Glycoside hydrolase family 57 glycogen branching enzymes (GH57GBE) catalyze the formation of an α-1,6 glycosidic bond between α-1,4 linked glucooliogosaccharides. As an atypical family, a limited number of GH57GBEs have been biochemically characterized so far. This study aimed at acquiring a better understanding of the GH57GBE family by a systematic sequence-based bioinformatics analysis of almost 2,500 gene sequences and determining the branching activity of several native and mutant GH57GBEs. A correlation was found between a very low or even no branching activity with the absence of a flexible loop, a tyrosine at the loop tip, and two β-sheets.

Summary: This study evaluates through modeling the possible individual and combined effect of three populational parameters of pathogens (reproduction rate; rate of novelty emergence; and propagule size) on the colonization of new host species – putatively the most fundamental process leading to the emergence of new infectious diseases. The results are analyzed under the theoretical framework of the Stockholm Paradigm using IBM simulations to better understand the evolutionary dynamics of the pathogen population and the possible role of Ecological Fitting. The simulations suggest that all three parameters positively influence the success of colonization of new hosts by a novel parasite population but contrary to the prevailing belief, the rate of novelty emergence (e.g. mutations) is the least important factor. Maximization of all parameters result in a synergetic facilitation of the colonization and emulates the expected scenario for pathogenic microorganisms. The simulations also provide theoretical support for the retention of the capacity of fast-evolving lineages to retro-colonize their previous host species/lineage by ecological fitting. Capacity is, thus, much larger than we can anticipate. Hence, the results support the empirical observations that opportunity of encounter (i.e. the breakdown in mechanisms for ecological isolation) is a fundamental determinant to the emergence of new associations – especially Emergent Infectious Diseases - and the dynamics of host exploration, as observed in SARS-CoV-2. Insights on the dynamics of Emergent Infectious Diseases derived from the simulations and from the Stockholm Paradigm are discussed.

Background Timing of aortic valve intervention is dependent on the accuracy and reproducibility of echocardiographic (ECHO) parameters. We aimed to assess haemodynamic subsets of aortic stenosis (AS), their change over time, and variability of ECHO parameters. Method This retrospective, longitudinal study compared sequential ECHO over 15 months to identify concordant or discordant aortic valve area (AVA) and mean pressure gradient (MPG). Results We included 143 patients with a mean age of 76.0 years. The median length of time between studies was 112 days (IQR 38-208). Initially participants were classified as 10 (7.0%) mild, 49 (34.3%) moderate and 84 (58.7%) severe AS. In 80 (55.9%) AVA and MPG were concordant; stroke volume index (SVi) was <35ml/m2 in 53 (74.6%). AS severity was downgraded in 33 (23.1%) patients. MPG was most consistent and AVA was the least consistent between successive investigations (intraclass correlation coefficients R=0.86 and R=0.76, respectively). Even small variations in left ventricular outflow tract (LVOT) measurement of 1 standard deviation reclassified up to 67% of participants from severe to non-severe. Conclusion Almost half of patients with AS have valve area/gradient discordance. Variations in LVOT diameter measurement commensurate with clinical practice reclassified AS severity in up to 2/3 of cases. Change in AS severity should only be accepted following careful scrutiny of all available ECHO data.

Pathogen-mediated selection (PMS) is thought to maintain the high level of allelic diversity observed in the major histocompatibility complex (MHC) class II genes. A comprehensive way to demonstrate contemporary selection is to examine associations between MHC variation and individual fitness. As individual fitness is hard to measure, many studies examine associations between MHC diversity and phenotypic traits which include direct or indirect measures of adaptive immunity thought to contribute to fitness. Here, we tested associations between MHC class II variation and five representative phenotypic traits measured in August: weight, strongyle faecal egg count, and plasma IgA, IgE and IgG immunoglobulin titres against the gastrointestinal nematode parasite Teladorsagia circumcincta in a free-living population of Soay sheep. We found no association between MHC class II variation and August weight or strongyle faecal egg count. We did however find associations between MHC class II variation and immunoglobulin levels which varied with age, isotype and sex. Our results suggest associations between MHC and phenotypic traits are more likely to be found for traits more closely associated with pathogen defence than integrative traits such as body weight and highlight a useful role of MHC-antibody associations in examining selection on MHC genes.

Arctium lappa has a long medicinal and edible history with great economic importance. We combined Illumina and PacBio sequences to generate the first high-quality chromosome-level draft genome of A. lappa. The assembled genome is approximately 1.79 Gb with a N50 contig size of 6.88 Mb. Approximately 1.70 Gb (95.4%) of the contig sequences were anchored onto 18 chromosomes using Hi-C data; the scaffold N50 was improved to be 91.64 Mb. Furthermore, we obtained 1.12 Gb (68.46%) of repetitive sequences and 32,771 protein-coding genes; 616 positively selected candidate genes were identified. Additionally, we compared the transcriptomes of A. lappa roots at three different developmental stages and identified 8,943 differentially expressed genes (DEGs) in these tissues. Among candidate genes related to lignan biosynthesis, the following were found to be highly correlated with the accumulation of arctiin: 4-coumarate-CoA ligase (4CL), dirigent protein (DIR), and hydroxycinnamoyl transferase (HCT). These data can be utilized to identify genes related to A. lappa quality or provide a basis for molecular identification and comparative genomics among related species.

This paper is concerned with a 2-dimensional Klein-Gordon-Schrödinger system subject to two types of locally distributed damping on a compact Riemannian manifold $\mathcal{M}$ without boundary. Making use of unique continuation property, the observability inequalities, and the smoothing effect due to Aloui, we obtain exponential stability results.

In this paper, we discuss a hyperbolic-parabolic system modeling biological phenomena evolving on a network. The global existence of the is obtained by using energy estimates with suitable the transmission conditions at interior. Moreover, for the case of acyclic network, the existence and uniqueness of stationary solution to the system is proposed and it is proved that these ones are asymptotic profiles for a class of global solutions

Background: Identification of elevation in pulmonary pressures during exercise may provide prognostic and therapeutic implications in patients with connective tissue disease (CTD). Interstitial lung disease (ILD) is common in CTD patients and subtle interstitial abnormalities detected by lung ultrasound could predict exercise-induced pulmonary hypertension (PH). Methods and Results: Echocardiography and lung ultrasound were performed at rest and bicycle exercise in CTD patients (n=41) and control subjects without CTD (n=24). Ultrasound B-lines were quantified by scanning four intercostal spaces in the right hemithorax. We examined the association between total B-lines at rest and the development of exercise-induced PH during ergometry exercise. Compared to controls, the number of total B-lines at rest was higher in CTD patients (0 [0, 0] vs. 2 [0, 9], p<0.0001) and was correlated with radiological severity of ILD assessed by computed tomography (fibrosis score, r=0.70, p<0.0001). Pulmonary artery systolic pressure (PASP) was increased with ergometry exercise in CTD compared to controls (48±14 vs. 35±13 mmHg, p=0.0006). The number of total B-lines at rest was highly correlated with higher PASP (r=0.52, p<0.0001) and poor right ventricular pulmonary artery coupling (tricuspid annular plane systolic excursion/PASP ratio, r=-0.31, p=0.01) during peak exercise. The number of resting B-lines predicted the development of exercise-induced PH with an area under the curve 0.79 (p=0.0003). Conclusions: These data may suggest the value of a simple resting assessment of lung ultrasound as a potential tool for assessing the risk of exercise-induced PH in CTD patients.

The goal of CASP experiments is to monitor the progress in the protein structure prediction field. During the 14th CASP edition we aimed to test our capabilities of predicting structures of protein complexes. Our protocol for modeling protein assemblies included both template-based modeling and free docking. Structural templates were identified using sensitive sequence-based searches. If sequence-based searches failed, we performed structure-based template searches using selected CASP server models. In the absence of reliable templates we applied free docking starting from monomers generated by CASP servers. We evaluated and ranked models of protein complexes using an improved version of protein structure quality assessment method, VoroMQA, taking into account both interaction interface and global structure scores. If reliable templates could be identified, generally accurate models of protein assemblies were generated with the exception of an antibody-antigen interaction. The success of free docking mainly depended on the accuracy of initial subunit models and on the scoring of docking solutions. To put our overall results in perspective, we analyzed our performance in the context of other CASP groups. Although the subunits in our assembly models often were not of the top quality, these models had, overall, the best predicted interfaces according to several protein-protein interface accuracy measures. Since we did not use co-evolution-based prediction of inter-chain contacts, we attribute our relative success in predicting interfaces primarily to the emphasis on the interaction interface when modeling and scoring.

Objective: 7-50% of children with medulloblastoma (MB) develop postoperative cerebellar mutism syndrome (pCMS). pCMS has a short-term negative impact on intelligence, but results on long-term outcomes are contradictory. The aim of this study was to assess long-term effects of pCMS in MB patients on aspects of intelligence (IQ) and its perioperative risk factors. Methods: In this single centre retrospective cohort study, 31 children with MB were included of which 14 had pCMS. Peri-operative risk factors included brainstem invasion, vermis incision, pre-and post-operative hydrocephalus, tumor size, duration and severity of pCMS, neurological symptoms on day 10 after surgery, mean body temperature (BT) on days 1-4 post surgery, and age at resection. Age appropriate Wechsler Intelligence tests were assessed within a structured follow up programme. Results: No significant differences in IQ scores were found between pCMS and non pCMS groups. The pCMS group had a clinically relevant difference of 10 points when compared to age norms on verbal IQ (VIQ). Bilateral pyramidal and swallowing problems were risk factors for lower performance in this group. In the overall group, tumor size, younger age at surgery, and raised mean BT on days 1-4 post-surgery were negatively correlated with aspects of IQ. Conclusions: We found a clinically significant reduction of VIQ in the pCMS patient group. pCMS patients with a larger tumor size, younger age at surgery, a higher mean BT in the first days after surgery, bilateral pyramidal symptoms, and swallowing problems 10 days post-surgery are more at risk for VIQ deficits at long-term.

Ryanodine receptor 1 (RyR1) is an intracellular calcium ion (Ca2+) release channel required for skeletal muscle contraction. Although cryo-electron microscopy identified binding sites of three coactivators Ca2+, ATP and caffeine (CFF), the mechanism of co-regulation and synergy of these activators is unknown. Here, we report allosteric connections among the three ligand binding sites and pore region in (i) Ca2+ bound-closed, (ii) ATP/CFF bound- closed, (iii) Ca2+/ATP/CFF bound-closed, and (iv) Ca2+/ATP/CFF bound-open RyR1 states. We identified two dominant interactions that mediate interactions between the Ca2+ binding site and pore region in Ca2+ bound-closed state, which partially overlapped with the pore communications in ATP/CFF bound-closed RyR1 state. In Ca2+/ATP/CFF bound-closed and -open RyR1 states, co-regulatory interactions were analogous to communications in the Ca2+ bound-closed and ATP/CFF bound- closed states. Both ATP- and CFF- binding sites mediate communication between the Ca2+ binding site and the pore region in Ca2+/ATP/CFF bound - open RyR1 structure. We conclude that Ca2+, ATP, and CFF propagate their effects to the pore region through a network of overlapping interactions that mediate allosteric control and molecular synergy in channel regulation.

The bronchus-associated lymphoid tissue (BALT) lymphoma is a rare subtype of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), affecting roughly 9% of all MALT lymphomas. The underlying pathomechanism of BALT lymphomas is not completely resolved and a standard of care treatment is so far not available.

Place identity is the emotional connection between people and a place. It is significant for local development and people’s satisfaction and happiness in where they reside. The physical environment is one of the most important factors affecting people’s emotions toward a place. In order to clarify the theoretical analytical framework of the process from village space morphology to place identity, this study takes the area of Aihui along the Heilongjiang River, China, as an example. The research was conducted regarding two aspects: First, we analyzed the space morphology of the villages in the Aihui district and interpreted their locality. On this basis, we conducted a survey of villagers’ subjective perceptions of the village space and their place identity through in-depth interviews. From the collected interview texts, we extracted, verified, and analyzed the role of morphological constituents in the construction of place identity. Finally, a comprehensive framework was established. The features of space morphology are the projections of locality in physical space. People use morphological constituents to construct an image of the village and scenes of local life; morphological constituents with local characteristics can help enhance people’s place identity.

Response to Letter to the Editor: “Impact of preoperative troponin levels on cardiac function following coronary surgery for myocardial infarction”Nicholas Hess MD1, Arman Kilic MD2

Commentary to JOCS-2020-RA-1888

Bruton’s tyrosine kinase (BTK) is a non-receptor kinase best known for its role in B lymphocyte development that is critical for proliferation, and survival of leukaemia cells in B cell malignancies. However, BTK is expressed in myeloid cells, particularly monocytes and macrophages where its inhibition has been reported to exhibit anti-inflammatory properties. Therefore, we explored the role of BTK on the migration of myeloid cells in vitro and in vivo. Using the zymosan induced peritonitis model of sterile inflammation we demonstrated that acute (1 h prior to zymosan) inhibition of BTK using a wide range of FDA (Ibrutinib and Acalabrutinib) and non-FDA approved inhibitors (ONO-4059, CNX-774, Olumatinib and LFM-A13) reduced neutrophil and monocyte recruitment. XID mice, which have a point mutation in the Btk gene had reduced neutrophil and monocyte recruitment to the peritoneum following zymosan challenge. To better understand the role of BTK in myeloid cell recruitment we investigated both chemotaxis and chemokine production in monocytes and macrophages. Pharmacological or genetic inhibition of BTK signalling substantially reduced human monocyte and murine macrophage chemotaxis to a range of chemoattractants (complement C5a and CCL2). We also demonstrated that inhibition of BTK in tissue resident macrophages significantly decreases chemokine secretion by reducing NF-kB activity and Akt signalling. Our work has identified a new role of BTK in regulating myeloid cell recruitment via two mechanisms, 1) reducing monocyte/macrophages’ ability to undergo chemotaxis, and 2) reducing chemokine secretion, via reduced NF-kB activity in tissue resident macrophages.

Abstract Background: There has been no trial evaluating the psychopathology in breastfeeding mothers of infants with food allergy (FA). Objective: To investigate the effect of dietary elimination on maternal psychopathology, specifically stress/anxiety and mother-to-infant bonding and explore the importance of sociodemographic features on these variables. Methods: Breastfeeding mothers following an elimination diet due to FA in their children aged 1-to-12 months were compared with the healthy controls. Physician-diagnosed FA group were divided into IgE-, non-IgE-mediated and infants with some minor symptoms which were not enough to make the diagnosis of FA were classified as Indecisive symptoms for FA group. Mothers completed standardized questionnaires including Symptom Checklist 90R, Beck Depression/Anxiety Inventories (BDI/BAI), Postpartum Bonding Questionnaire (Bonding). Results: Of 179 mother-infants, 64 were healthy, 89 were FA, 16 were indecisive symptoms for FA. The mean age of the mothers and infants were 31.1±4.7 years and 6.3±3.6 months. The physician diagnosed FA groups had higher scores for anxiety (p=0.008), anger (p=0.042), depression (p<0.001), obsession (p=0.002), phobia (p=0.008), somatization (p=0.002) and general symptom index (GSI) (p=0.001), BDI (p<0.001), BAI (p=0.008) and Bonding [attachment (p=0.001), anger (p=0.019) and total (p=0.036)] than the healthy. The indecisive symptoms for FA group had a similar score pattern to physician-diagnosed FA except interpersonal sensitivity, BDI and attachment. Conclusion: Breastfeeding mothers of infants with FA were anxious, depressive and had many psychopathologies which affected bonding. Interventions targeting negativity in caregivers’ social relationships are urgently needed.

A series of pyrazine-interior-embodied MOF-74 composites (py-MOF-74) were successfully synthesized by a post vapor modification method, concomitant with the loading ratio of pyrazine easily controlled in this process. Here, pyrazine molecules perform as a cavity-occupant to block the wide pores of MOF-74, which accentuates the adsorption discrepancy of a pair of gases on MOFs and consequently reinforces the adsorption selectivity (typically for CO2/N2, CO2/CH4). Different from the “physical confinement” of occupants, pyrazine molecule with dual “para-nitrogen” atoms donates one N atom to bond with the open metal ion of MOF-74 for stability, and remains the other N atom available for potential CO2 trapping site. Pyrazine-interior-embodied MOF-74 composites manifest significantly improved CO2/N2 and CO2/CH4 adsorption selectivity. Typically, py-MOF-74c with ultimate pyrazine insertion displays selectivity greatly superior to MOF-74 in the equimolar CO2/CH4 (598 vs. 35) and the simulated CO2/N2 flue gas (471 vs. 49) at 100 kPa and 298 K.