julilili42/papers huggingface dataset:
Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations
2022-11-18

Abstract SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96–100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.
When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
2022-11-18

Abstract Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an αAF‐2‐trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist‐induced conformational changes in the FXR ligand‐binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand‐specific influence on conformations of different FXR‐LBD regions, including the α5/α6 region, αAF‐2, and α9‐11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF‐2 destabilization, which prevents both co‐activator and co‐repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.
Optimization of the precursor supply for an enhanced FK506 production in Streptomyces tsukubaensis
2022-11-18

Tacrolimus (FK506) is a macrolide widely used as immunosuppressant to prevent transplant rejection. Synthetic production of FK506 is not efficient and costly, whereas the biosynthesis of FK506 is complex and the level produced by the wild type strain, Streptomyces tsukubaensis , is very low. We therefore engineered FK506 biosynthesis and the supply of the precursor L-lysine to generate strains with improved FK506 yield. To increase FK506 production, first the intracellular supply of the essential precursor lysine was improved in the native host S. tsukubaensis NRRL 18488 by engineering the lysine biosynthetic pathway. Therefore, a feedback deregulated aspartate kinase AskSt* of S. tsukubaensis was generated by site directed mutagenesis. Whereas overexpression of AskSt* resulted only in a 17% increase in FK506 yield, heterologous overexpression of a feedback deregulated AskCg* from Corynebacterium glutamicum was proven to be more efficient. Combined overexpression of AskCg* and DapASt, showed a strong enhancement of the intracellular lysine pool following increase in the yield by approximately 73% compared to the wild type. Lysine is coverted into the FK506 building block pipecolate by the lysine cyclodeaminase FkbL. Construction of a ∆fkbL mutant led to a complete abolishment of the FK506 production, confirming the indispensability of this enzyme for FK506 production. Chemical complementation of the ∆fkbL mutant by feeding pipecolic acid and genetic complementation with fkbL as well as with other lysine cyclodeaminase genes ( pipAf, pipASt , originating from Actinoplanes friuliensis and Streptomyces pristinaespiralis , respectively) completely restored FK506 production. Subsequently, FK506 production was enchanced by heterologous overexpression of PipAf and PipASp in S. tsukubaensis . This resulted in a yield increase by 65% compared to the WT in the presence of PipAf from A. friuliensis . For further rational yield improvement, the crystal structure of PipAf from A. friuliensis was determined at 1.3 Å resolution with the cofactor NADH bound and at 1.4 Å with its substrate lysine. Based on the structure the Ile91 residue was replaced by Val91 in PipAf, which resulted in an overall increase of FK506 production by approx. 100% compared to the WT.
Realtime blur simulation of varifocal spectacle lenses in virtual reality
2022-11-18

Virtual reality is a promising tool to study the influence of ophthalmic lenses on human perception. Independent of the actual refractive errors of the users' eye, vision through different types of lenses can be simulated while allowing free eye and head movements and easy measurement of behavioural parameters. Especially for presbyopia, existing solutions often lead to visual discomfort. Multifocal spectacle lenses have a spatially varying optical power distribution leading to changing strength and orientation of blurred vision. Understanding the contribution of blur to visual discomfort and studying behavioral changes under the influence of lens blur is a promising application of a spectacle lens simulator. Here we present our framework to simulate spherical and astigmatic blur of corrective spectacle lenses. Size and orientation of a location dependent blur ellipse is calculated live in virtual reality using the depth information of the scene and precalculated power distribution of the lens.
Synthesis of Homo- and Heteromultivalent Fucosylated and Sialylated Oligosaccharide Conjugates via Preactivated N-Methyloxyamine Precision Macromolecules and Their Binding to Polyomavirus Capsid Proteins
2022-11-18

Glycoconjugates are a versatile class of bioactive molecules that have found application as vaccines and antivirals and in cancer therapy. Their synthesis typically involves elaborate functionalization and use of protecting groups on the carbohydrate component in order to ensure efficient and selective conjugation. Alternatively, non-functionalized, non-protected carbohydrates isolated from biological sources or derived through biotechnological methods can be directly conjugated <i>via N</i>-methyloxyamine groups. In this study, we introduce such <i>N</i>-methyloxyamine groups into a variety of multivalent scaffolds─from small to oligomeric to polymeric scaffolds─making use of solid-phase polymer synthesis to assemble monodisperse sequence-defined macromolecules. These scaffolds are then successfully functionalized with different types of human milk oligosaccharides deriving a library of homo- and heteromultivalent glycoconjugates. Glycomacromolecules presenting oligosaccharide side chains with either α2,3- or α2,6-linked terminal sialic acid are used in a binding study with two types of polyomavirus capsid proteins showing that the multivalent presentation through the <i>N</i>-methyloxyamine-derived scaffolds increases the number of contacts with the protein. Overall, a straightforward route to derive glycoconjugates from complex oligosaccharides with high variability yet control in the multivalent scaffold is presented, and applicability of the derived structures is demonstrated.
Evaluation of functional and metabolic tumor volume using voxel-wise analysis in childhood rhabdomyosarcoma
2022-11-18

Abstract Background Cross-sectional imaging-based morphological characteristics of pediatric rhabdomyosarcoma have failed to predict outcomes. Objective To evaluate the feasibility and possible value of generating tumor sub-volumes using voxel-wise analysis of metabolic and functional data from positron emission tomography/magnetic resonance imaging (PET/MR) or PET/computed tomography (CT) and MRI in rhabdomyosarcoma. Materials and methods Thirty-four examinations in 17 patients who received PET/MRI or PET/CT plus MRI were analyzed. The volume of interest included total tumor volume before and after therapy. Apparent diffusion coefficients (ADC) and standard uptake values (SUV) were determined voxel-wise. Voxels were assigned to three different groups based on ADC and SUV: “viable tumor tissue,” “intermediate tissue” or “possible necrosis.” In a second approach, data were grouped into three clusters using the Gaussian mixture model. The ratio of these clusters to total tumor volume and changes due to chemotherapy were correlated with clinical and histopathological data. Results After chemotherapy, the proportion of voxels in the different groups changed significantly. A significant reduction of the proportion of voxels assigned to cluster 1 was found, from a mean of 36.4% to 2.5% ( P &lt; 0.001). There was a significant increase in the proportion of voxels in cluster 3 following chemotherapy from 24.8% to 81.6% ( P = 0.02). The proportion of voxels in cluster 2 differed depending on the presence or absence of tumor recurrence, falling from 48% to 10% post-chemotherapy in the group with no tumor recurrence ( P &lt; 0.05) and from 29% to 23% ( P &gt; 0.05) in the group with tumor recurrence. Conclusion Voxel-wise evaluation of multimodal data in rhabdomyosarcoma is feasible. Our initial results suggest that the different distribution of sub-volumes before and after therapy may have prognostic significance.
Alternative Best Effort (ABE) for Service Differentiation: Trading Loss Versus Delay
2022-11-18

The idea of an Alternative Best Effort (ABE) per-hop behaviour (PHB) emerged about 20 years ago. It provides a low-delay traffic class in the Internet at the expense of more packet loss than Best Effort (BE). Therefore, ABE is better suited than BE for loss-tolerant but delay-sensitive applications. Furthermore, ABE traffic should not degrade the service for BE traffic in terms of packet loss and delay. Therefore, Internet service providers may leave the choice of using BE or ABE to their customers as they achieve service differentiation without compromising other traffic. In this work, we revisit ABE and pursue the fundamental question whether an ABE service is technically feasible, how its service would look like and interact with existing transport protocols? We present a novel scheduler called Deadlines, Saved Credits, and Decay (DSCD) for combined scheduling of BE and ABE traffic. It allows to control ABE’s delay advantage over BE and copes with varying bandwidth. We provide an implementation of DSCD in the Linux network stack and demonstrate its efficiency. A side product of the implementation is an efficient approximation of the exponential function in the kernel and a bandwidth estimation method that even works at moderate link utilization. We study DSCD in a semi-virtualized testbed with real networking stacks to understand implications for transport protocols in a BE/ABE Internet. The study analyzes ABE’s impact on loss and delay under various conditions and gives recommendations for configuration.
Basic mathematical skills and fraction understanding predict percentage understanding: Evidence from an intelligent tutoring system
2022-11-18

Longitudinal studies indicated that basic mathematical skills (e.g., basic arithmetic operations) are a significant predictor of understanding fractions, which itself is critical for later academic and life prospects. However, it is still unclear whether the understanding of other forms of rational numbers, such as percentages, is also predicted by basic mathematical skills and it is particularly unclear whether such predictions are reflected in data from intelligent tutoring systems (ITSs). Therefore, we leveraged a large-scale dataset (2,798 students; working on 4.1 million mathematical problems) from an ITS to predict percentage understanding based on basic mathematical skills (i.e., arithmetic, measurement units, and geometry) and fraction understanding. In a first step, we observed that skills in advanced arithmetic, measurement units, and geometry, as well as fraction understanding significantly predicted percentage understanding. Closer inspection in a second step indicated that percentage understanding was best predicted by problems with similar features (e.g., fraction word problems, fraction/natural number multiplication/division problems). Together, our results point practitioners and software developers to consider the revision of specific subtopics which share similar features of percentage problems for students who face difficulties with percentages.
Machine learning-based personalized composite score dissects risk and protective factors for cognitive and motor function in elderly
2022-11-18

Abstract Most nations worldwide have aging populations. With age, sensory, cognitive and motor abilities decline and the risk for neurodegenerative disorders increases. These multiple impairments influence the quality of life and increase the need for care, thus putting a high burden on society, the economy, and the healthcare system. Therefore, it is important to identify factors that influence healthy aging, in particular ones that are potentially modifiable by each subject through choice of lifestyle. However, large-scale studies that investigate the influence of multiple multi-modal factors on a global description of healthy aging measured by multiple clinical assessments are sparse. Here, we propose a Machine Learning (ML) model that simultaneously predicts multiple cognitive and motor outcome measurements on a personalized level recorded from one learned composite score. This personalized composite score is derived by the model from a large set of multi-modal components from the TREND cohort including genetic, biofluid, clinical, demographic and lifestyle factors. We found that a model based on a single composite score was able to predict cognitive and motor abilities almost as well as a flexible regression model specifically trained for each single clinical score. In contrast to the flexible regression model, our composite score-based model is able to identify factors that globally influence cognitive and motoric abilities as measured by multiple clinical scores. We used the model to identify several risk and protective factors for healthy aging and recover physical exercise as a major, modifiable, protective factor.
Pyruvate-conjugation of PEGylated liposomes effectively enhances their uptake in retinal photoreceptors
2022-11-18

Abstract Despite several promising candidates there is a paucity of drug treatments available for patients suffering from retinal diseases. An important reason for this is the lack of suitable delivery systems that can achieve sufficiently high drug uptake in the retina and its photoreceptors. A promising and versatile method for drug delivery to specific cell types involves liposomes, surface-coated with substrates for transporter proteins highly expressed on the target cell. We identified strong lactate transporter (monocarboxylate transporter, MCT) expression on photoreceptors as a potential target for drug delivery vehicles. To evaluate MCT suitability for drug targeting, we used PEG-coated liposomes and conjugated these with different monocarboxylates, including lactate, pyruvate, and cysteine. Monocarboxylate-conjugated dye-loaded liposomes were tested on both human-derived cell-lines and murine retinal explant cultures. We found that liposomes conjugated with pyruvate consistently displayed higher cell uptake than unconjugated liposomes or liposomes conjugated with lactate or cysteine. Pharmacological inhibition of MCT1 and MCT2 reduced internalization, suggesting an MCT-mediated uptake mechanism. Pyruvate-conjugated liposomes loaded with the drug candidates CN03 and CN04 reduced photoreceptor cell death in murine rd1 and rd10 retinal degeneration models. Overall, this study proposes pyruvate-conjugated liposomes as a vehicle for drug delivery specifically to photoreceptors. Notably, in retinal degeneration models, free drug solutions could not achieve the same therapeutic effect. Our study thus highlights pyruvate-conjugated liposomes as a promising system for drug delivery to retinal photoreceptors, as well as other neuronal cell types displaying high expression of MCT-type proteins.
Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons
2022-11-18

Abstract Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection causes neurological disease in some patients suggesting that infection can affect both the peripheral and central nervous system (PNS and CNS, respectively). It is not clear whether the outcome of SARS-CoV-2 infection of PNS and CNS neurons is similar, and which are the key factors that cause neurological disease: SARS-CoV-2 infection or the subsequent immune response. Here, we addressed these questions by infecting human induced-pluripotent stem cell-derived CNS and PNS neurons with the β strain of SARS-CoV-2. Our results show that SARS-CoV-2 infects PNS neurons more efficiently than CNS neurons, despite lower expression levels of angiotensin converting enzyme 2. Infected PNS neurons produced interferon λ1, several interferon stimulated genes and proinflammatory cytokines. They also displayed neurodegenerative-like alterations, as indicated by increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein and lower levels of nicotinamide mononucleotide adenylyltransferase 2 and β-III-tubulin. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neurodegeneration, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS.
Save our surgeons (SOS) – an explorative comparison of surgeons’ muscular and cardiovascular demands, posture, perceived workload and discomfort during robotic vs. laparoscopic surgery
2022-11-19

Abstract Purpose Conventional laparoscopic surgery (CLS) imposes an increased risk of work-related musculoskeletal disorders. Technical innovations, such as robotic-assisted laparoscopic surgery (RALS), may provide ergonomic benefits. We compare the surgeon`s work-related demands of CLS vs RALS for benign hysterectomies. Methods Five specialists (3 females, 2 males) each performed four RALS and four CLS as part of their daily clinical routine. During the surgical procedures, muscular demands were assessed by bipolar surface electromyograms of the descendent trapezius, extensor digitorum and flexor carpi radialis muscles as well as cardio-vascular demands by electrocardiography, and neck, arm and torso posture by gravimetrical position sensors. Additionally, the subjects rated their level of perceived workload (NASA TLX questionnaire with 6 dimension) and musculoskeletal discomfort (11-point Likert-scale, 0–10). Results Muscular demands of the trapezius and flexor carpi radialis muscles were lower with RALS but extensor digitorum demands increased. Cardiovascular demands were about 9 heart beats per minute (bpm) lower for RALS compared to CLS with a rather low median level for both surgical techniques (RALS = 84 bpm; CLS 90 bpm). The posture changed in RALS with an increase in neck and torso flexion, and a reduction in abduction and anteversion position of the right arm. The perceived workload was lower in the physical demands dimension but higher in the mental demands dimension during RALS. Subjective musculoskeletal discomfort was rare during both surgical techniques. Conclusions This explorative study identified several potential ergonomic benefits related to RALS which now can be verified by studies using hypothesis testing designs. However, potential effects on muscular demands in the lower arm extensor muscles also have to be addressed in such studies.
Knockout of SLy1 decreases double‐negative thymocyte proliferation and protects mice from p53‐induced tumor formation
2022-11-19

Abstract The lymphocyte‐specific adapter protein SLy1 has previously been identified as indispensable for thymocyte development and T‐cell proliferation and, recently, as a cause of X‐linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in SLy1 KO and SLy1 d/d mice. As SLy1 KO NK cells show increased levels of p53, we focused our research on the interdependency of SLy1 and p53 for thymocyte development. Using RT‐PCR and immunoblot analysis, we observed increased levels of p53 as well as DNA damage response proteins in SLy1 KO thymocytes. To test for rescue from SLy1‐induced deficiencies in thymocyte development like reduced thymocyte numbers and reduced DN to DP progression, we generated a mouse model with T cell‐specific p53‐deficiency on an SLy1 KO background and analyzed lymphocyte populations in these mice and respective controls. Astonishingly, SLy1 KO ‐typical deficiencies were retained, showing that SLy1 is mechanistically independent of p53. Studies of apoptosis and proliferation in SLy1KO thymocytes revealed decreased proliferation in the DN3 subpopulation as a possible reason for the decreased thymocyte number. In mice with p53‐deficient T cells, we observed tumor formation leading to reduced survival, preferentially in SLy1 WT mice. Thus, we suggest that a SLy1‐deficiency reduces proliferation, resulting in less hematologic tumors initiated by the p53‐deficiency.
Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series
2022-11-20

Abstract Objective Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging. Methods A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy. Results Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2). Conclusion The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning.