation. In line with our hypotheses, we observed a positive correlation between cardiorespiratory fitness and verbal memory, which was mediated by plasticity‐related cortical disinhibition. Our novel finding implicates cortical disinhibition as a mechanism through which the effects of acute bouts of exercise may translate to improved memory in older adults. This finding extends current understanding of the physiological mechanisms underlying the positive influence of cardiorespiratory fitness for memory function in older adults, and further highlights the importance of promoting exercise engagement to maintain cognitive health in later life.
Key points
There are well established benefits of regular exercise for memory function in older adults, but the mechanisms are unclear. Cortical disinhibition is important for laying down new memories, and is enhanced following acute exercise in young adults, suggesting it is a potential mechanism underlying these benefits in ageing.
Older adults completed a fitness test and assessments of memory, followed by two sessions involving either 20 min of exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired‐pulse transcranial magnetic stimulation.
Cardiorespiratory fitness was positively associated with memory performance. Higher fitness was associated with enhanced cortical disinhibition following acute exercise.
Cortical disinhibition completely mediated the relationship between fitness and memory.
This novel finding provides a mechanistic account for the positive influence of cardiorespiratory fitness on memory in later life, and emphasises the importance of regular exercise for cognitive health in older populations.
figure legend We examined plasticity‐related cortical disinhibition following acute exercise as a mediator of the relationship between cardiorespiratory fitness and memory in older adults. Participants completed a graded maximal exercise test and memory assessments, followed by two sessions involving high intensity interval training (HIIT) exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired‐pulse transcranial magnetic stimulation. We found a positive association between cardiorespiratory fitness and associative verbal memory, which was mediated by post‐HIIT cortical disinhibition. These results implicate cortical disinhibition following acute bouts of exercise as a potential mechanism underlying the benefits of fitness for memory function in older adults.
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