BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

INTRODUCTION: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. CONCLUSION: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

Network modeling predicts personalized gene expression and drug responses in valve myofibroblasts cultured with patient sera.

Aortic valve stenosis (AVS) patients experience pathogenic valve leaflet stiffening due to excessive extracellular matrix (ECM) remodeling. Numerous microenvironmental cues influence pathogenic expression of ECM remodeling genes in tissue-resident valvular myofibroblasts, and the regulation of complex myofibroblast signaling networks depends on patient-specific extracellular factors. Here, we combined a manually curated myofibroblast signaling network with a data-driven transcription factor network to predict patient-specific myofibroblast gene expression signatures and drug responses. Using transcriptomic data from myofibroblasts cultured with AVS patient sera, we produced a large-scale, logic-gated differential equation model in which 11 biochemical and biomechanical signals were transduced via a network of 334 signaling and transcription reactions to accurately predict the expression of 27 fibrosis-related genes. Correlations were found between personalized model-predicted gene expression and AVS patient echocardiography data, suggesting links between fibrosis-related signaling and patient-specific AVS severity. Further, global network perturbation analyses revealed signaling molecules with the most influence over network-wide activity, including endothelin 1 (ET1), interleukin 6 (IL6), and transforming growth factor ß (TGFß), along with downstream mediators c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription (STAT), and reactive oxygen species (ROS). Lastly, we performed virtual drug screening to identify patient-specific drug responses, which were experimentally validated via fibrotic gene expression measurements in valvular interstitial cells cultured with AVS patient sera and treated with or without bosentan-a clinically approved ET1 receptor inhibitor. In sum, our work advances the ability of computational approaches to provide a mechanistic basis for clinical decisions including patient stratification and personalized drug screening.

Life-long oligodendrocyte development and plasticity.

Oligodendrocyte precursor cells (OPCs) originate in localized germinal zones in the embryonic neural tube, then migrate and proliferate to populate the entire central nervous system, both white and gray matter. They divide and generate myelinating oligodendrocytes (OLs) throughout postnatal and adult life. OPCs express NG2 and platelet-derived growth factor receptor alpha subunit (PDGFRα), two functionally important cell surface proteins, which are also widely used as markers for OPCs. The proliferation of OPCs, their terminal differentiation into OLs, survival of new OLs, and myelin synthesis are orchestrated by signals in the local microenvironment. We discuss advances in our mechanistic understanding of paracrine effects, including those mediated through PDGFRα and neuronal activity-dependent signals such as those mediated through AMPA receptors in OL survival and myelination. Finally, we review recent studies supporting the role of new OL production and "adaptive myelination" in specific behaviours and cognitive processes contributing to learning and long-term memory formation. Our article is not intended to be comprehensive but reflects the authors' past and present interests.

SAGES/AHPBA guidelines for the use of minimally invasive surgery for the surgical treatment of colorectal liver metastases (CRLM).

BACKGROUND: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM. METHODS: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research. RESULTS: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence. CONCLUSIONS: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM.

Surgical approach to microwave and radiofrequency liver ablation for hepatocellular carcinoma and colorectal liver metastases less than 5 cm: a systematic review and meta-analysis.

BACKGROUND: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the two most common malignant neoplasms of the liver. The objective of this study was to assess outcomes of surgical approaches to liver ablation comparing laparoscopic versus percutaneous microwave ablation (MWA), and MWA versus radiofrequency ablation (RFA) in patients with HCC or CRLM lesions smaller than 5 cm. METHODS: A systematic review was conducted across seven databases, including PubMed, Embase, and Cochrane, to identify all comparative studies between 1937 and 2021. Two independent reviewers screened for eligibility, extracted data for selected studies, and assessed study bias using the modified Newcastle Ottawa Scale. Random effects meta-analyses were subsequently performed on all available comparative data. RESULTS: From 1066 records screened, 11 studies were deemed relevant to the study and warranted inclusion. Eight of the 11 studies were at high or uncertain risk for bias. Our meta-analyses of two studies revealed that laparoscopic MW ablation had significantly higher complication rates compared to a percutaneous approach (risk ratio = 4.66; 95% confidence interval = [1.23, 17.22]), but otherwise similar incomplete ablation rates, local recurrence, and oncologic outcomes. The remaining nine studies demonstrated similar efficacy of MWA and RFA, as measured by incomplete ablation, complication rates, local/regional recurrence, and oncologic outcomes, for both HCC and CRLM lesions less than 5 cm (p > 0.05 for all outcomes). There was no statistical subgroup interaction in the analysis of tumors < 3 cm. CONCLUSION: The available comparative evidence regarding both laparoscopic versus percutaneous MWA and MWA versus RFA is limited, evident by the few studies that suffer from high/uncertain risk of bias. Additional high-quality randomized trials or statistically matched cohort studies with sufficient granularity of patient variables, institutional experience, and physician specialty/training will be useful in informing clinical decision making for the ablative treatment of HCC or CRLM.

SAGES/AHPBA guidelines for the use of microwave and radiofrequency liver ablation for the surgical treatment of hepatocellular carcinoma or colorectal liver metastases less than 5 cm.

BACKGROUND: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver's two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies. METHODS: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations. RESULTS: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence). CONCLUSION: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines.

Shifts in sage-grouse arthropod food sources across grazing and environmental gradients in upland meadow communities.

Groundwater dependent systems are extremely important habitats for a wide variety of taxa in the Great Basin of North America. The impacts of grazing on these habitats cause shifts in resources and subsequent change in species composition. The Greater sage-grouse, a keystone species of Great Basin ecosystems, rear offspring in these areas during spring and summer months using forbs and arthropods. To examine the impact of grazing on arthropod abundance in these ecosystems, seven meadows, each made up of three unique vegetative communities, were grazed at three intensities across two years (2019-2020) and monitored for environmental variables and abundance of arthropods during peak sage-grouse utilization periods. Additionally, the relationship of field measurements and near-surface digital cameras (phenocams) was examined to better understand how remote sensing technologies can be used to monitor these insect abundance shifts on larger scales. Arthropod taxa abundance responded differently to grazing management and environmental variables. Coleoptera abundance during peak sage-grouse usage periods increased roughly 50% in some meadows with increased grazing intensity. For year-to-year environmental variability in precipitation, Lepidoptera abundance was 114% higher in the drier year, while Coleoptera was 39% lower. Near-surface cameras had varied success with predicting peak insect abundance levels. Lepidoptera and Coleoptera capture rates had strong correlations with phenological indices derived from phenocams, while Formicidae had much weaker relationships.

Ensemble machine learning model identifies patients with HFpEF from matrix-related plasma biomarkers.

Arterial hypertension can lead to structural changes within the heart including left ventricular hypertrophy (LVH) and eventually heart failure with preserved ejection fraction (HFpEF). The initial diagnosis of HFpEF is costly and generally based on later stage remodeling; thus, improved predictive diagnostic tools offer potential clinical benefit. Recent work has shown predictive value of multibiomarker plasma panels for the classification of patients with LVH and HFpEF. We hypothesized that machine learning algorithms could substantially improve the predictive value of circulating plasma biomarkers by leveraging more sophisticated statistical approaches. In this work, we developed an ensemble classification algorithm for the diagnosis of HFpEF within a population of 480 individuals including patients with HFpEF, patients with LVH, and referent control patients. Algorithms showed strong diagnostic performance with receiver-operating-characteristic curve (ROC) areas of 0.92 for identifying patients with LVH and 0.90 for identifying patients with HFpEF using demographic information, plasma biomarkers related to extracellular matrix remodeling, and echocardiogram data. More impressively, the ensemble algorithm produced an ROC area of 0.88 for HFpEF diagnosis using only demographic and plasma panel data. Our findings demonstrate that machine learning-based classification algorithms show promise as a noninvasive diagnostic tool for HFpEF, while also suggesting priority biomarkers for future mechanistic studies to elucidate more specific regulatory roles.NEW & NOTEWORTHY Machine learning algorithms correctly classified patients with heart failure with preserved ejection fraction with over 90% area under receiver-operating-characteristic curves. Classifications using multidomain features (demographics and circulating biomarkers and echo-based ventricle metrics) proved more accurate than previous studies using single-domain features alone. Excitingly, HFpEF diagnoses were generally accurate even without echo-based measurements, demonstrating that such algorithms could provide an early screening tool using blood-based measurements before sophisticated imaging.

The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin.

Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide alpha Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous scar appearance by 47% 9-month postsurgery. While Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the peptide in scar mitigation at cellular and tissue levels remains to be further characterized. Scar histoarchitecture in αCT1 and vehicle-control treated skin wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on scar structure of a range of epidermal and dermal variables examined was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds-a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on scar collagen order observed in Phase I testing in humans was recapitulated in Sprague-Dawley rats and the IAF hairless guinea pig. Transient increase in histologic collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix postwounding that is similar to unwounded skin-changes that correlate with long-term improvement in scar appearance.

CK20/CK7 double-negative Merkel cell carcinoma in situ: A case report.

An 83-year-old male with a history of both melanoma and non-melanoma skin cancers presented with a light pink non-ulcerated slightly raised 0.6 × 0.5-cm papule on his left lower extremity. Biopsy specimen revealed a proliferation of intraepidermal round blue cells. On immunohistochemical staining, CD56, chromogranin, and pancytokeratin were faintly positive within the lesional population, while synaptophysin was strongly positive. CD45, CK5/6, CK7, CK20, Melan-A, SOX10, and TTF-1 stains were negative. There was no dermal component identified. A Merkel cell polyomavirus stain was negative. Distant metastases and other in situ pathologies were excluded and a diagnosis of Merkel cell carcinoma in situ (MMCIS) was made. The majority of MCCIS lesions reported in the literature have been discovered amongst other non-melanoma neoplasms. Our findings of an MCCIS with purely intraepidermal involvements without the association with another squamous cell neoplasm is rare finding.

Minimally invasive versus open hepatectomy for the resection of colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: While surgical resection has a demonstrated utility for patients with colorectal liver metastases (CRLM), it is unclear whether minimally invasive surgery (MIS) or an open approach should be used. This review sought to assess the efficacy and safety of MIS versus open hepatectomy for isolated, resectable CRLM when performed separately from (Key Question (KQ) 1) or simultaneously with (KQ2) the resection of the primary tumor. METHODS: PubMed, Embase, Google Scholar, Cochrane CENTRAL, International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov databases were searched to identify both randomized controlled trials (RCTs) and non-randomized comparative studies published during January 2000-September 2020. Two independent reviewers screened literature for eligibility, extracted data from included studies, and assessed internal validity using the Cochrane Risk of Bias 2.0 Tool and the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed using risk ratios (RR) and mean differences (MD). RESULTS: From 2304 publications, 35 studies were included for meta-analysis. For staged resections, three RCTs and 20 observational studies were included. Data from RCTs indicated MIS having similar disease-free survival (DFS) at 1-year (RR 1.03, 95%CI 0.70-1.50), overall survival (OS) at 5-years (RR 1.04, 95%CI 0.84-1.28), fewer complications of Clavien-Dindo Grade III (RR 0.62, 95%CI 0.38-1.00), and shorter hospital length of stay (LOS) (MD -6.6 days, 95%CI -10.2, -3.0). For simultaneous resections, 12 observational studies were included. There was no evidence of a difference between MIS and the open group for DFS-1-year, OS-5-year, complications, R0 resections, blood transfusions, along with lower blood loss (MD -177.35 mL, 95%CI -273.17, -81.53) and shorter LOS (MD -3.0 days, 95%CI -3.82, -2.17). CONCLUSIONS: Current evidence regarding the optimal approach for CRLM resection demonstrates similar oncologic outcomes between MIS and open techniques, however MIS hepatectomy had a shorter LOS, lower blood loss and complication rate, for both staged and simultaneous resections.

Interpretable machine learning predicts cardiac resynchronization therapy responses from personalized biochemical and biomechanical features.

BACKGROUND: Cardiac Resynchronization Therapy (CRT) is a widely used, device-based therapy for patients with left ventricle (LV) failure. Unfortunately, many patients do not benefit from CRT, so there is potential value in identifying this group of non-responders before CRT implementation. Past studies suggest that predicting CRT response will require diverse variables, including demographic, biomarker, and LV function data. Accordingly, the objective of this study was to integrate diverse variable types into a machine learning algorithm for predicting individual patient responses to CRT. METHODS: We built an ensemble classification algorithm using previously acquired data from the SMART-AV CRT clinical trial (n = 794 patients). We used five-fold stratified cross-validation on 80% of the patients (n = 635) to train the model with variables collected at 0 months (before initiating CRT), and the remaining 20% of the patients (n = 159) were used as a hold-out test set for model validation. To improve model interpretability, we quantified feature importance values using SHapley Additive exPlanations (SHAP) analysis and used Local Interpretable Model-agnostic Explanations (LIME) to explain patient-specific predictions. RESULTS: Our classification algorithm incorporated 26 patient demographic and medical history variables, 12 biomarker variables, and 18 LV functional variables, which yielded correct prediction of CRT response in 71% of patients. Additional patient stratification to identify the subgroups with the highest or lowest likelihood of response showed 96% accuracy with 22 correct predictions out of 23 patients in the highest and lowest responder groups. CONCLUSION: Computationally integrating general patient characteristics, comorbidities, therapy history, circulating biomarkers, and LV function data available before CRT intervention can improve the prediction of individual patient responses.

The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population.

Peripheral nerves are highly regenerative, in contrast to the poor regenerative capabilities of the central nervous system (CNS). Here, we show that adult peripheral nerve is a more quiescent tissue than the CNS, yet all cell types within a peripheral nerve proliferate efficiently following injury. Moreover, whereas oligodendrocytes are produced throughout life from a precursor pool, we find that the corresponding cell of the peripheral nervous system, the myelinating Schwann cell (mSC), does not turn over in the adult. However, following injury, all mSCs can dedifferentiate to the proliferating progenitor-like Schwann cells (SCs) that orchestrate the regenerative response. Lineage analysis shows that these newly migratory, progenitor-like cells redifferentiate to form new tissue at the injury site and maintain their lineage, but can switch to become a non-myelinating SC. In contrast, increased plasticity is observed during tumourigenesis. These findings show that peripheral nerves have a distinct mechanism for maintaining homeostasis and can regenerate without the need for an additional stem cell population.This article has an associated 'The people behind the papers' interview.

Musashi interaction with poly(A)-binding protein is required for activation of target mRNA translation.

The Musashi family of mRNA translational regulators controls both physiological and pathological stem cell self-renewal primarily by repressing target mRNAs that promote differentiation. In response to differentiation cues, Musashi can switch from a repressor to an activator of target mRNA translation. However, the molecular events that distinguish Musashi-mediated translational activation from repression are not understood. We have previously reported that Musashi function is required for the maturation of Xenopus oocytes and specifically for translational activation of specific dormant maternal mRNAs. Here, we employed MS to identify cellular factors necessary for Musashi-dependent mRNA translational activation. We report that Musashi1 needs to associate with the embryonic poly(A)-binding protein (ePABP) or the canonical somatic cell poly(A)-binding protein PABPC1 for activation of Musashi target mRNA translation. Co-immunoprecipitation studies demonstrated an increased Musashi1 interaction with ePABP during oocyte maturation. Attenuation of endogenous ePABP activity severely compromised Musashi function, preventing downstream signaling and blocking oocyte maturation. Ectopic expression of either ePABP or PABPC1 restored Musashi-dependent mRNA translational activation and maturation of ePABP-attenuated oocytes. Consistent with these Xenopus findings, PABPC1 remained associated with Musashi under conditions of Musashi target mRNA de-repression and translation during mammalian stem cell differentiation. Because association of Musashi1 with poly(A)-binding proteins has previously been implicated only in repression of Musashi target mRNAs, our findings reveal novel context-dependent roles for the interaction of Musashi with poly(A)-binding protein family members in response to extracellular cues that control cell fate.

Anaerobic microbial communities and their potential for bioenergy production in heavily biodegraded petroleum reservoirs.

Most of the oil in low temperature, non-uplifted reservoirs is biodegraded due to millions of years of microbial activity, including via methanogenesis from crude oil. To evaluate stimulating additional methanogenesis in already heavily biodegraded oil reservoirs, oil sands samples were amended with nutrients and electron acceptors, but oil sands bitumen was the only organic substrate. Methane production was monitored for over 3000 days. Methanogenesis was observed in duplicate microcosms that were unamended, amended with sulfate or that were initially oxic, however methanogenesis was not observed in nitrate-amended controls. The highest rate of methane production was 0.15 µmol CH4 g-1 oil d-1 , orders of magnitude lower than other reports of methanogenesis from lighter crude oils. Methanogenic Archaea and several potential syntrophic bacterial partners were detected following the incubations. GC-MS and FTICR-MS revealed no significant bitumen alteration for any specific compound or compound class, suggesting that the very slow methanogenesis observed was coupled to bitumen biodegradation in an unspecific manner. After 3000 days, methanogenic communities were amended with benzoate resulting in methanogenesis rates that were 110-fold greater. This suggests that oil-to-methane conversion is limited by the recalcitrant nature of oil sands bitumen, not the microbial communities resident in heavy oil reservoirs.

Clinical spotlight review for the management of choledocholithiasis.

Choledocholithiasis is a common presentation of symptomatic cholelithiasis that can result in biliary obstruction, cholangitis, and pancreatitis. A systematic English literature search was conducted in PubMed to determine the appropriate management strategies for choledocholithiasis. The following clinical spotlight review is meant to critically review the available evidence and provide recommendations for the work-up, investigations as well as the endoscopic, surgical and percutaneous techniques in the management of choledocholithiasis.

Systematic review of diagnostic accuracy of patient history, clinical findings, and physical tests in the diagnosis of lumbar spinal stenosis.

PURPOSE: To update evidence of diagnostic potential for identification of lumbar spinal stenosis (LSS) based on demographic and patient history, clinical findings, and physical tests, and report posttest probabilities associated with test findings. METHODS: An electronic search of PubMed, CINAHL and Embase was conducted combining terms related to low back pain, stenosis and diagnostic accuracy. Prospective or retrospective studies investigating diagnostic accuracy of LSS using patient history, clinical findings and/or physical tests were included. The risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS 2) tool. Diagnostic accuracy including sensitivities (SN), specificities (SP), likelihood ratios (+LR and -LR) and posttest probabilities (+PTP and -PTP) with 95% confidence intervals were summarized. RESULTS: Nine studies were included (pooled n = 36,228 participants) investigating 49 different index tests (30 demographic and patient history and 19 clinical findings/physical tests). Of the nine studies included, only two exhibited a low risk of bias and seven exhibited good applicability according to QUADAS 2. The demographic and patient history measures (self-reported history questionnaire, no pain when seated, numbness of perineal region) and the clinical findings/physical tests (two-stage treadmill test, symptoms after a March test and abnormal Romberg test) highly improved positive posttest probability by > 25% to diagnose LSS. CONCLUSION: Outside of one study that was able to completely rule out LSS with no functional neurological changes none of the stand-alone findings were strong enough to rule in or rule out LSS. These slides can be retrieved under Electronic Supplementary Material.

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding.

Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation.

Astrocytes and disease: a neurodevelopmental perspective.

Astrocytes are no longer seen as a homogenous population of cells. In fact, recent studies indicate that astrocytes are morphologically and functionally diverse and play critical roles in neurodevelopmental diseases such as Rett syndrome and fragile X mental retardation. This review summarizes recent advances in astrocyte development, including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis. We propose here that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead advances in understanding and treating a variety of neuropsychiatric diseases.

Effects of Collagen Heterogeneity on Myocardial Infarct Mechanics in a Multiscale Fiber Network Model.

The scar that forms after a myocardial infarction is often characterized by a highly disordered architecture but generally exhibits some degree of collagen fiber orientation, with a resulting mechanical anisotropy. When viewed in finer detail, however, the heterogeneity of the sample is clear, with different subregions exhibiting different fiber orientations. In this work, we used a multiscale finite element model to explore the consequences of the heterogeneity in terms of mechanical behavior. To do so, we used previously obtained fiber alignment maps of rat myocardial scar slices (n = 15) to generate scar-specific finite element meshes that were populated with fiber models based on the local alignment state. These models were then compared to isotropic models with the same sample shape and fiber density, and to homogeneous models with the same sample shape, fiber density, and average fiber alignment as the scar-specific models. All simulations involved equibiaxial extension of the sample with free motion in the third dimension. We found that heterogeneity led to a lower degree of mechanical anisotropy and a higher level of local stress concentration than the corresponding homogeneous model, and also that fibers failed in the heterogeneous model at much lower macroscopic strains than in the isotropic and homogeneous models. Taken together, these results suggest that scar heterogeneity may impair myocardial mechanical function both in terms of anisotropy and strength, and that individual variations in scar heterogeneity could be an important consideration for understanding scar remodeling and designing therapeutic interventions for patients after myocardial infarction.