The daily solar cycle allows organisms to synchronize their circadian rhythms and sleep-wake cycles to the correct temporal niche. Changes in day-length, shift-work, and transmeridian travel lead to ...mood alterations and cognitive function deficits. Sleep deprivation and circadian disruption underlie mood and cognitive disorders associated with irregular light schedules. Whether irregular light schedules directly affect mood and cognitive functions in the context of normal sleep and circadian rhythms remains unclear. Here we show, using an aberrant light cycle that neither changes the amount and architecture of sleep nor causes changes in the circadian timing system, that light directly regulates mood-related behaviours and cognitive functions in mice. Animals exposed to the aberrant light cycle maintain daily corticosterone rhythms, but the overall levels of corticosterone are increased. Despite normal circadian and sleep structures, these animals show increased depression-like behaviours and impaired hippocampal long-term potentiation and learning. Administration of the antidepressant drugs fluoxetine or desipramine restores learning in mice exposed to the aberrant light cycle, suggesting that the mood deficit precedes the learning impairments. To determine the retinal circuits underlying this impairment of mood and learning, we examined the behavioural consequences of this light cycle in animals that lack intrinsically photosensitive retinal ganglion cells. In these animals, the aberrant light cycle does not impair mood and learning, despite the presence of the conventional retinal ganglion cells and the ability of these animals to detect light for image formation. These findings demonstrate the ability of light to influence cognitive and mood functions directly through intrinsically photosensitive retinal ganglion cells.
In the last three decades, all efforts in bone tissue engineering were driven by the dogma that the ideal pore size in bone substitutes lies between 0.3 and 0.5 mm in diameter. Newly developed ...additive manufacturing methodologies for ceramics facilitate the total control over pore size, pore distribution, bottleneck size, and bottleneck distribution. Therefore, this appears to be the method of choice with which to test the aforementioned characteristics of an ideal bone substitute. To this end, we produced a library of 15 scaffolds with diverse defined pore/bottleneck dimensions and distributions, tested them
in a calvarial bone defect model in rabbits, and assessed the clinically most relevant parameters: defect bridging and bony regenerated area. Our
data revealed that the ideal pore/bottleneck dimension for bone substitutes is in the range of 0.7-1.2 mm, and appears therefore to be twofold to fourfold more extended than previously thought. Pore/bottleneck dimensions of 1.5 and 1.7 mm perform significantly worse and appear unsuitable in bone substitutes. Thus, our results set the ideal range of pore/bottleneck dimensions and are likely to have a significant impact on the microarchitectural design of future bone substitutes for use in orthopedic, trauma, cranio-maxillofacial and oral surgery.
Epigenetics describes mechanisms which control gene expression and cellular processes without changing the DNA sequence. The main mechanisms in epigenetics are DNA methylation in CpG-rich promoters, ...histone modifications and non-coding RNAs (ncRNAs). DNA methylation modifies the function of the DNA and correlates with gene silencing. Histone modifications including acetylation/deacetylation and phosphorylation act in diverse biological processes such as transcriptional activation/inactivation and DNA repair. Non-coding RNAs play a large part in epigenetic regulation of gene expression in addition to their roles at the transcriptional and post-transcriptional level. Osteoporosis is the most common skeletal disorder, characterized by compromised bone strength and bone micro-architectural deterioration that predisposes the bones to an increased risk of fracture. It is most often caused by an increase in bone resorption that is not sufficiently compensated by a corresponding increase in bone formation. Nowadays it is well accepted that osteoporosis is a multifactorial disorder and there are genetic risk factors for osteoporosis and bone fractures. Here we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling.
ABSTRACT
We present the results from the search for Lyman alpha emitters (LAEs) in the proximity of 11 C iv absorption systems at z > 4.7 in the spectrum of the QSO J1030+0524, using data from ...Multi-Unit Spectroscopic Explorer. We have found multiple LAE candidates close to four C iv systems at $z_{{\rm{C {\small IV}}}=4.94$–5.74 with $\log _{10}(N_{{\rm{C {\small IV}}}$cm−2) > 13.5. At z = 5–6, C iv systems with W$_0({\rm{C {\small IV}}})\gt 0.2$ Å seem more likely to have galaxies with Ly α emission within ρ < 200 proper kpc (4/5 cases) than the C iv systems with W$_0({\rm{C {\small IV}}})\lt 0.2$ Å (0/6 cases). The impact parameter of LAE–C iv systems with equivalent widths W0(C iv) > 0.5 Å is in the range $11\, \lesssim \, \rho \, \lesssim \, 200$ proper kpc (pkpc). Furthermore, all candidates are in the luminosity range 0.18–1.15 L$^{\star }_{\rm{{Ly\alpha}}}(z=5.7)$, indicating that the environment of C iv systems within 200 pkpc is populated by the faint end of the Ly α luminosity function. We report a 0.28 L$^{\star }_{\rm{{Ly\alpha}}}$ galaxy at a separation of ρ = 11 pkpc from a strong C iv absorption ($\log _{10}(N_{{\rm{C {\small IV}}}$cm−2) = 14.52) at $z_{{\rm{C {\small IV}}}=5.72419$. The prevalence of sub-L$^{\star }_{\rm{{Ly\alpha}}}$ galaxies in the proximity of z > 4.9 C iv systems suggest that the absorbing material is rather young, likely ejected in the recent past of the identified galaxies. The connection between faint LAEs and high-ionization absorption systems reported in this work is potentially a consequence of the role of low-mass galaxies in the early evolution of the circum-galactic and intergalactic media.
Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) ...alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35-50% humidity; n=8) or HS conditions (35°C; 24-43% humidity; n=8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P=0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-α (P=0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na(+)/K(+) ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P=0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport.
Recent studies suggest that the elevation of intracellular cyclic adenosine monophosphate (cAMP) and the activation of the protein kinase A regulate BMP-induced osteogenesis. However, the precise ...mechanisms underlying the enhancing effect of cAMP on BMP2 signaling were not completely revealed. In this study we investigated the effect of elevated cAMP level and PKA activation on the BMP2-induced osteoblastic differentiation in pluripotent C2C12 cells. Alkaline phosphatase activity and its mRNA were consistently induced by BMP2 treatment. The pretreatment of C2C12 cells with Forskolin, a cAMP generating agent, dbcAMP, an analogue of cAMP, or IBMX (3-isobutyl 1-methyl xanthine), and a nonspecific inhibitor of phosphodiesterases elicited further activation of alkaline phosphatase. Furthermore, elevated intracellular cAMP level increased BMP2-induced MKP1. On the other hand, BMP2-induced Erk phosphorylation (p44/p42) and cell proliferation were suppressed in the presence of cAMP. Thus, cAMP might enhance BMP2-induced osteoblastic differentiation by a MKP1-Erk-dependent mechanism.
Overfunding of crowdfunded product-development projects would seem to be a welcome outcome for entrepreneurs, yet initial theory and evidence suggest that overfunding can have both positive and ...negative consequences. To overcome these contradictory predictions, we develop theory linking research on slack resources, audience expectations, and product category spanning to hypothesize boundary conditions for whether and when overfunding has a positive or negative effect on the product-development outcomes of product release and audience-perceived product quality. Post-crowdfunding data on video-game development projects show that entrepreneurs with high-category-spanning products benefit substantially less from overfunding than entrepreneurs with low-category-spanning products. Our study provides novel insights into the relation between overfunding and product release as well as audience-perceived product quality. It also contributes to our emerging understanding of the role of categories in the context of crowdfunding. We discuss implications for theory and practice.
Plain English Summary
For entrepreneurs receiving more funding than sought in a crowdfunding campaign would seem to be a welcome outcome. However, prior studies have shown that such overfunding can have both positive and negative effects on subsequent product-development outcomes. To shed light on when the effects of overfunding are predominantly positive and when are they predominantly negative, we derive theory on how a product’s category spanning—that is, the positioning of a product in multiple product categories—may impact the effect of overfunding; specifically, on the probability that a product is released and on audience perceptions of the product’s quality. We test these predictions with data from video-game product-development projects crowdfunded on Kickstarter. Our results show that for products with low category spanning, overfunding can be beneficial in terms of both product release and audience perceptions of quality, while high overfunding for products with high category spanning can have detrimental effects for audience perceptions of quality.
High-level evidence supports nonoperative treatment for first-time lateral acute patellar dislocations. Surgical intervention is often indicated for recurrent dislocations. Recurrent instability is ...often multifactorial and can be the result of a combination of coronal limb malalignment, patella alta, malrotation secondary to internal femoral or external tibial torsion, a dysplastic trochlea, or disrupted and weakened medial soft tissue, including the medial patellofemoral ligament (MPFL) and the vastus medialis obliquus. MPFL reconstruction requires precise graft placement for restoration of anatomy and minimal graft tension. MPFL reconstruction is safe to perform in skeletally immature patients and in revision surgical settings. Distal realignment procedures should be implemented in recurrent instability associated with patella alta, increased tibial tubercle-trochlear groove distances, and lateral and distal patellar chondrosis. Groove-deepening trochleoplasty for Dejour type-B and type-D dysplasia or a lateral elevation or proximal recession trochleoplasty for Dejour type-C dysplasia may be a component of the treatment algorithm; however, clinical outcome data are lacking. In addition, trochleoplasty is technically challenging and has a risk of substantial complications.
This paper outlines a hierarchical Bayesian framework for interoception, homeostatic/allostatic control, and meta-cognition that connects fatigue and depression to the experience of chronic ...dyshomeostasis. Specifically, viewing interoception as the inversion of a generative model of viscerosensory inputs allows for a formal definition of dyshomeostasis (as chronically enhanced surprise about bodily signals, or, equivalently, low evidence for the brain's model of bodily states) and allostasis (as a change in prior beliefs or predictions which define setpoints for homeostatic reflex arcs). Critically, we propose that the performance of interoceptive-allostatic circuitry is monitored by a metacognitive layer that updates beliefs about the brain's capacity to successfully regulate bodily states (allostatic self-efficacy). In this framework, fatigue and depression can be understood as sequential responses to the interoceptive experience of dyshomeostasis and the ensuing metacognitive diagnosis of low allostatic self-efficacy. While fatigue might represent an early response with adaptive value (cf. sickness behavior), the experience of chronic dyshomeostasis may trigger a generalized belief of low self-efficacy and lack of control (cf. learned helplessness), resulting in depression. This perspective implies alternative pathophysiological mechanisms that are reflected by differential abnormalities in the effective connectivity of circuits for interoception and allostasis. We discuss suitably extended models of effective connectivity that could distinguish these connectivity patterns in individual patients and may help inform differential diagnosis of fatigue and depression in the future.
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