•α-Synuclein can act as a DAMP activating TLRs, a key component of the immune system.•TLRs may be an important mediator of neuroinflammation in PD and α-synucleinopathies.•Targeting TLRs could be an ...effective therapeutic strategy to slow PD progression.
Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson’s disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson’s and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.
Nephrogenesis is ongoing at the time of birth for the majority of preterm infants, but whether postnatal renal development follows a similar trajectory to normal in utero growth is unknown. Here, we ...examined tissue collected at autopsy from 28 kidneys from preterm neonates, whose postnatal survival ranged from 2 to 68 days, including 6 that had restricted intrauterine growth. In addition, we examined kidneys from 32 still-born gestational controls. We assessed the width of the nephrogenic zone, number of glomerular generations, cross-sectional area of the renal corpuscle, and glomerular maturity and morphology. Renal maturation accelerated after preterm birth, with an increased number of glomerular generations and a decreased width of the nephrogenic zone in the kidneys of preterm neonates. Of particular concern, compared with gestational controls, preterm kidneys had a greater percentage of morphologically abnormal glomeruli and a significantly larger cross-sectional area of the renal corpuscle, suggestive of renal hyperfiltration. These observations suggest that the preterm kidney may have fewer functional nephrons, thereby increasing vulnerability to impaired renal function in both the early postnatal period and later in life.
Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to ...osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-1-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P1,3 receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P.
This study aimed to determine the long term effects of resolution of SDB in preschool children, either following treatment or spontaneous recovery, on cognition and behavior. Children diagnosed with ...SDB at 3-5y (N = 35) and non-snoring controls (N = 25), underwent repeat polysomnography (PSG) and cognitive and behavioral assessment 3 years following a baseline study. At follow-up, children with SDB were grouped into Resolved and Unresolved. Resolution was defined as: obstructive apnea hypopnea index (OAHI) ≤1 event/h; no snoring detected on PSG; and no parental report of habitual snoring. 57% (20/35) of children with SDB received treatment, with SDB resolving in 60% (12/20). 43% (15/35) were untreated, of whom 40% (6/15) had spontaneous resolution of SDB. Cognitive reduced between baseline and follow-up, however this was not related to persistent disease, with no difference in cognitive outcomes between Resolved, Unresolved or Control groups. Behavioral functioning remained significantly worse in children originally diagnosed with SDB compared to control children, regardless of resolution. Change in OAHI did not predict cognitive or behavioral outcomes, however a reduction in nocturnal arousals, irrespective of full resolution, was associated with improvement in attention and aggressive behavior. These results suggest that resolution of SDB in preschool children has little effect on cognitive or behavioral outcomes over the long term. The association between sleep fragmentation and behavior appears independent of SDB, however may be moderated by concomitant SDB. This challenges the assumption that treatment of SDB will ameliorate associated cognitive and behavioural deficits and supports the possibility of a SDB phenotype.
A decade ago, scientists and practitioners working in environmental water management crystallised the progress and direction of environmental flows science, practice and policy in The Brisbane ...Declaration and Global Action Agenda (2007), during the 10th International Riversymposium and International Environmental Flows Conference held in Brisbane, Australia. The 2007 Declaration highlights the significance of environmental water allocations for humans and freshwater-dependent ecosystems, and sets out a nine-point global action agenda. This was the first consensus document that bought together the diverse experiences across regions and disciplines, and was significant in setting a common vision and direction for environmental flows internationally. After a decade of uptake and innovation in environmental flows, the 2007 declaration and action agenda was revisited at the 20th International Riversymposium and Environmental Flows Conference, held in Brisbane, Australia, in 2017. The objective was to publicize achievements since 2007 and update the declaration and action agenda to reflect collective progress, innovation, and emerging challenges for environmental flows policy, practice and science worldwide. This paper on The Brisbane Declaration and Global Action Agenda on Environmental Flows (2018) describes the inclusive consultation processes that guided the review of the 2007 document. The 2018 Declaration presents an urgent call for action to protect and restore environmental flows and aquatic ecosystems for their biodiversity, intrinsic values and ecosystem services, as a central element of integrated water resources management, and as a foundation for achievement of water-related Sustainable Development Goals. The Global Action Agenda (2018) makes 35 actionable recommendations to guide and support implementation of environmental flows through legislation and regulation, water management programs, and research, linked by partnership arrangements involving diverse stakeholders. An important new element of the Declaration and Action Agenda is the emphasis given to full and equal participation of all cultures, and respect for their rights, responsibilities and systems of governance in environmental water decisions. These social and cultural dimensions of e-flow management warrant far more attention. Actionable recommendations present a pathway forward for a new era of scientific research and innovation, shared visions, collaborative implementation programs and adaptive governance of environmental flows, suited to new social and environmental contexts
Purpose
Abdominally based autologous breast reconstruction (ABABR) is common after mastectomy, but carries a risk of complex abdominal wall hernias. We report experience with posterior component ...separation (PCS) and transversus abdominis release (TAR) with permanent synthetic mesh repair of ABABR-related hernias.
Methods
Patients at Cleveland Clinic Foundation and Penn State Health were identified retrospectively. Outcomes included postoperative complications, hernia recurrence, and patient-reported outcomes (PROs): Hernia Recurrence Inventory, HerQLes Summary Score, Patient-Reported Outcome Measurement Information System (PROMIS) Pain Intensity 3a Survey, and the Decision Regret Scale (DRS).
Results
Forty patients underwent PCS/TAR repair of hernias resulting from pedicled (35%), free (5%), muscle-sparing TRAMs (15%), and DIEPs (28%) from August 2014 to March 2021. Following PCS, 30-day complications included superficial surgical site infection (13%), seroma (8%), and superficial wound breakdown (5%). Five patients (20%) developed clinical hernia recurrence. At a minimum of 1 year, 17 (63%) reported a bulge, 12 (44%) reported pain, median HerQLes Quality Of Life Scores improved from 33 to 63/100 (
p
value < 0.01), PROMIS 3a Pain Intensity Scores improved from 52 to 38 (
p
value < 0.05), and DRS scores were consistent with low regret (20/100).
Conclusion
ABABR-related hernias are complex and technically challenging due to missing abdominal wall components and denervation injury. After repair with PCS/TAR, patients had high rates of recurrence and bulge, but reported improved quality of life and pain and low regret. Surgeons should set realistic expectations regarding postoperative bulge and risk of hernia recurrence.
gene clusters encode transcription factors that drive regional specialization during animal development: for example the Hox factor Ubx is expressed in the insect metathoracic (T3) wing appendages ...and differentiates them from T2 mesothoracic identities.
transcriptional regulation requires silencing activities that prevent spurious activation and regulatory crosstalks in the wrong tissues, but this has seldom been studied in insects other than
, which shows a derived
dislocation into two genomic clusters that disjoined
(
) and
(
). Here, we investigated how
is restricted to the hindwing in butterflies, amidst a contiguous
cluster. By analysing Hi-C and ATAC-seq data in the butterfly
, we show that a Topologically Associated Domain (TAD) maintains a hindwing-enriched profile of chromatin opening around
. This TAD is bordered by a Boundary Element (BE) that separates it from a region of joined wing activity around the
locus. CRISPR mutational perturbation of this BE releases ectopic
expression in forewings, inducing homeotic clones with hindwing identities. Further mutational interrogation of two non-coding RNA encoding regions and one putative
regulatory module within the
TAD cause rare homeotic transformations in both directions, indicating the presence of both activating and repressing chromatin features. We also describe a series of spontaneous forewing homeotic phenotypes obtained in
butterflies, and discuss their possible mutational basis. By leveraging the extensive wing specialization found in butterflies, our initial exploration of
regulation demonstrates the existence of silencing and insulating sequences that prevent its spurious expression in forewings.
Trials are at risk of contamination bias which can occur when participants in the control group are inadvertently exposed to the intervention. This is a particular risk in rehabilitation studies ...where it is easy for trial interventions to be either intentionally or inadvertently adopted in control settings. The Falls in Care Homes (FinCH) trial is used in this paper as an example of a large randomised controlled trial of a complex intervention to explore the potential risks of contamination bias. We outline the FinCH trial design, present the potential risks from contamination bias, and the strategies used in the design of the trial to minimise or mitigate against this. The FinCH trial was a multi-centre randomised controlled trial, with embedded process evaluation, which evaluated whether systematic training in the use of the Guide to Action Tool for Care Homes reduced falls in care home residents. Data were collected from a number of sources to explore contamination in the FinCH trial. Where specific procedures were adopted to reduce risk of, or mitigate against, contamination, this was recorded. Data were collected from study e-mails, meetings with clinicians, research assistant and clinician network communications, and an embedded process evaluation in six intervention care homes. During the FinCH trial, there were six new falls prevention initiatives implemented outside the study which could have contaminated our intervention and findings. Methods used to minimise contamination were: cluster randomisation at the level of care home; engagement with the clinical community to highlight the risks of early adoption; establishing local collaborators in each site familiar with the local context; signing agreements with NHS falls specialists that they would maintain confidentiality regarding details of the intervention; opening additional research sites; and by raising awareness about the importance of contamination in research among participants.
Complex rehabilitation trials are at risk of contamination bias. The potential for contamination bias in studies can be minimized by strengthening collaboration and dialogue with the clinical community. Researchers should recognise that clinicians may contaminate a study through lack of research expertise.
Deletion of the c-src gene impairs osteoclast bone resorbing activity, causing osteopetrosis. Although it has been concluded that restoring only the Src adaptor function at least partly rescues the ...cell attachment and skeletal phenotypes, the contribution of Src kinase activity remains controversial. Src forms a complex with Pyk2 and Cbl after adhesion-induced stimulation of αVβ3 integrin. To demonstrate the importance of the Pyk2-Src association in osteoclasts and to distinguish the contributions of the Src adaptor and kinase activities in cytoskeletal organization and osteoclast function, we expressed mutants of Src and Pyk2 in osteoclasts using adenovirus vectors. Eliminating the Src-binding site on Pyk2 (Pyk2Y402F) markedly inhibited bone resorption by osteoclast-like cells, whereas kinase-dead Pyk2 had little effect. Kinase-dead Src, unlike kinase-dead Pyk2, markedly inhibited the bone-resorbing activity of wild type osteoclasts and failed to significantly restore bone-resorbing activity to Src-/- osteoclast-like cells. Activation of Src kinase by overexpressing kinase-dead Csk failed to reverse the inhibitory effect of Pyk2Y402F, suggesting that osteoclastic bone resorption requires both c-Src kinase activity and the targeting of Src kinase by Pyk2. Src-catalyzed phosphorylation of Cbl on Tyr-731 is reported to induce the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Expressing the CblY731F mutant in osteoclasts markedly reduced their bone resorbing activity, suggesting that phosphorylation of CblY731 and the subsequent recruitment and activation of phosphatidylinositol 3-kinase may be critical signaling events downstream of Src in osteoclasts.
PDF
