Directed evolution of genetically encoded LYTACs for cell-mediated delivery.

Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin-like growth factor 2 (IGF2). After showing initial efficacy with wild-type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially selective targeted protein degradation.

Level frequency postulate and the dice analog.

A level frequency postulate is proposed in the context of the Onsager regression hypothesis, and is utilized to demonstrate Fourier fluctuation time between levels in an analog system composed of red and white dice. This dice system is shown to be analogous to an isolated composite system of particles through derivation of the level probability distribution. Level fluctuation time is developed as an algebraic expression involving average energy and a Gaussian parameter, with quasistatic evolution demonstrated as an integral over fluctuation time.

Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery.

Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin like growth factor 2 (IGF2). After showing initial efficacy with wild type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially-selective targeted protein degradation.

Application of emerging technologies for gut microbiome research

Microbiome is associated with a wide range of diseases. The gut microbiome is also a dynamic reflection of health status, which can be modified, thus representing great potential to exploit the mechanisms that influence human physiology. Recent years have seen a dramatic rise in gut microbiome studies, which has been enabled by the rapidly evolving high-throughput sequencing methods (i.e. 16S rRNA sequencing and shotgun sequencing). As the emerging technologies for microbiome research continue to evolve (i.e. metatranscriptomics, metabolomics, culturomics, synthetic biology), microbiome research has moved beyond phylogenetic descriptions and towards mechanistic analyses. In this review, we highlight different approaches to study the microbiome, in particular, the current limitations and future promise of these techniques. This review aims to provide clinicians with a framework for studying the microbiome, as well as to accelerate the adoption of these techniques in clinical practice.

Comparison of early outcomes of arthroscopic labral repair or debridement : a study using the UK Non-Arthroplasty Hip Registry dataset.

AIMS: This study uses prospective registry data to compare early patient outcomes following arthroscopic repair or debridement of the acetabular labrum. METHODS: Data on adult patients who underwent arthroscopic labral debridement or repair between 1 January 2012 and 31 July 2019 were extracted from the UK Non-Arthroplasty Hip Registry. Patients who underwent microfracture, osteophyte excision, or a concurrent extra-articular procedure were excluded. The EuroQol five-dimension (EQ-5D) and International Hip Outcome Tool 12 (iHOT-12) questionnaires were collected preoperatively and at six and 12 months post-operatively. Due to concerns over differential questionnaire non-response between the two groups, a combination of random sampling, propensity score matching, and pooled multivariable linear regression models were employed to compare iHOT-12 improvement. RESULTS: A total of 2,025 labral debridements (55%) and 1,659 labral repairs (45%) were identified. Both groups saw significant (p < 0.001) EQ-5D and iHOT-12 gain compared to preoperative scores at 12 months (iHOT-12 improvement: labral repair = +28.7 (95% confidence interval (CI) 26.4 to 30.9), labral debridement = +24.7 (95% CI 22.5 to 27.0)), however there was no significant difference between procedures after multivariable modelling. Overall, 66% of cases achieved the minimum clinically important difference (MCID) and 48% achieved substantial clinical benefit at 12 months. CONCLUSION: Both labral procedures were successful in significantly improving early functional outcome following hip arthroscopy, regardless of age or sex. Labral repair was associated with superior outcomes in univariable analysis, however there was no significant superiority demonstrated in the multivariable model. Level of evidence: III Cite this article: Bone Jt Open 2022;3(4):291-301.

Demystifying Medico-legal Challenges of Artificial Intelligence Applications in Molecular Imaging and Therapy.

Artificial Intelligence (AI) has been rapidly embraced by imaging fields and offers a variety of benefits in nuclear medicine; however, the biggest hurdles to AI in health care will likely not be technological but legal. What happens when an error occurs in the AI setting? A variety of legal causes of action, ranging from medical malpractice, to notions of vicarious liability/agency to products liability may come into play in an AI-related lawsuit. Physicians working with AI need to understand these causes of action, stay abreast of legal developments in AI, and advocate for appropriate guidelines and legislation.

Convergence and divergence in prediction from vocabulary and speed of word processing.

Toddler vocabulary knowledge and speed of word processing are associated with downstream language and cognition. Here, we investigate whether these associations differ across measures. At age two, 101 participants (55 monolingual French-speaking and 46 monolingual English-speaking children) completed a two-alternative forced choice task, yielding measures of decontextualized vocabulary (number of correct responses) and haptic speed of word processing (latency of correct responses). At ages three, four, and five children completed a battery of language assessments and an executive function task. Growth curve models revealed that age-two vocabulary significantly predicted age-three performance (but not growth from age three to four or four to five) across all language assessments but speed of processing did not predict language outcomes in final models. Finally, speed of processing was correlated with executive function at age three whereas vocabulary was not. Results suggest that vocabulary is associated with a range of downstream language abilities whereas haptic speed of processing may be associated with executive control.

Academy of Medicine, Singapore clinical guideline on endoscopic surveillance and management of gastric premalignant lesions

Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions.

Prognostic Value of Electrocardiographic QRS Diminution in Patients Hospitalized With COVID-19 or Influenza.

During the clinical care of hospitalized patients with COVID-19, diminished QRS amplitude on the surface electrocardiogram (ECG) was observed to precede clinical decompensation, culminating in death. This prompted investigation into the prognostic utility and specificity of low QRS complex amplitude (LoQRS) in COVID-19. We retrospectively analyzed consecutive adults admitted to a telemetry service with SARS-CoV-2 (n = 140) or influenza (n = 281) infection with a final disposition-death or discharge. LoQRS was defined as a composite of QRS amplitude <5 mm or <10 mm in the limb or precordial leads, respectively, or a ≥50% decrease in QRS amplitude on follow-up ECG during hospitalization. LoQRS was more prevalent in patients with COVID-19 than influenza (24.3% vs 11.7%, p = 0.001), and in patients who died than survived with either COVID-19 (48.1% vs 10.2%, p <0.001) or influenza (38.9% vs 9.9%, p <0.001). LoQRS was independently associated with mortality in patients with COVID-19 when adjusted for baseline clinical variables (odds ratio [OR] 11.5, 95% confidence interval [CI] 3.9 to 33.8, p <0.001), presenting and peak troponin, D-dimer, C-reactive protein, albumin, intubation, and vasopressor requirement (OR 13.8, 95% CI 1.3 to 145.5, p = 0.029). The median time to death in COVID-19 from the first ECG with LoQRS was 52 hours (interquartile range 18 to 130). Dynamic QRS amplitude diminution is a strong independent predictor of death over not only the course of COVID-19 infection, but also influenza infection. In conclusion, this finding may serve as a pragmatic prognostication tool reflecting evolving clinical changes during hospitalization, over a potentially actionable time interval for clinical reassessment.

Perceptions on undertaking regular asymptomatic self-testing for COVID-19 using lateral flow tests: A qualitative study of university students and staff

BackgroundThere has been an increased interest from governments in implementing mass testing for COVID-19 of asymptomatic individuals using Lateral Flow Tests (LFTs). Successful implementation of such programmes depends on several factors, including feasibility, acceptability and how people act on test results. There is a paucity of studies examining these issues. ObjectiveWe aimed to examine experiences of university students and staff with experience of regular asymptomatic self-testing using LFTs, and their subsequent behaviours. MethodsWe invited people who were participating in a weekly testing feasibility study. We conducted semi-structured remote interviews between December 2020 and January 2021. Additional qualitative data from a survey were also analysed. Data were analysed thematically. ResultsWe interviewed 18 and surveyed 214 participants. Participants were motivated to regularly self-test as they wanted to know whether or not they were infected with SARS-CoV-2. Most reported that a negative test result did not change their behaviour but it did provide them with reassurance to engage with permitted activities. In contrast, some participants reported making decisions about visiting other people when they would not have done so otherwise, because they felt reassured by a negative test result. Participants valued the test training but some participants still doubted their ability to carry out the test. Participants were concerned about safety of attending test sites with lots of people and reported home testing was most convenient. ConclusionsIf governments want to increase uptake of LFT use, clear messages highlighting the benefits of regular testing for family, friends and society in identifying asymptomatic cases are needed. This should be coupled with transparent communication about accuracy of LFTs and how to act on either a positive or negative result. Concerns about safety, convenience of testing, and ability to do tests need to be addressed to ensure successful scaling up asymptomatic testing.

Chlorinated Spiroconjugated Fused Extended Aromatics for Multifunctional Organic Electronics.

The synthesis of a new molecule, SFIC-Cl, is reported, which features enhanced π-electron delocalization by spiroconjugation and narrowed bandgap by chlorination. SFIC-Cl is integrated into a single-crystal transistor (OFET) and organic light-emitting diode (OLED). The material demonstrates remarkable transport abilities across various solution-processed OFETs and retains efficient radiance in a near-infrared OLED emitting light at 700 nm. Furthermore, the intermolecular multi-dimensional connection of SFIC-Cl enables the fabrication of a single-component large-area (2 × 2 cm2 ) near-infrared OLED by spin-coating. The SFIC-Cl-acceptor-based solar cell shows excellent power conversion efficiency of 10.16% resulting from the broadened and strong absorption and well-matched energy levels. The study demonstrates that chlorinated spiroconjugated fused systems offer a novel direction toward the development of high-performance organic semiconductor materials for hybrid organic electronic devices.

Proteolytic Restriction of Chordin Range Underlies BMP Gradient Formation.

A fundamental question in developmental biology is how morphogens, such as bone morphogenetic protein (BMP), form precise signaling gradients to impart positional and functional identity to the cells of the early embryo. We combine rigorous mutant analyses with quantitative immunofluorescence to determine that the proteases Bmp1a and Tolloid spatially restrict the BMP antagonist Chordin in dorsoventral (DV) axial patterning of the early zebrafish gastrula. We show that maternally deposited Bmp1a plays an unexpected and non-redundant role in establishing the BMP signaling gradient, while the Bmp1a/Tolloid antagonist Sizzled is surprisingly dispensable. Combining computational modeling and in vivo analyses with an immobile Chordin construct, we demonstrate that long-range Chordin diffusion is not necessary for BMP gradient formation and DV patterning. Our data do not support a counter-gradient of Chordin and instead favor a Chordin sink, established by Bmp1a and Tolloid, as the primary mechanism that drives BMP gradient formation.

Noncovalent π-stacked robust topological organic framework.

Organic frameworks (OFs) offer a novel strategy for assembling organic semiconductors into robust networks that facilitate transport, especially the covalent organic frameworks (COFs). However, poor electrical conductivity through covalent bonds and insolubility of COFs limit their practical applications in organic electronics. It is known that the two-dimensional intralayer π∙∙∙π transfer dominates transport in organic semiconductors. However, because of extremely labile inherent features of noncovalent π∙∙∙π interaction, direct construction of robust frameworks via noncovalent π∙∙∙π interaction is a difficult task. Toward this goal, we report a robust noncovalent π∙∙∙π interaction-stacked organic framework, namely πOF, consisting of a permanent three-dimensional porous structure that is held together by pure intralayer noncovalent π∙∙∙π interactions. The elaborate porous structure, with a 1.69-nm supramaximal micropore, is composed of fully conjugated rigid aromatic tetragonal-disphenoid-shaped molecules with four identical platforms. πOF shows excellent thermostability and high recyclability and exhibits self-healing properties by which the parent porosity is recovered upon solvent annealing at room temperature. Taking advantage of the long-range π∙∙∙π interaction, we demonstrate remarkable transport properties of πOF in an organic-field-effect transistor, and the mobility displays relative superiority over the traditional COFs. These promising results position πOF in a direction toward porous and yet conductive materials for high-performance organic electronics.

Mother-adolescent emotion dynamics during conflicts: Associations with perspective taking.

Parent-adolescent emotion dynamics are central to psychosocial adjustment during this developmental period. Perspective taking-the ability to take another's point of view into consideration-develops significantly during adolescence and is important for successful interpersonal functioning in contexts such as conflicts between family members. We used grid-sequence analysis (Brinberg, Fosco, & Ram, 2017) to examine interdyad differences in mother-adolescent emotion dynamics during a conflict discussion, and whether interdyad differences were associated with maternal and adolescent perspective taking. Mothers and their typically developing adolescents (N = 49, Mage = 14.84 years) were video-recorded during a 10-min conflict discussion. We identified patterns of multistep chains of expressed emotions that unfolded during the conflict and how interdyad differences in those patterns were associated with maternal and adolescent perspective taking. Dyads differed with respect to whether they showed turn taking in validation and interest behaviors, or whether they showed patterns of reciprocated negative affect. Higher adolescent but not maternal perspective taking was associated with dyadic turn taking of validation and interest. Maternal and adolescent perspective taking were not associated with the pattern of reciprocated negative affect. Taken together, results highlight the importance of examining the complex process of emotion dynamics in parent-adolescent interactions. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Constructive molecular configurations for surface-defect passivation of perovskite photovoltaics.

Surface trap-mediated nonradiative charge recombination is a major limit to achieving high-efficiency metal-halide perovskite photovoltaics. The ionic character of perovskite lattice has enabled molecular defect passivation approaches through interaction between functional groups and defects. However, a lack of in-depth understanding of how the molecular configuration influences the passivation effectiveness is a challenge to rational molecule design. Here, the chemical environment of a functional group that is activated for defect passivation was systematically investigated with theophylline, caffeine, and theobromine. When N-H and C=O were in an optimal configuration in the molecule, hydrogen-bond formation between N-H and I (iodine) assisted the primary C=O binding with the antisite Pb (lead) defect to maximize surface-defect binding. A stabilized power conversion efficiency of 22.6% of photovoltaic device was demonstrated with theophylline treatment.

Coupled s-excess HMM for vessel border tracking and segmentation.

In this paper, we present a novel image segmentation technique, based on hidden Markov model (HMM), which we then apply to simultaneously segment interior and exterior walls of fluorescent confocal images of lymphatic vessels. Our proposed method achieves this by tracking hidden states, which are used to indicate the locations of both the inner and outer wall borders throughout the sequence of images. We parameterize these vessel borders using radial basis functions (RBFs), thus enabling us to minimize the number of points we need to track as we progress through multiple layers and therefore reduce computational complexity. Information about each border is detected using patch-wise convolutional neural networks (CNN). We use the softmax function to infer the emission probability and use a proposed new training algorithm based on s-excess optimization to learn the transition probability. We also introduce a new optimization method to determine the optimum sequence of the hidden states. Thus, we transform the segmentation problem into one that minimizes an s-excess graph cut, where each hidden state is represented as a graph node and the weight of these nodes are defined by their emission probabilities. The transition probabilities are used to define relationships between neighboring nodes in the constructed graph. We compare our proposed method to the Viterbi and Baum-Welch algorithms. Both qualitative and quantitative analysis show superior performance of the proposed methods.

Author Correction: Enabling low voltage losses and high photocurrent in fullerene-free organic photovoltaics.

The original PDF version of this Article contained an error in the Additional information section, which incorrectly included the statement 'This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019'. This has been removed from the PDF version of the Article. The HTML version was correct from the time of publication.

Enabling low voltage losses and high photocurrent in fullerene-free organic photovoltaics.

Despite significant development recently, improving the power conversion efficiency of organic photovoltaics (OPVs) is still an ongoing challenge to overcome. One of the prerequisites to achieving this goal is to enable efficient charge separation and small voltage losses at the same time. In this work, a facile synthetic strategy is reported, where optoelectronic properties are delicately tuned by the introduction of electron-deficient-core-based fused structure into non-fullerene acceptors. Both devices exhibited a low voltage loss of 0.57 V and high short-circuit current density of 22.0 mA cm-2, resulting in high power conversion efficiencies of over 13.4%. These unconventional electron-deficient-core-based non-fullerene acceptors with near-infrared absorption lead to low non-radiative recombination losses in the resulting organic photovoltaics, contributing to a certified high power conversion efficiency of 12.6%.

Performance Assessment of a Custom, Portable, and Low-Cost Brain-Computer Interface Platform.

OBJECTIVE: Conventional brain-computer interfaces (BCIs) are often expensive, complex to operate, and lack portability, which confines their use to laboratory settings. Portable, inexpensive BCIs can mitigate these problems, but it remains unclear whether their low-cost design compromises their performance. Therefore, we developed a portable, low-cost BCI and compared its performance to that of a conventional BCI. METHODS: The BCI was assembled by integrating a custom electroencephalogram (EEG) amplifier with an open-source microcontroller and a touchscreen. The function of the amplifier was first validated against a commercial bioamplifier, followed by a head-to-head comparison between the custom BCI (using four EEG channels) and a conventional 32-channel BCI. Specifically, five able-bodied subjects were cued to alternate between hand opening/closing and remaining motionless while the BCI decoded their movement state in real time and provided visual feedback through a light emitting diode. Subjects repeated the above task for a total of 10 trials, and were unaware of which system was being used. The performance in each trial was defined as the temporal correlation between the cues and the decoded states. RESULTS: The EEG data simultaneously acquired with the custom and commercial amplifiers were visually similar and highly correlated ( ρ = 0.79). The decoding performances of the custom and conventional BCIs averaged across trials and subjects were 0.70 ± 0.12 and 0.68 ± 0.10, respectively, and were not significantly different. CONCLUSION: The performance of our portable, low-cost BCI is comparable to that of the conventional BCIs. SIGNIFICANCE: Platforms, such as the one developed here, are suitable for BCI applications outside of a laboratory.

"Current training" in Cardiac devices - a Cardiology trainee perspective: a questionnaire survey.

This article was migrated. The article was marked as recommended. A national survey (questionnaire) on Cardiology trainees undertaken on behalf of the author by the British Junior Cardiologists Association (BJCA) on training opportunities, needs, attitudes and perceived barriers that exist within "current training" in cardiac devices suggests lack of opportunity for hands on training and poor attitude to training resulting in a perceived lack of competence. The conflict between service commitment and training was a recurring theme.