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Abstract Craniofacial microsomia (CFM) is a congenital condition associated with orbital, mandibular, ear, nerve, and soft tissue anomalies. We present a standardized, two-dimensional, digital photographic protocol designed to capture the common craniofacial features associated with CFM.

Background: Dietary-resistant starch is emerging as a potential therapeutic tool to limit the negative effects of diabetes on the kidneys. However, its metabolic and immunomodulatory effects have not yet been fully elucidated., Methods: Six-week-old db/db mice were fed a diet containing 12.5% resistant starch or a control diet matched for equivalent regular starch for 10 weeks. db/m mice receiving the control diet were utilised as non-diabetic controls. Freshly collected kidneys were digested for flow cytometry analysis of immune cell populations. Kidney injury was determined by measuring albuminuria, histology, and immunohistochemistry. Portal vein plasma was collected for targeted analysis of microbially-derived metabolites. Intestinal histology and tight junction protein expression were assessed., Results: Resistant starch limited the development of albuminuria in db/db mice. Diabetic db/db mice displayed a decline in portal vein plasma levels of acetate, propionate, and butyrate, which was increased with resistant starch supplementation. Diabetic db/db mice receiving resistant starch had a microbially-derived metabolite profile similar to that of non-diabetic db/m mice. The intestinal permeability markers lipopolysaccharide and lipopolysaccharide binding protein were increased in db/db mice consuming the control diet, which was not seen in db/db mice receiving resistant starch supplementation. Diabetes was associated with an increase in the kidney neutrophil population, neutrophil activation, number of C5aR1+ neutrophils, and urinary complement C5a excretion, all of which were reduced with resistant starch. These pro-inflammatory changes appear independent of fibrotic changes in the kidney., Conclusions: Resistant starch supplementation in diabetes promotes beneficial circulating microbially-derived metabolites and improves intestinal permeability, accompanied by a modulation in the inflammatory profile of the kidney including neutrophil infiltration, complement activation, and albuminuria. These findings indicate that resistant starch can regulate immune and inflammatory responses in the kidney and support the therapeutic potential of resistant starch supplementation in diabetes on kidney health., (© 2024. The Author(s).)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition; however, its relationship with renal cell carcinoma (RCC) remains unclear. This paper aims to establish the prevalence of RCC and its subtypes amongst ADPKD patients., Methods: A database search was conducted to retrieve studies reporting RCC occurrence within ADPKD patients until July 2023. Key outcomes included number and subtype of RCC cases, and number of RCCs presenting incidentally. A random-effects meta-analysis was performed., Results: Our search yielded 569 articles, 16 met the inclusion criteria. Nephrectomy specimens from 1,147 ADPKD patients were identified. Of studies reporting per-kidney results (n = 13), 73 RCCs were detected amongst 1,493 kidneys, equating to a per-kidney prevalence of 4.3% (95% CI, 3.1-5.7, I2 = 15.7%). 75 ADPKD patients were found to have RCC (75/1,147), resulting in a per-person prevalence of 5.7% (95% CI, 3.7-7.9, I2 = 40.3%) (n = 16). As 7 patients had bilateral disease, 82 RCCs were detected in total. Of these, 39 were clear cell RCC, 35 were papillary and 8 were other. As such, papillary RCCs made up 41.1% (95% CI, 25.9-56.9, I2 = 18.1%) of detected cancers. The majority of RCCs were detected incidentally (72.5% [95% CI, 43.7-95.1, I2 = 66.9%])., Conclusion: ADPKD appears to be associated with the papillary RCC subtype. The clinical implications of these findings are unclear, however, may become apparent as outcomes and life expectancy amongst APDKD patients improve., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Male bighorn sheep ( Ovis canadensis ) participate in seasonal ramming bouts that can last for hours, yet they do not appear to suffer significant brain injury. Previous work has shown that the keratin-rich horn and boney horncore may play an important role in mitigating brain injury by reducing brain cavity accelerations through energy dissipating elastic mechanisms. However, the extent to which specific horn shapes (such as the tapered spiral of bighorn sheep) may reduce accelerations post-impact remains unclear. Thus, the goals of this work were to (a) quantify bighorn sheep horn shape, particularly the cross-sectional areal properties related to bending that largely dictate post-impact deformations, and (b) investigate the effects of different tapered horn shapes on reducing post-impact accelerations in an impact model with finite element analysis. Cross-sectional areal properties indicate bighorn sheep horns have a medial-lateral bending preference at the horn tip ( p = 0.006), which is likely to dissipate energy through medial-lateral horn tip oscillations after impact. Finite element modeling showed bighorn sheep native horn geometry reduced the head injury criterion (HIC 15 ) by 48% compared to horns with cross-sections rotated by 90° to have a cranial-caudal bending preference, and by 125% compared to a circular tapered spiral model. These results suggest that the tapered spiral horn shape of bighorn sheep is advantageous for dissipating energy through elastic mechanisms following an impact. These findings can be used to broadly inform the design of improved safety equipment and impact systems., (© 2023 IOP Publishing Ltd.)

Diabetes is the leading cause of kidney disease, and as the number of individuals with diabetes increases there is a concomitant increase in the prevalence of diabetic kidney disease (DKD). Diabetes contributes to the development of DKD through a number of pathways, including inflammation, oxidative stress, and the gut-kidney axis, which may be amenable to dietary therapy. Resistant starch (RS) is a dietary fibre that alters the gut microbial consortium, leading to an increase in the microbial production of short chain fatty acids. Evidence from animal and human studies indicate that short chain fatty acids are able to attenuate inflammatory and oxidative stress pathways, which may mitigate the progression of DKD. In this review, we evaluate and summarise the evidence from both preclinical models of DKD and clinical trials that have utilised RS as a dietary therapy to limit the progression of DKD.

Background: Standardized testing of hip muscle strength and fatigue in the sagittal plane is important for assessing, treating and preventing a number of trunk and lower extremity pathologies. Furthermore, individuals displaying asymmetries of muscle strength between limbs are more likely to sustain an injury., Purpose: To evaluate the test-retest reliability of isometric strength and isokinetic fatigue measurements of the hip flexor and hip extensor muscles, and to examine whether there is a significant limb dominance effect on strength, fatigue and flexor-extensor ratios., Study Design: Cross-sectional study., Methods: To evaluate reliability, 30 healthy individuals (33.2 + /- 13.1 years) were included. On a separate occasion, 24 healthy individuals (29.0 + /- 10.3 years) participated to assess between-limb differences. Reliability was established using intraclass correlation coefficients (ICCs), standard error of measurements (SEM) and minimal detectable change (MDC). Isometric strength (best peak torque of three maximal contractions; Nm/kg), isokinetic fatigue (total work of 20 consecutive maximal concentric flexor-extensor contractions at 120 °/s; Joule/kg), and flexor-extensor ratios, were recorded using a Biodex dynamometer., Results: Reliability was good-to-excellent (ICCs>0.83) and measurement errors were acceptable (SEM<13.6% and MDC%<37.8%). No significant between-limb differences in strength, fatigue and flexor-extensor ratios were detected., Conclusions: Isometric strength and isokinetic fatigue of the hip flexor and hip extensor muscles can be reliably assessed in healthy individuals using the Biodex dynamometer. Limb dominance did not significantly affect strength, fatigue or flexor-extensor ratios., Level of Evidence: 2b., (© 2020 by the Sports Physical Therapy Section.)

Background: Blood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer., Methods: Whole-genome sequencing was performed on cfDNA extracted from plasma samples (N = 546 colorectal cancer and 271 non-cancer controls). Reads aligning to protein-coding gene bodies were extracted, and read counts were normalized. cfDNA tumor fraction was estimated using IchorCNA. Machine learning models were trained using k-fold cross-validation and confounder-based cross-validations to assess generalization performance., Results: In a colorectal cancer cohort heavily weighted towards early-stage cancer (80% stage I/II), we achieved a mean AUC of 0.92 (95% CI 0.91-0.93) with a mean sensitivity of 85% (95% CI 83-86%) at 85% specificity. Sensitivity generally increased with tumor stage and increasing tumor fraction. Stratification by age, sequencing batch, and institution demonstrated the impact of these confounders and provided a more accurate assessment of generalization performance., Conclusions: A machine learning approach using cfDNA achieved high sensitivity and specificity in a large, predominantly early-stage, colorectal cancer cohort. The possibility of systematic technical and institution-specific biases warrants similar confounder analyses in other studies. Prospective validation of this machine learning method and evaluation of a multi-analyte approach are underway.

Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T EX ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T EX into durable memory T cells (T MEM ) is unclear. We found that reinvigoration of T EX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T EX became reexhausted if antigen concentration remained high and failed to become T MEM upon antigen clearance. T EX acquired an epigenetic profile distinct from that of effector T cells (T EFF ) and T MEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T EX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the T EX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Isokinetic dynamometry is a useful tool to objectively assess muscle strength of children and adults in athletic and rehabilitative settings. This study examined test-retest reliability of isokinetic knee strength measurements in children aged 8 to 10 years and defined limits for the minimum difference (MD) in strength that indicates a clinically important change., Hypothesis: Isokinetic knee strength measurements (using the Biodex System 4) in children will provide reliable results., Study Design: Descriptive laboratory study., Methods: In 22 healthy children, 5 maximal concentric (CON) knee extensor (KE) and knee flexor (KF) contractions at 2 angular velocities (60 deg/s and 180 deg/s) and 5 maximal eccentric (ECC) KE/KF contractions at 60 deg/s were assessed 7 days apart. The intraclass correlation coefficient (ICC 2.1 ) was used to examine relative reliability, and the MD was calculated on the basis of standard error of measurement., Results: ICCs for CON KE/KF peak torque measurements were fair to excellent (range, 0.49-0.81). The MD% values for CON KE and KF ranged from 31% to 37% at 60 deg/s and from 34% to 39% at 180 deg/s. ICCs in the ECC mode were good (range, 0.60-0.70), but associated MD% values were high (>50%). There was no systematic error for CON KE/KF and ECC KE strength measurements at 60 deg/s, but systematic error was found for all other measurements., Conclusion: The dynamometer provides a reliable analysis of isokinetic CON knee strength measurements at 60 deg/s in children aged 8 to 10 years. Measurements at 180 deg/s and in the ECC mode were not reliable, indicating a need for more familiarization prior to testing., Clinical Relevance: The MD values may help clinicians to determine whether a change in knee strength is due to error or intervention.

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces "SASP-like" inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression., (© 2016 Capell et al.; Published by Cold Spring Harbor Laboratory Press.)

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.

Despite overwhelming evidence that transcriptional activation by TP53 is critical for its tumor suppressive activity, the mechanisms by which TP53 engages the genome in the context of chromatin to activate transcription are not well understood. Using a compendium of novel and existing genome-wide data sets, we examined the relationship between TP53 binding and the dynamics of the local chromatin environment. Our analysis revealed three distinct categories of TP53 binding events that differ based on the dynamics of the local chromatin environment. The first class of TP53 binding events occurs near transcriptional start sites (TSS) and is defined by previously characterized promoter-associated chromatin modifications. The second class comprises a large cohort of preestablished, promoter-distal enhancer elements that demonstrates dynamic histone acetylation and transcription upon TP53 binding. The third class of TP53 binding sites is devoid of classic chromatin modifications and, remarkably, fall within regions of inaccessible chromatin, suggesting that TP53 has intrinsic pioneer factor activity and binds within structurally inaccessible regions of chromatin. Intriguingly, these inaccessible TP53 binding sites feature several enhancer-like properties in cell types within the epithelial lineage, indicating that TP53 binding events include a group of "proto-enhancers" that become active enhancers given the appropriate cellular context. These data indicate that TP53, along with TP63, may act as pioneer factors to specify epithelial enhancers. Further, these findings suggest that rather than following a global cell-type invariant stress response program, TP53 may tune its response based on the lineage-specific epigenomic landscape., (© 2015 Sammons et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Fear of falling (FOF) is common in Parkinson's disease (PD), and it is considered a vital aspect of comprehensive balance assessment in PD. FOF can be conceptualized differently. The Falls-Efficacy Scale (FES) assesses fall-related self-efficacy, whereas the Survey of Activities and Fear of Falling in the Elderly (SAFFE) assesses activity avoidance due to the risk of falling. This study aimed at investigating the validity and reliability of FES and SAFFE in people with PD., Methods: Seventy-nine people with PD (mean age; 64 years, SD 7.2) completed the Swedish version of FES(S), SAFFE and the physical functioning (PF) scale of the 36-Item Short-Form Health Survey (SF-36). FES(S) and SAFFE were administered twice, with an 8.8 (SD 2.3) days interval. Assumptions for summing item scores into total scores were examined and score reliability (Cronbach's alpha and test-retest reliability) were calculated. Construct validity was assessed by examining the pattern of Spearman correlations (rs) between the FES(S)/SAFFE and other variables, and by examining differences in FES(S)/SAFFE scores between fallers and non-fallers, genders, and between those reporting FOF and unsteadiness while turning., Results: For both scales, item mean scores (and standard deviations) were roughly similar and corrected item-total correlations exceeded 0.4. Reliabilities were ≥ 0.87. FES(S)-scores correlated strongest (rs, -0.74, p < 0.001) with SAFFE-scores, whereas SAFFE-scores correlated strongest with PF-scores (rs, -0.76, p < 0.001). Both scales correlated weakest with age (rs ≤ 0.08). Experiencing falls, unsteadiness while turning, and FOF was associated with lower fall-related self-efficacy and higher activity avoidance., Conclusions: This study provides initial support for the score reliability and validity of the FES(S) and SAFFE in people with PD.