Aplasia cutis congenita, terminal limb defects and falciform retinal folds: confirmation of a distinct syndrome of vascular disruption

We describe a son of consanguineous parents with congenital scalp defects, transverse limb abnormalities, hypoplasia of the corpus callosum and bilateral falciform retinal folds. Aplasia cutis congenita with transverse limb defects are features of Adams-Oliver syndrome, which is usually inherited as an autosomal dominant condition. The association of bilateral retinal folds and brain abnormalities with scalp defects and terminal limb defects has only once been previously described. It is possible that these cases represent a severe variant of Adams-Oliver syndrome. We, however, suggest that they may characterize a new, distinct, autosomal recessive syndrome, involving vascular disruption.     

Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes

Structural maintenance of chromosomes (SMC) complexes are essential for chromatin organization and functions throughout the cell cycle. The cohesin and condensin SMCs fold and tether DNA, while Smc5/6 directly promotes DNA replication and repair. The functions of SMCs rely on their abilities to engage DNA, but how Smc5/6 binds and translocates on DNA remains largely unknown. Here, we present a 3.8 Å cryogenic electron microscopy (cryo-EM) structure of DNA-bound Saccharomyces cerevisiae Smc5/6 complex containing five of its core subunits, including Smc5, Smc6, and the Nse1-3-4 subcomplex. Intricate interactions among these subunits support the formation of a clamp that encircles the DNA double helix. The positively charged inner surface of the clamp contacts DNA in a nonsequence-specific manner involving numerous DNA binding residues from four subunits. The DNA duplex is held up by Smc5 and 6 head regions and positioned between their coiled-coil arm regions, reflecting an engaged-head and open-arm configuration. The Nse3 subunit secures the DNA from above, while the hook-shaped Nse4 kleisin forms a scaffold connecting DNA and all other subunits. The Smc5/6 DNA clamp shares similarities with DNA-clamps formed by other SMCs but also exhibits differences that reflect its unique functions. Mapping cross-linking mass spectrometry data derived from DNA-free Smc5/6 to the DNA-bound Smc5/6 structure identifies multi-subunit conformational changes that enable DNA capture. Finally, mutational data from cells reveal distinct DNA binding contributions from each subunit to Smc5/6 chromatin association and cell fitness. In summary, our integrative study illuminates how a unique SMC complex engages DNA in supporting genome regulation.

Structural maintenance of chromosomes (SMC) complexes are essential genome regulators in both prokaryotes and eukaryotes. In eukaryotes, the cohesin and condensin SMC complexes organize DNA, while the Smc5/6 complex (referred to as Smc5/6) directly regulates DNA replication and repair (1). At the structural level, SMC complexes share similarities while possessing unique attributes (1). Each complex contains a pair of SMC subunits and a set of non-SMC subunits. The SMC subunits define the tripartite filamentous architecture of the complex: their approximal 50-nm long coiled coil arm region connects their dimerized hinge and adenosine triphosphatase (ATPase) head regions (1). A non-SMC kleisin subunit uses its N- and C-terminal domains to link the head of one SMC to the head-proximal arm region (neck) of another SMC, forming a trimeric SMC-kleisin structure. In cohesin and condensin, two large U-shaped HEAT (Huntington, elongation factor 3, PR65/A, TOR) repeat HAWK (HEAT proteins associated with kleisins) subunits attach to the middle region of the kleisin. By contrast, the Smc5/6 kleisin (Nse4) binds to smaller WH (winged helix)-containing KITE (kleisin interacting tandem WH elements) subunits (Nse1 and Nse3) (2).SMC-mediated functions depend on interactions with DNA. Recent cryogenic electron microscopy (cryo-EM) structures of DNA-bound cohesin and condensin revealed that their HAWK subunits and the SMC head-neck regions form a clamp to enclose a single DNA double helix (3–7). DNA clamping can be critical for cohesin and condensin to extrude DNA loops for chromatin folding (5, 7–9). DNA loop extrusion additionally requires arm bending at a region called the elbow, which is found in both cohesin and condensin (5, 7–9). By contrast, a lack of arm bending in Smc5/6 was suggested by negative stain EM and cross-linking mass spectrometry (CLMS) data (10–14). Since Smc5/6 does not contain HAWK proteins nor shows arm-bending, it has remained unclear how Smc5/6 engages DNA to accomplish its multiple functions.Here we address the molecular mechanisms by which this unique SMC complex binds DNA using an integrative approach, coupling a cryo-EM-based structural characterization with CLMS analyses and functional investigation. Our atomic structure of a DNA-bound Saccharomyces cerevisiae Smc5/6 complex reveals that the head-neck Smc5-6 regions and the Nse1-3-4 subcomplex together form a clamp entrapping the DNA helix. The structure further reveals protein subunit folds and association, as well as how the subunits collaborate to entrap DNA. Comparison of CLMS analyses of DNA-free Smc5/6 with the structure of the DNA-bound Smc5/6 unveils large scale, multi-subunit conformational changes that enable Smc5/6 to encircle DNA. Finally, our mutational data suggest distinct contributions from each of the DNA binding regions to Smc5/6 chromatin association and cellular fitness. Comparison of our findings with those of other SMCs reveals that diverse SMC complexes use a similar DNA clamping strategy despite structural differences, and that Smc5/6 possesses unique features distinct from cohesin, condensin, and prokaryotic SMCs. Our work lays the foundation for an in-depth understanding of how Smc5/6 fulfills unique roles in genome protection.     

Algorithm for Determining Time Series of Phase Transformations in the Solid State Using Long-Short-Term Memory Neural Network

In the numerical analysis of manufacturing processes of metal parts, many material properties depending on, for example, the temperature or stress state, must be taken into account. Often these data are dependent on the temperature changes over time. Strongly non-linear material property relationships are usually represented using diagrams. In numerical calculations, these diagrams are analyzed in order to take into account the coupling between the properties. An example of these types of material properties is the dependence of the kinetics of phase transformations in the solid state on the rate and history of temperature change. In literature, these data are visualized Continuous Heating Transformation (CHT) and Continuous Cooling Transformation (CCT) diagrams. Therefore, it can be concluded that time series analysis is important in numerical modeling. This analysis can also be performed using neural networks. This work presents a new approach to storing and analyzing the data contained in the discussed CCT diagrams. The application of Long-Short-Term Memory (LSTM) neural networks and their architecture to determine the correct values of phase fractions depending on the history of temperature change was analyzed. Moreover, an area of research was elements that determine what type of information should be stored by LSTM network coefficients, e.g., whether the network should store information about changes of single phase transformations, or whether it would be better to extract data from differences between several networks with similar architecture. The purpose of the studied network is strongly different from typical applications of artificial neural networks. The main goal of the network was to store information (even by overfitting the network) rather than some form of generalization that allows computation for unknown cases. Therefore, the authors primarily investigated in the ability of the layer-based LSTM network to store nonlinear time series data. The analyses presented in this paper are an extension of the issues presented in the paper entitled “Model of the Austenite Decomposition during Cooling of the Medium Carbon Steel Using LSTM Recurrent Neural Network”.     

Dasatinib and interferon alpha synergistically induce pyroptosis-like cell death in philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1β were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.     

Association of body mass index with risk of prediabetes in Chinese adults: A population‐based cohort study

Aims/IntroductionOverweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population.Materials and MethodsThe cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut‐off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m², normal‐weight: 18.5–24.9 kg/m², pre‐obese: 25.0–29.9 kg/m², obese class I: 30.0–34.9 kg/m², obese class II: 35.0–39.9 kg/m², and obese class III ≥40 kg/m²). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively.ResultsIn the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre‐obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose–response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m² might be a potential intervention threshold for prediabetes.ConclusionsThe national cohort study found that the association of BMI with prediabetes follows a positive dose–response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m².     

Prevalence of Orthorexia in Groups of Students with Varied Diets and Physical Activity (Silesia,Poland)

(1) Background: The literature emphasizes the role of many factors influencing the onset of eating disorders (EDs) and their mutual influence on each other. Therefore, this study aimed to evaluate and compare the prevalence of orthorexic behaviors in groups of health-related and non-health-related students in terms of their differential health behaviors—diet and physical activity levels. (2) The study included 300 individuals representing two equal groups of fields of study, which for the study were called the health-related field (HRF) and the non-health-related field (NRF). (3) Results: Based on the results of the dietary assessment, it was found that the best dietary model was characterized by the HRF group; in this group, 97.2% of students were characterized by a very good and good dietary mode. The NRF group, on the other hand, was dominated by a sufficient dietary mode for 64.4% of all cases in this group (94 people), while the dietary model marked as “good” was less popular, at 24.6% of this group (36 people). (4) Conclusions: Based on the cited self-research and information from the literature, it can be concluded that the problem of orthorexia is still a new issue at the level of social sciences, medical sciences, and health sciences. The psychometric tools used in this study allowed us to demonstrate the prevalence of the aforementioned eating disorders in the sample groups of students.     

Live‐attenuated influenza vaccine effectiveness against hospitalization in children aged 2–6 years,the first three seasons of the childhood influenza vaccination program in England, 2013/14–2015/16

IntroductionIn 2013, the United Kingdom began to roll‐out a universal annual influenza vaccination program for children. An important component of any new vaccination program is measuring its effectiveness. Live‐attenuated influenza vaccines (LAIVs) have since shown mixed results with vaccine effectiveness (VE) varying across seasons and countries elsewhere. This study aims to assess the effectiveness of influenza vaccination in children against severe disease during the first three seasons of the LAIV program in England.MethodsUsing the screening method, LAIV vaccination coverage in children hospitalized with laboratory‐confirmed influenza infection was compared with vaccination coverage in 2–6‐year‐olds in the general population to estimate VE in 2013/14–2015/16.ResultsThe overall LAIV VE, adjusted for age group, week/month and geographical area, for all influenza types pooled over the three influenza seasons was 50.1% (95% confidence interval [CI] 31.2, 63.8). By age, there was evidence of protection against hospitalization from influenza vaccination in both the pre‐school (2–4‐year‐olds) (48.1%, 95% CI 27.2, 63.1) and school‐aged children (5–6‐year‐olds) (62.6%, 95% CI 2.6, 85.6) over the three seasons.ConclusionLAIV vaccination in children provided moderate annual protection against laboratory‐confirmed influenza‐related hospitalization in England over the three influenza seasons. This study contributes further to the limited literature to date on influenza VE against severe disease in children.