Structure and sequence at an RNA template 5' end influence insertion of transgenes by an R2 retrotransposon protein.

R2 non-long terminal repeat retrotransposons insert site-specifically into ribosomal RNA genes (rDNA) in a broad range of multicellular eukaryotes. R2-encoded proteins can be leveraged to mediate transgene insertion at 28S rDNA loci in cultured human cells. This strategy, recise NA-mediated sertion of ransgenes (PRINT), relies on the codelivery of an mRNA encoding R2 protein and an RNA template encoding a transgene cassette of choice.

Harnessing eukaryotic retroelement proteins for transgene insertion into human safe-harbor loci.

Current approaches for inserting autonomous transgenes into the genome, such as CRISPR-Cas9 or virus-based strategies, have limitations including low efficiency and high risk of untargeted genome mutagenesis. Here, we describe precise RNA-mediated insertion of transgenes (PRINT), an approach for site-specifically primed reverse transcription that directs transgene synthesis directly into the genome at a multicopy safe-harbor locus. PRINT uses delivery of two in vitro transcribed RNAs: messenger RNA encoding avian R2 retroelement-protein and template RNA encoding a transgene of length validated up to 4 kb.

Detecting residents at risk of attrition - A Singapore pathology residency's experience.

The SingHealth Pathology Residency Program (SHPRP) is a 5-year postgraduate training program in Singapore. We face the problem of resident attrition, which has a significant impact on the individual, program and healthcare providers. Our residents are regularly evaluated, using in-house evaluations as well as assessments required in our partnership with the Accreditation Council for Graduate Medical Education International (ACGME-I).

The Lateral Epidermis Actively Counteracts Pulling by the Amnioserosa During Dorsal Closure.

Dorsal closure is a prominent morphogenetic process during embryogenesis, which involves two epithelial tissues, that is, the squamous amnioserosa and the columnar lateral epidermis. Non-muscle myosin II-driven constriction in the amnioserosa leads to a decrease in the apical surface area and pulls on the adjacent lateral epidermis, which subsequently moves dorsally. The pull by the amnioserosa becomes obvious in an elongation of the epidermal cells, especially of those in the first row.

Absence of pure voltage instabilities in the third-order model of power grid dynamics.

Secure operation of electric power grids fundamentally relies on their dynamical stability properties. For the third-order model, a paradigmatic model that captures voltage dynamics, three routes to instability are established in the literature: a pure rotor angle instability, a pure voltage instability, and one instability induced by the interplay of both. Here, we demonstrate that one of these routes, the pure voltage instability, requires infinite voltage amplitudes and is, thus, nonphysical.

Observational study on wearable biosensors and machine learning-based remote monitoring of COVID-19 patients.

Patients infected with SARS-CoV-2 may deteriorate rapidly and therefore continuous monitoring is necessary. We conducted an observational study involving patients with mild COVID-19 to explore the potentials of wearable biosensors and machine learning-based analysis of physiology parameters to detect clinical deterioration. Thirty-four patients (median age: 32 years; male: 52.

Topological Determinants of Perturbation Spreading in Networks.

Spreading phenomena essentially underlie the dynamics of various natural and technological networked systems, yet how spatiotemporal propagation patterns emerge from such networks remains largely unknown. Here we propose a novel approach that reveals universal features determining the spreading dynamics in diffusively coupled networks and disentangles them from factors that are system specific. In particular, we first analytically identify a purely topological factor encoding the interaction structure and strength, and second, numerically estimate a master function characterizing the universal scaling of the perturbation arrival times across topologically different networks.

Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1.

Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in establishing a telomere length set point remains elusive. Here, we characterize the contribution of the shorter isoform of TPP1 (TPP1S) and the amino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length control.

Vulnerability in dynamically driven oscillatory networks and power grids.

Vulnerability of networks has so far been quantified mainly for structural properties. In driven systems, however, vulnerability intrinsically relies on the collective response dynamics. As shown recently, dynamic response patterns emerging in driven oscillator networks and AC power grid models are highly heterogeneous and nontrivial, depending jointly on the driving frequency, the interaction topology of the network, and the node or nodes driven.

The Emergent Yo-yo Movement of Nuclei Driven by Cytoskeletal Remodeling in Pseudo-synchronous Mitotic Cycles.

Many aspects in tissue morphogenesis are attributed to a collective behavior of the participating cells. Yet, the mechanism for emergence of dynamic tissue behavior is not well understood. Here, we report that the "yo-yo"-like nuclear movement in the Drosophila syncytial embryo displays emergent features indicative of collective behavior.

Fluctuation-induced distributed resonances in oscillatory networks.

Across physics, biology, and engineering, the collective dynamics of oscillatory networks often evolve into self-organized operating states. How such networks respond to external fluctuating signals fundamentally underlies their function, yet is not well understood. Here, we present a theory of dynamic network response patterns and reveal how distributed resonance patterns emerge in oscillatory networks once the dynamics of the oscillatory units become more than one-dimensional.

Quantifying transient spreading dynamics on networks.

Spreading phenomena on networks are essential for the collective dynamics of various natural and technological systems, from information spreading in gene regulatory networks to neural circuits and from epidemics to supply networks experiencing perturbations. Still, how local disturbances spread across networks is not yet quantitatively understood. Here, we analyze generic spreading dynamics in deterministic network dynamical systems close to a given operating point.

Escape routes, weak links, and desynchronization in fluctuation-driven networks.

Shifting our electricity generation from fossil fuel to renewable energy sources introduces large fluctuations to the power system. Here, we demonstrate how increased fluctuations, reduced damping, and reduced intertia may undermine the dynamical robustness of power grid networks. Focusing on fundamental noise models, we derive analytic insights into which factors limit the dynamic robustness and how fluctuations may induce a system escape from an operating state.

Network susceptibilities: Theory and applications.

We introduce the concept of network susceptibilities quantifying the response of the collective dynamics of a network to small parameter changes. We distinguish two types of susceptibilities: vertex susceptibilities and edge susceptibilities, measuring the responses due to changes in the properties of units and their interactions, respectively. We derive explicit forms of network susceptibilities for oscillator networks close to steady states and offer example applications for Kuramoto-type phase-oscillator models, power grid models, and generic flow models.

Endogenous Telomerase Reverse Transcriptase N-Terminal Tagging Affects Human Telomerase Function at Telomeres In Vivo.

Telomerase action at telomeres is essential for the immortal phenotype of stem cells and the aberrant proliferative potential of cancer cells. Insufficient telomere maintenance can cause stem cell and tissue failure syndromes, while increased telomerase levels are associated with tumorigenesis. Both pathologies can arise from only small perturbation of telomerase function.

Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies.

We dissected the importance of human telomerase biogenesis and trafficking pathways for telomere maintenance. Biological stability of human telomerase RNA (hTR) relies on H/ACA proteins, but other eukaryotes use other RNP assembly pathways. To investigate additional rationale for human telomerase assembly as H/ACA RNP, we developed a minimized cellular hTR.

Critical Links and Nonlocal Rerouting in Complex Supply Networks.

Link failures repeatedly induce large-scale outages in power grids and other supply networks. Yet, it is still not well understood which links are particularly prone to inducing such outages. Here we analyze how the nature and location of each link impact the network's capability to maintain a stable supply.

Flexible and free-standing ternary Cd₂GeO₄ nanowire/graphene oxide/CNT nanocomposite film with improved lithium-ion battery performance.

To realize flexible lithium-ion batteries (LIBs), the design of flexible electrode/current collector materials with high mechanical flexibility, superior conductivity and excellent electrochemical performance and electrical stability are highly desirable. In this work, we developed a new ternary Cd2GeO4 nanowire/graphene oxide/carbon nanotube nanocomposite (Cd2GeO4 NW/GO/CNT) film electrode. Benefiting from the efficient combination of GO and Cd2GeO4 NWs, our Cd2GeO4 NW/GO/CNT composite film exhibits a capacity of 784 mA h g(-1) after 30 cycles at 200 mA g(-1), which is 2.

Predictability of critical transitions.

Critical transitions in multistable systems have been discussed as models for a variety of phenomena ranging from the extinctions of species to socioeconomic changes and climate transitions between ice ages and warm ages. From bifurcation theory we can expect certain critical transitions to be preceded by a decreased recovery from external perturbations. The consequences of this critical slowing down have been observed as an increase in variance and autocorrelation prior to the transition.

APP intracellular domain-WAVE1 pathway reduces amyloid-β production.

An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells.

Upregulation of SET expression by BACE1 and its implications in Down syndrome.

Down syndrome (DS) is one of the most common genetic diseases. Patients with DS display growth delay and intellectual disabilities and develop Alzheimer's disease (AD) neuropathology after middle age, including neuritic plaques and neurofibrillary tangles. Beta-site amyloid β precursor protein (APP) cleaving enzyme 1 (BACE1), essential for Aβ production and neuritic plaque formation, is elevated in DS patients.

Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis.

Cleavage of amyloid-β precursor protein (APP) at the Asp1 β-secretase site of the amyloid-β protein (Aβ) domain by β-site Aβ precursor protein-cleaving enzyme 1 (BACE1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (AD) brain. In this study, we found that Aβ Glu11 is the major β-secretase site for cleavage of APP by BACE1 to generate soluble secreted APP (sAPPβ)(606) and the C-terminal membrane-bound fragment (CTF)β product C89. Cleavage of C89 by γ-secretase resulted in truncated Aβ generation in a non-amyloidogenic pathway.