The chordae tendinae connect the papillary muscles to the mitral valve. While the first-order chordae serve to secure the leaflets to maintain valve closure and prevent mitral valve prolapse, the second-order chordae are believed that they play a role in maintaining normal LV size and geometry. The papillary muscles, from where the chordae tendinae originate, function as shock absorbers that compensate for the geometric changes of the left ventricular wall. The second-order chordae connect the PMs to both trigons under tension. The tension distributed towards the second-order chordae has been demonstrate to be more than three-fold that in the first-order counterpart. Cutting the second-order chordae puts all the tension on the first-order chordae, that can go closer to their rupture point. However, it has been experimentally demonstrated that the tension where the first-order chordae break is 6.8 N, by far higher than the maximal tension reached, that is 0.4 N. Even if the clinical reports have been favorable, the importance of cutting the second-order chordae to recover curvature of the anterior leaflet and increasing the coaptation length between the mitral leaflet has been slowly absorbed by the surgical world. Nevertheless, there are progressive demonstrations that chordal tethering affects the anterior leaflet not only in secondary, but also in primary mitral regurgitation, having a not negligeable role in the long-term outcome of mitral repair.

Mutations in the PAX6 gene are generally associated with aniridia. We describe a family with Juvenile onset open angle glaucoma (JOAG), where two siblings were detected to have a pathogenic variant in the PAX6 gene in the absence of aniridia. Whole exome sequencing was performed for the family where the proband and her sibling were detected to have JOAG and Juvenile ocular hypertension respectively. None of the other family members had any ocular disease. All previously described gene mutations for glaucoma were looked for in the family. The potential pathogenicity of the identified variants was assessed by determining their frequency in large public exome databases; as well as using the current ACMG guidelines. Except, for PAX6 gene no pathogenic variants were found in any of the known genes for glaucoma. A de novo heterozygous variant at NM_001368894.2: c.1166C>A; p. Pro375Gln in the PAX6 gene was detected in the proband and her affected brother. The variant has been described in aniridia patients before and is known to be likely pathogenic by ACMG guidelines. This report expands the phenotypic spectrum of the PAX6 gene to include Juvenile onset open angle glaucoma.

This paper introduces coupled fixed points of maps in MIFSMS. The notion of compatible maps and weakly compatible maps is also defined. Common coupled fixed point theorem for weakly compatible maps have been proved in the setting of MIFSMS. Moreover, some corollaries and an example is given to validate our new result. Also, to show the usability of our findings, we have applied our new result to get the solution of nonlinear Fredholm integral equation.

The industrial production of plants promoter like auxins is gaining interest, in consequence it is important to un- derstand the metabolism of the microorganisms involved and the optimal conditions for their industrial production. In this study the metabolic model of Bacillus subtilis was used to estimate intracellular fluxes and the robustness of the principal branching points of aerobic propionate metabolism for the 3-indoleacetic acid (IAA) production. The robustness analyzes of the metabolic network showed the enzymes that participate in the synthesis of erythrose 4-phosphate and glyceraldehyde 3-phosphate as possible limiting metabolites in the synthesis of IAA and might be a target for metabolic engineering strategies. The phenotype phase plane analysis allowed the identification of the opti- mal rate growth conditions to produce the auxin (less than 0.1 h −1).

n this work, a class of nonlinear multi-point BVPs fractional differential equations involving the Riesz-Caputo derivative is proposed. The nonlinearity term f involves the left Caputo derivative. Under given some conditions, the existence and uniqueness of the solution are provided. Our analysis relies on the Krasnoselskii's fixed point theorem, Schauder fixed point theorem and the Banach contraction principle. Finally, some examples are given to illustrate our main results.

In this paper, we focus on the following nonlinear Schr\”odinger equations with linear couples \begin{equation*} \begin{cases} -\Delta u+V_1(x)u+\lambda_1u=\mu _1\int\limits_{\mathbb{R}^{3}}\frac{|u(y)|^p}{|x-y|}\,dy|u|^{p-2}u+\beta v \hspace{5mm} \text{in} \hspace{1mm}\mathbb R^{3},\\ -\Delta v+V_2(x)v+\lambda_2v=\mu _2\int\limits_{\mathbb{R}^{3}}\frac{|v(y)|^q}{|x-y|}\,dy|v|^{q-2}v+\beta u \hspace{5mm} \text{in} \hspace{1mm}\mathbb R^{3},\\ \int\limits_{\mathbb{R}^{3}}|u|^2\,dx=a, \hspace{1mm} \int\limits_{\mathbb{R}^{3}}|v|^2\,dx=b, \end{cases} \end{equation*} where $\frac{5}{3}0$, $a,b\geq 0$, $\beta \in \mathbb{R}\setminus\{0\}$, $\lambda_1,\lambda_2\in\mathbb{R}$ are Lagrange multipliers and $V_1(x),V_2(x):\mathbb{R}^{3}\to \mathbb{R}$ are trapping potentials. We prove the existence of the solutions with prescribed $L^2(\mathbb{R})$-norm with trivial trapping potentials and nontrivial trapping potentials by applying the rearrangement inequalities.

Ingested-derived DNA (iDNA) from insects can represent a powerful tool for assessing vertebrate diversity because insects are easy to sample, have a varied diet, and are widely distributed. Despite these advantages, the use of iDNA for mammalian detection is still little explored, especially in the neotropical region. Here we aimed to compare the effectiveness of mosquitoes and flies to detect mammals in a semi-controlled area of a Zoo that houses native and non-native species. We evaluated the number of mammal species detected by the iDNA samplers and verified the distance range of each sampler group for detecting the mammal species. To capture mosquitoes and flies we used CDC (Center for Disease Control) and fish-baited plastic bottle traps, respectively, distributed in eight sampling points during five days. Using two mini-barcodes (12SrRNA and 16SrRNA) and the metabarcoding approach, we identified 45 Operational Taxonomic Units from 10 orders. There was no difference between the number of species recovered per individual insect, although the number of flies captured was higher, resulting in more mammal species recovered by this insect group. Eight species were recorded exclusively by mosquitoes and 20 by flies, suggesting that using both samplers allowed a more comprehensive screening of the biodiversity. The maximum distance recorded was 337 m for flies and 289 m for mosquitoes, but the average range distance did not differ between insect groups. Our essay proved to be quite efficient for the mammal detection, considering the high number of species detected with a reduced sampling effort. Thus, combining iDNA from different samplers and metabarcoding can be a powerful tool for mammal survey and monitoring in the neotropics.

Background: Since circulating tumor cells (CTCs) are precursors of metastatic lesions, extracting CTCs from whole blood is useful in obtaining information for cancer treatment. One of the CTC extraction methods is the size selection method; however, since the conventional methods are expensive and cumbersome, we developed an affordable and simple filter, whose usefulness is verified in this study. Methods: The new filter (hereafter, soft micropore filter [SMPF]) is made up of a polyethylene film with a thickness of 15 μm and conical pores having a diameter of 8–10 μm, which are opened uniformly (opening rate, 20%). This filter can filter whole blood by free-falling under gravity. The possibilities of the filter’s usage for model CTC extraction, immunostaining, short-term cell culture, and gene mutation detection in extracted model CTCs were verified. Results: S-MPF was able to extract model CTCs with an extraction rate of up to 15%. These model CTCs were detected by cytology, immunostaining, and culture by short-term incubation of filtered cells. Furthermore, genetic mutations were identified in the cultured cells. In addition, CTC extraction from the peripheral blood of patients with lung cancer was demonstrated by setting the volume of collected blood to 15 mL to prevent a low recovery rate. Conclusions: The S-MPF can be used to extract model CTCs quickly and easily. Moreover, cytological diagnosis, immunostaining, short-term culture, and gene mutation search are possible with this filter. Given its proven applicability in clinical samples, this sample can be used in clinical settings.

Mitral valve regurgitation (MR) is a common valvular disorder occurring in up to 10% of the general population. Mitral valve reconstructive strategies may address any of the components, annulus, leaflets and chords, involved in the valvular competence. The classical repair technique involves the resection of the prolapsing tissue. Chordal replacement was introduced already in the ’60, but in the mid ’80, some surgeons started to use expanded polytetrafluoroethylene (ePTFE) Gore-Tex sutures. In the last years, artificial chords have been exploited because of transcatheter techniques such as NeoChord DS 1000 (Neochord, USA) and Harpoon TSD-5. The first step is to achieve a good exposure of the papillary muscles that before approaching the implant of the artificial chords. Then, the chords are attached to the papillary muscle, with or without the use of supportive pledgets. The techniques to correctly implant artificial chords are many and might vary considerably from one center to another, but they can be summarized into three big families of suturing techniques: single, running or loop. Regardless of how to anchor to the mitral leaflet, the real challenge that many surgeons have taken on, giving rise to some very creative solutions, has been to establish an adequate length of the chords. It can be established basing on anatomically healthy chords, but it is important to bear in mind that surgeons work on the mitral valve when the heart is arrested in diastole, so this length could fail to replicate the required length in the full, beating heart. Hence, some surgeons suggested techniques to overcome this problem. Herein, we aimed to describe the current use of artificial chords in real world surgery, summarizing all the tips and tricks.

Gastrointestinal stromal tumors (GISTs) are rare life-threatening forms of cancer representing 0.1%-3% of all gastrointestinal (GI) malignancies. Nursing has become a critical component in handling patients with gastrointestinal tumors. This case report investigates the role of nursing in ruptured GISTs in adolescents and young adults (AYA).

In vitro cell culture experiments are widely used to study cellular behavior in most biological research fields. Except for suspension cells, most human cell types are cultured as adherent monolayers on a plastic surface. While technically convenient, monolayer cultures can suffer from limitations in terms of physiological relevance, as their resemblance to complex in vivo tissue structures is limited. To address these limitations, three-dimensional (3D) cell culture systems have gained increased interest as they mimic key structural and functional properties of their in vivo tissue counterparts. Nevertheless, protocols established on monolayer cell cultures may require adjustments if they are to be applied to 3D cell cultures. As gene expression quantification is an essential part of many in vitro experiments, we evaluated and optimized a direct cell lysis, reverse transcription and qPCR protocol applicable for 3D cell cultures. The newly developed protocol wherein gene expression is determined directly from crude cell lysates showed improved cell lysis compared to the standard protocol, accurate gene expression quantification, hereby avoiding time-consuming cell harvesting and RNA extraction.

Coffin-Siris syndrome is a rare disorder which can be difficult to recognize. A broad spectrum of nonspecific clinical features is associated with Coffin-Siris syndrome and expression of these features is diverse. We describe two cases with Coffin-Siris syndrome with mutations in the ARID1A gene, with dissimilar presentation and clinical course.

We describe the initial results of Emicizumab prophylaxis in twins diagnosed with severe Hemophilia A and inhibitors with intron 22 inversion. Prophylaxis was initiated in both the twins showing high annual bleed rate and difficult venous access. The treatment resulted in zero spontaneous bleeds and there were no adverse events.

A document by Jiyun Han. Click on the document to view its contents.

Glycoprotein (GP) IIb/IIIa are now being widely used in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). With the growing use of these medications, there is an increase in adverse events related to them being reported in the literature, including severe thrombocytopenia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID19-causing virus, is a zoonotic pathogen. There is concern that it may spillover into wildlife species which may then serve as reservoirs for future infection of humans, domestic animals, or other wildlife species. Furthermore, impacts of the virus on potentially susceptible wildlife species are currently unknown. There is, therefore, an urgent need to develop a single test that could be used for the serosurveillance of multiple wildlife species for exposure to SARS-CoV-2. While serological tests to detect antibodies in SARS-CoV-2 infected and/or exposed human patients have been developed, few assays have the capacity to detect antibodies in a wide variety of species. Here, we describe the development of a competitive enzyme-linked immunosorbent assay (cELISA) to detect SARS-CoV-2 antibodies in animals for which species-specific reagents are not available. This cELISA was developed to detect SARS-CoV-2 spike 1 (S1), spike 2 (S2) and nucleocapsid (N) specific antibodies and was validated using sera from experimentally infected hamsters. We further validated our cELISA by comparing it with results obtained from the surrogate virus neutralization test (cPASS, GenScript) and indirect ELISA using anti-hamster horse radish peroxidase (HRP) conjugated reagents. This cELISA will have broad applications in screening potential animal reservoirs for SARS-CoV-2, and uses multiple targets, including more conserved structural proteins which are subjected to less selective immunological pressure. These would allow detection of exposure to variants missed by conventional assays that target antibodies against the viral receptor binding domain. This assay will be a valuable tool which can be implemented in surveillance programs investigating evidence of exposure to SARS-CoV-2 in multiple domestic, captive, or wild animal species, and in studies investigating impacts of SARS-CoV-2 on wildlife populations.

Background: Dental caries is a global public health problem, being the most common non-communicable disease. Streptococcus mutans is the causative agent that develops cariogenic dental biofilms in humans due to its ability to produce glycosyltransferases (Gtfs). These Gtfs act in the exopolysaccharides synthesis (EPS) that form biofilms. The gene expression encoding Gtfs is modulated by the VicRK system, which are promising targets for dental biofilm inhibitor developments. Objective: Predict druggable sites of Streptococcus mutans VicK protein through molecular docking with catechols. Methods: The prediction of VicK druggable sites was performed by PockDrug and FTMap servers. From these data, a virtual screening of 383 catechols was performed on AutoDock4.2. After docking analysis some ligand efficiency indexes were calculated: LE, LELP, LLE and BEI. Results: Three interaction sites (S1, S2 and S3) were predicted for VicK, covering most important residues for its stability and enzymatic activity. The catechols selected by the virtual screening interacted with main amino acids for VicK auto kinase, and phosphatase activity and showed optimal values ​​of ligand efficiency (LE, LELP, LLE and BEI). Conclusion: After Virtual Screening calculations, some catechols interacted favorably with essential residues for VicK autokinase and phosphatase activities and presented optimal values ​​of ligand efficiency (LE, LELP, LLE and BEI). Thus, catechols are promising compounds for future in vitro tests aiming to develop new anticariogenic and antimicrobial agents.

Background: Cereblon, an extensively studied multifunctional protein, is a Cullin 4-RING E3 ubiquitin ligase complex component and a well-known target of thalidomide and its derivatives. Cereblon is involved in the apoptosis of multiple myeloma cells. When ligands such as lenalidomide bind to cereblon, it recognizes various neosubstrates based on the ligand shape and properties. We have identified novel CRBN inhibitors, namely DHFO and its analogs, with structural features that are slightly different from thalidomide but stronger cereblon-binding affinity. We selected indanedione and indanone derivatives from the literature to understand and compare their cereblon-mediated substrate recognition potential. Methods: Computational investigations of possible cereblon inhibitors were investigated by molecular docking. ADME/T and drug-likeness properties of the molecules were studied. A molecular dynamics study was carried out for selected molecules, and the molecular interactions were analyzed using PCA-based FEL methods. The binding affinity was calculated using the MM-PBSA method. Results: We conducted computational investigations on 68 indanedione and indanone derivatives binding with cereblon. Ten molecules showed better CRBN binding affinity than thalidomide. We studied the drug-likeness properties of the selected ten molecules, and four of the most promising molecules (DHFO, THOH, DIMS, and DTIN) were chosen for molecular dynamics studies. The MM/PBSA calculations showed that the DHFO, already shown to be a 5-LOX/COX2 inhibitor, has the highest binding affinity of -163.16 KJ/mol with cereblon. Conclusion: The selected CRBN inhibitor DHFO has demonstrated the highest binding affinity with cereblon protein compared to other molecules. DHFO creates an interaction hotspot on the cereblon surface, thereby serving as a novel alternative for thalidomide and its derivatives. Ease of chemical synthesis, low toxicity, versatile therapeutic options, and pleiotropism of DHPO analogues provide an opportunity for exploring clinical alternatives with versatile therapeutic potential for a new category of indanedione molecules as novel modulators of E3 ubiquitin ligases.

1. Camera traps are popular for monitoring animal populations and communities, primarily because they eliminate physical handling of animals. However, image acquisition typically outpaces information extraction. Most deep-learning based animal classifiers do not localize animals, limiting their applicability. Existing networks that localize animals have relatively high training data and hardware requirements. 2. To reduce the hardware and training data requirements, we extended the the Machine Learning for Wildlife Image Classification network (MLWIC2) to a Faster R-CNN. MLWIC2 is currently the most accurate wildlife classification network, and also the shallowest at 18 layers. We compared our model’s performance at object localization, species identification, and deployment speed to the performance of a generically pre-trained 50-layer Faster R-CNN to determine a) relative importance of task similarity in pre-training vs. backbone depth, b) whether additionally finetuning the backbones during training is advantageous c) whether the Faster R-CNN architecture benefits from incorporating the feature pyramid network (FPN) and cascading pyramid network (CPN) modules, and d) how backbone depth and the additional modules affect deployment speeds. 3. We found that the deeper network provides a slight advantage for classification accuracy, while the shallower network with higher task similarity produces a slight advantage for object localization. The additional modules provided dramatic gains for the 18 layer backbone for both classification and localization. On a NVIDIA 1080-ti gpu, the 18-layer backbone trains ~ 30% faster than the 50-layer backbone. In deployment the 18-layer backbone is 2.5x faster than the 50-layer backbone, and 9.4x faster than Megadetector. These results show that backbone network task similarity, paired with the FPN and CPN modules, can substitute for depth, which improves deployment speeds. Our model is suitable for modest hardware and for integration into more complex pipelines. These are important steps towards the automation of data acquisition from camera trap images.

Various post translational modifications like hyper phosphorylation, O-GlycNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N–glycosylation of tau protein in the abnormal folding and tau aggregation. Hence in this study, we performed microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tend to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347&Lys370 helped maintaining the stability of the protein in the folded state.

East Yunnan-Guizhou Plateau is rich in biodiversity in China. Complex geographical and climatic conditions, and rich bird resources made this area an ideal system for studying the spatial distribution mechanism and influencing factors of birds, which were still unknown. Bird community data from 37 sites in this region were collected, including 505 bird species and 164 species of resident passerine bird analyzed. The taxonomic diversity, phylogenetic diversity, functional diversity, and community structure index were calculated. Redundancy analysis (RDA), ordinary least square (OLS), and structural equation model (SEM), were used to explore the relationship between bird diversity index and 12 environmental factors used to describe the habitat conditions of birds. Results indicated that the vascular plant species richness, habitat area, and vertical altitude difference were the three most critical factors affecting bird diversity. The phylogenetic structure of bird community was dispersed in west and clustered in east, and significantly related to latitude, habitat area, and vertical altitude difference. The functional structure was dispersed in all sites, and significantly related to mean annual precipitation and longitude. This suggest that the distribution pattern of bird diversity was caused by the comprehensive action of various habitat factors which were mainly related to food availability and habitat heterogeneity. Considering the protection of birds in this area, it is necessary to continuously promote the construction of nature reserve system proposed by the Chinese government, and pay attention to the protection of urban green space such as campus and urban parks, to maintain the area and integrity of bird habitat, while only a high plant species and area is not enough, improving the habitat heterogeneity is of great significance.

Backgroud: To determine the most suitable effect-site concentration of remifentanil and propofol for keeping proper anesthesia depth and early recover quickly under guidance of patient state index (PSI). Methodsː Elective gynecological laparoscopic surgery patients received concentration of propofol in high concentration (3 ug/mL, N = 25), middle concentration (2.5 ug/mL, N = 24), low concentration (2 ug/mL, N = 28) during maintenance. After finished intubation, propofol was adjusted to the target concentration by grouping, the concentration of remifentanil relied on the reaction of the formerly tested patient using 0.4 ng/mL as a step size began with 3.5ng/mL under PSI monitored. The primary measurements were the concentration of remifentanil, the change of intra-procedural data, and post-operation data including times to handle the change of the depth of anesthesia, blood pressure (BP) and heart rate (HR), extubation time, duration in PACU, hospital day, VAS score in the first day after sugery. Secondary measurements were density spectral array, intra-operative awareness, postoperative delirium. Results: The group of middle concentration required the minimum time for extubation and staying in PACU, kept steady process of anesthesia (P<0.05), the EC50 of remifentanil to suppression irritation from incision were 2.96 ng/mL (95% CI 2.75 to 3.14 ng/mL) in this group. Besides, low doses of remifentanil were more obvious than high doses in alpha wave of Density spectral array. Conclusions: With PSI guided anesthesia, the effect-site concentration of propofol was 2.5 ug/mL, keep stable anesthesia process and effective early postoperative recovery, meanwhile, EC50 of remifentanil was 2.96 ng/mL.

The COVID-19 pandemic has disrupted seeking and delivery of healthcare. Different Australian jurisdictions implemented different COVID-19 restrictions. We used Australian national pharmacy dispensing data to conduct interrupted time series analyses to examine the incidence and prevalence of opioid dispensing in different jurisdictions. Following nationwide COVID-19 restrictions, the opioid incidence dropped by -0.40 [-0.50, -0.31], -0.33 [-0.46, -0.21] and -0.21 [-0.37, -0.04] /1000 people/week and prevalence dropped by -0.85 [-1.39, -0.31], -0.54 [-1.01, -0.07] and -0.62 [-0.99, -0.25] /1000 people/week in Victoria, New South Wales and other jurisdictions, respectively. Incidence and prevalence increased by 0.29 [0.13, 0.44] and 0.72 [0.11, 1.33] /1000 people/week, respectively in Victoria post-lockdown; no significant changes were observed in other jurisdictions. No significant changes were observed in the initiation of long-term opioid use in any jurisdictions. More stringent restrictions coincided with more pronounced reductions in overall opioid initiation, but initiation of long-term opioid use did not change.

Biodiversity refers to a variety of life forms and ecological complexes in which these components are interacting. The impacts of human-induced factors on biodiversity have become a hot issue and globally recognized. Instantaneously, conservation of biodiversity in National Parks of Ethiopia is faced with huge problems nowadays and this work aims to review on effects of human-induced factors as the threats to biodiversity and associated conservation challenges in selected National Parks of Ethiopia. This review paper was prepared based on a comprehensive review of different articles, journals, newspapers, and reports. The selection criterion was following their relevance to the review objectives. The representative for protected areas; namely, Dhati Wolel, Bale Mountain National parks, and Simien Mountain National were intelligently selected for the review based on biodiversity richness and conservation challenges. In conclusion, the biodiversity threats and ecological degradation have become crucial issues in Ethiopia and the pronounced factors which put biodiversity under significant threat came from the human-induced factors. The consequence is loss of biodiversity and climate change. Hence, this review suggested that all the concerned bodies including stakeholders, managers and civil organizations should cooperate on conservation issues and have a common understanding for confronting the current fragmentary biodiversity and ecological challenges.