Role of a Pdlim5:PalmD complex in directing dendrite morphology.

Neuronal connectivity is regulated during normal brain development with the arrangement of spines and synapses being dependent on the morphology of dendrites. Further, in multiple neurodevelopmental and aging disorders, disruptions of dendrite formation or shaping is associated with atypical neuronal connectivity. We showed previously that Pdlim5 binds delta-catenin and promotes dendrite branching. We report here that Pdlim5 interacts with PalmD, a protein previously suggested by others to interact with the cytoskeleton (e.g., via adducin/spectrin) and to regulate membrane shaping. Functionally, the knockdown of PalmD or Pdlim5 in rat primary hippocampal neurons dramatically reduces branching and conversely, PalmD exogenous expression promotes dendrite branching as does Pdlim5. Further, we show that each proteins' effects are dependent on the presence of the other. In summary, using primary rat hippocampal neurons we reveal the contributions of a novel Pdlim5:PalmD protein complex, composed of functionally inter-dependent components responsible for shaping neuronal dendrites.

Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway.

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, we identified potent anticancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and epithelial-mesenchymal transition pathways, concurrently suppressing epidermal growth factor-induced nuclear factor kappa B nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and CD spectra indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high intraperitoneal (ip) peptide doses of 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anticancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo.

Role of a Pdlim5:PalmD complex in directing dendrite morphology.

Neuronal connectivity is regulated during normal brain development with the arrangement of spines and synapses being dependent on the morphology of dendrites. Further, in multiple neurodevelopmental and aging disorders, disruptions of dendrite formation or shaping is associated with atypical neuronal connectivity. We showed previously that Pdlim5 binds delta-catenin and promotes dendrite branching (Baumert et al., J Cell Biol 2020). We report here that Pdlim5 interacts with PalmD, a protein previously suggested by others to interact with the cytoskeleton (e.g., via adducin/ spectrin) and to regulate membrane shaping. Functionally, the knockdown of PalmD or Pdlim5 in rat primary hippocampal neurons dramatically reduces branching and conversely, PalmD exogenous expression promotes dendrite branching as does Pdlim5. Further, we show that effects of each protein are dependent on the presence of the other. In summary, using primary rat hippocampal neurons we reveal the contributions of a novel Pdlim5:PalmD protein complex, composed of functionally inter-dependent components responsible for shaping neuronal dendrites.

Brillouin zone folding driven bound states in the continuum.

Non-radiative bound states in the continuum (BICs) allow construction of resonant cavities with confined electromagnetic energy and high-quality (Q) factors. However, the sharp decay of the Q factor in the momentum space limits their usefulness for device applications. Here we demonstrate an approach to achieve sustainable ultrahigh Q factors by engineering Brillouin zone folding-induced BICs (BZF-BICs). All the guided modes are folded into the light cone through periodic perturbation that leads to the emergence of BZF-BICs possessing ultrahigh Q factors throughout the large, tunable momentum space. Unlike conventional BICs, BZF-BICs show perturbation-dependent dramatic enhancement of the Q factor in the entire momentum space and are robust against structural disorders. Our work provides a unique design path for BZF-BIC-based silicon metasurface cavities with extreme robustness against disorder while sustaining ultrahigh Q factors, offering potential applications in terahertz devices, nonlinear optics, quantum computing, and photonic integrated circuits.

Understanding Mutations in Human SARS-CoV-2 Spike Glycoprotein: A Systematic Review & Meta-Analysis.

Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system's evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection.

p120-catenin subfamily members have distinct as well as shared effects on dendrite morphology during neuron development in vitro.

Dendritic arborization is essential for proper neuronal connectivity and function. Conversely, abnormal dendrite morphology is associated with several neurological pathologies like Alzheimer's disease and schizophrenia. Among major intrinsic mechanisms that determine the extent of the dendritic arbor is cytoskeletal remodeling. Here, we characterize and compare the impact of the four proteins involved in cytoskeletal remodeling-vertebrate members of the p120-catenin subfamily-on neuronal dendrite morphology. In relation to each of their own distributions, we find that p120-catenin and delta-catenin are expressed at relatively higher proportions in growth cones compared to ARVCF-catenin and p0071-catenin; ARVCF-catenin is expressed at relatively high proportions in the nucleus; and all catenins are expressed in dendritic processes and the soma. Through altering the expression of each p120-subfamily catenin in neurons, we find that exogenous expression of either p120-catenin or delta-catenin correlates with increased dendritic length and branching, whereas their respective depletion decreases dendritic length and branching. While increasing ARVCF-catenin expression also increases dendritic length and branching, decreasing expression has no grossly observable morphological effect. Finally, increasing p0071-catenin expression increases dendritic branching, but not length, while decreasing expression decreases dendritic length and branching. These distinct localization patterns and morphological effects during neuron development suggest that these catenins have both shared and distinct roles in the context of dendrite morphogenesis.

In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding and drug interactions.

The molecular consequences of cancer associated mutations in Acute myeloid leukemia (AML) linked factors are not very well understood. Here, we interrogated the COSMIC database for missense mutations associated with the RUNX1 protein, that is frequently mis-regulated in AML, where we sought to identify recurrently mutated positions at the DNA-interacting interface. Indeed, six of the mutated residues, out of a total 417 residues examined within the DNA binding domain, evidenced reduced DNA association in in silico predictions. Further, given the prominence of RUNX1's compromised function in AML, we asked the question if the mutations themselves might alter RUNX1's interaction (off-target) with known FDA-approved drug molecules, including three currently used in treating AML. We identified several AML-associated mutations in RUNX1 that were calculated to enhance RUNX1's interaction with specific drugs. Specifically, we retrieved data from the COSMIC database for cancer-associated mutations of RUNX1 by using R package "data.table" and "ggplot2" modules. In the presence of DNA and/or drug, we used docking scores and energetics of the complexes as tools to evaluate predicted interaction strengths with RUNX1. For example, we performed predictions of drug binding pockets involving Enasidenib, Giltertinib, and Midostaurin (AML associated), as well as ten different published cancer associated drug compounds. Docking of wild type RUNX1 with these 13 different cancer-associated drugs indicates that wild-type RUNX1 has a lower efficiency of binding while RUNX1 mutants R142K, D171N, R174Q, P176H, and R177Q suggested higher affinity of drug association. Literature evidence support our prediction and suggests the mutation R174Q affects RUNX1 DNA binding and could lead to compromised function. We conclude that specific RUNX1 mutations that lessen DNA binding facilitate the binding of a number of tested drug molecules. Further, we propose that molecular modeling and docking studies for RUNX1 in the presence of DNA and/or drugs enables evaluation of the potential impact of RUNX1 cancer associated mutations in AML.

Delta-Catenin as a Modulator of Rho GTPases in Neurons.

Small Rho GTPases are molecular switches that are involved in multiple processes including regulation of the actin cytoskeleton. These GTPases are activated (turned on) and inactivated (turned off) through various upstream effector molecules to carry out many cellular functions. One such upstream modulator of small Rho GTPase activity is delta-catenin, which is a protein in the p120-catenin subfamily that is enriched in the central nervous system. Delta-catenin affects small GTPase activity to assist in the developmental formation of dendrites and dendritic spines and to maintain them once they mature. As the dendritic arbor and spine density are crucial for synapse formation and plasticity, delta-catenin's ability to modulate small Rho GTPases is necessary for proper learning and memory. Accordingly, the misregulation of delta-catenin and small Rho GTPases has been implicated in several neurological and non-neurological pathologies. While links between delta-catenin and small Rho GTPases have yet to be studied in many contexts, known associations include some cancers, Alzheimer's disease (AD), Cri-du-chat syndrome, and autism spectrum disorder (ASD). Drawing from established studies and recent discoveries, this review explores how delta-catenin modulates small Rho GTPase activity. Future studies will likely elucidate how PDZ proteins that bind delta-catenin further influence small Rho GTPases, how delta-catenin may affect small GTPase activity at adherens junctions when bound to N-cadherin, mechanisms behind delta-catenin's ability to modulate Rac1 and Cdc42, and delta-catenin's ability to modulate small Rho GTPases in the context of diseases, such as cancer and AD.

Dynamic Color Generation with Electrically Tunable Thin Film Optical Coatings.

Thin film optical coatings have a wide range of industrial applications from displays and lighting to photovoltaic cells. The realization of electrically tunable thin film optical coatings in the visible wavelength range is particularly important to develop energy efficient and dynamic color filters. Here, we experimentally demonstrate dynamic color generation using electrically tunable thin film optical coatings that consist of two different phase change materials (PCMs). The proposed active thin film nanocavity excites the Fano resonance that results from the coupling of a broadband and a narrowband absorber made up of phase change materials. The Fano resonance is then electrically tuned by structural phase switching of PCM layers to demonstrate active color filters covering the entire visible spectrum. In contrast to existing thin film optical coatings, the developed electrically tunable PCM based Fano resonant thin optical coatings have several advantages in tunable displays and active nanophotonic applications.

Active Control of Nanodielectric-Induced THz Quasi-BIC in Flexible Metasurfaces: A Platform for Modulation and Sensing.

A bound state in the continuum (BIC) is a nonradiating state of light embedded in the continuum of propagating modes providing drastic enhancement of the electromagnetic field and its localization at micro-nanoscale. However, access to such modes in the far-field requires symmetry breaking. Here, it is demonstrated that a nanometric dielectric or semiconductor layer, 1000 times thinner than the resonant wavelength (λ/1000), induces a dynamically controllable quasi-bound state in the continuum (QBIC) with ultrahigh quality factor in a symmetric metallic metasurface at terahertz frequencies. Photoexcitation of nanostrips of germanium activates ultrafast switching of a QBIC resonance with 200% transmission intensity modulation and complete recovery within 7 ps on a low-loss flexible substrate. The nanostrips also form microchannels that provide an opportunity for BIC-based refractive index sensing. An optimization model is presented for (switchable) QBIC resonances of metamaterial arrays of planar symmetric resonators modified with any (active) dielectric for inverse metamaterial design that can serve as an enabling platform for active micro-nanophotonic devices.

Directed Evolution of an Enhanced POU Reprogramming Factor for Cell Fate Engineering.

Transcription factor-driven cell fate engineering in pluripotency induction, transdifferentiation, and forward reprogramming requires efficiency, speed, and maturity for widespread adoption and clinical translation. Here, we used Oct4, Sox2, Klf4, and c-Myc driven pluripotency reprogramming to evaluate methods for enhancing and tailoring cell fate transitions, through directed evolution with iterative screening of pooled mutant libraries and phenotypic selection. We identified an artificially evolved and enhanced POU factor (ePOU) that substantially outperforms wild-type Oct4 in terms of reprogramming speed and efficiency. In contrast to Oct4, not only can ePOU induce pluripotency with Sox2 alone, but it can also do so in the absence of Sox2 in a three-factor ePOU/Klf4/c-Myc cocktail. Biochemical assays combined with genome-wide analyses showed that ePOU possesses a new preference to dimerize on palindromic DNA elements. Yet, the moderate capacity of Oct4 to function as a pioneer factor, its preference to bind octamer DNA and its capability to dimerize with Sox2 and Sox17 proteins remain unchanged in ePOU. Compared with Oct4, ePOU is thermodynamically stabilized and persists longer in reprogramming cells. In consequence, ePOU: 1) differentially activates several genes hitherto not implicated in reprogramming, 2) reveals an unappreciated role of thyrotropin-releasing hormone signaling, and 3) binds a distinct class of retrotransposons. Collectively, these features enable ePOU to accelerate the establishment of the pluripotency network. This demonstrates that the phenotypic selection of novel factor variants from mammalian cells with desired properties is key to advancing cell fate conversions with artificially evolved biomolecules.

Dynamic properties of high-Tc superconducting nano-junctions made with a focused helium ion beam.

The Josephson junction (JJ) is the corner stone of superconducting electronics and quantum information processing. While the technology for fabricating low Tc JJ is mature and delivers quantum circuits able to reach the "quantum supremacy", the fabrication of reproducible and low-noise high-Tc JJ is still a challenge to be taken up. Here we report on noise properties at RF frequencies of recently introduced high-Tc Josephson nano-junctions fabricated by mean of a Helium ion beam focused at sub-nanometer scale on a YBa2Cu3O7 thin film. We show that their current-voltage characteristics follow the standard Resistively-Shunted-Junction (RSJ) circuit model, and that their characteristic frequency fc = (2e/h)IcRn reaches ~300 GHz at low temperature. Using the "detector response" method, we evidence that the Josephson oscillation linewidth is only limited by the thermal noise in the RSJ model for temperature ranging from T ~ 20 K to 75 K. At lower temperature and for the highest He irradiation dose, the shot noise contribution must also be taken into account when approaching the tunneling regime. We conclude that these Josephson nano-junctions present the lowest noise level possible, which makes them very promising for future applications in the microwave and terahertz regimes.

Excitons in 2D perovskites for ultrafast terahertz photonic devices.

In recent years, two-dimensional (2D) Ruddlesden-Popper perovskites have emerged as promising candidates for environmentally stable solar cells, highly efficient light-emitting diodes, and resistive memory devices. The remarkable existence of self-assembled quantum well (QW) structures in solution-processed 2D perovskites offers a diverse range of optoelectronic properties, which remain largely unexplored. Here, we experimentally observe ultrafast relaxation of free carriers in 20 ps due to the quantum confinement of free carriers in a self-assembled QW structures that form excitons. Furthermore, hybridizing the 2D perovskites with metamaterials on a rigid and a flexible substrate enables modulation of terahertz fields at 50-GHz modulating speed, which is the fastest for a solution-processed semiconductor-based photonic device. Hence, an exciton-based ultrafast response of 2D perovskites opens up large avenues for a wide range of scalable dynamic photonic devices with potential applications in flexible photonics, ultrafast wavefront control, and short-range wireless terahertz communications.

Cancer-associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17.

The functional consequences of cancer-associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit-Oct-Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA-binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain-of-function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild-type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17-V118M is capable of inducing pluripotency. Furthermore, SOX17-V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high-performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer-associated mutations.

SOX17 in cellular reprogramming and cancer.

SOX17 is a transcription factor directing the specification and development of the primitive endoderm, primitive germ cells, definitive endoderm and, subsequently, is involved in the cardiovascular system and several endoderm-derived organs. The analysis of cancer genome sequencing data classified SOX17 as mutated cancer driver gene in endometrial cancer. These studies identified hotspot missense mutations within its DNA binding and transactivation domains. In somatic cell reprogramming, structure-based protein re-engineering showed a single missense mutation in SOX17 can change the DNA dependent heterodimer formation with OCT4 and enables the replacement of SOX2 with SOX17 mutants to induce pluripotency. This reveals the profound impact of specific missense mutations on gene function and regulatory activity. Here, we review the roles of SOX17 in cancer and discuss its cross-talk with the WNT/ß-catenin pathway, potentially reconciling its activity as re-engineered reprogramming factor and mutated cancer driver gene.

All-Dielectric Active Terahertz Photonics Driven by Bound States in the Continuum.

The remarkable emergence of all-dielectric meta-photonics governed by the physics of high-index dielectric materials offers a low-loss platform for efficient manipulation and subwavelength control of electromagnetic waves from microwaves to visible frequencies. Dielectric metasurfaces can focus electromagnetic waves, generate structured beams and vortices, enhance local fields for advanced sensing, and provide novel functionalities for classical and quantum technologies. Recent advances in meta-photonics are associated with the exploration of exotic electromagnetic modes called the bound states in the continuum (BICs), which offer a simple interference mechanism to achieve large quality factors (Q) through excitation of supercavity modes in dielectric nanostructures and resonant metasurfaces. Here, a BIC-driven terahertz metasurface with dynamic control of high-Q silicon supercavities that are reconfigurable at a nanosecond timescale is experimentally demonstrated. It is revealed that such supercavities enable low-power, optically induced terahertz switching and modulation of sharp resonances for potential applications in lasing, mode multiplexing, and biosensing.

Pluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2.

Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4defSox2). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance.

Modulating Fundamental Resonance in Capacitive Coupled Asymmetric Terahertz Metamaterials.

In this work, we experimentally investigate near-field capacitive coupling between a pair of single-gap split ring resonators (SRRs) in a terahertz metamaterial. The unit cell of our design comprises of two coupled SRRs with the split gaps facing each other. The coupling between two SRRs is examined by changing the gap of one resonator with respect to the other for several inter resonator separations. When split gap size of one resonator is increased for a fixed inter-resonator distance, we observe a split in the fundamental resonance mode. This split ultimately results in the excitation of narrow band low frequency resonance mode along with a higher frequency mode which gets blue shifted when the split gap increases. We attribute resonance split to the excitation of symmetric and asymmetric modes due to strong capacitive or electric interaction between the near-field coupled resonators, however blue shift of the higher frequency mode occurs mainly due to the reduced capacitance. The ability of near-field capacitive coupled terahertz metamaterials to excite split resonances could be significant in the construction of modulator and sensing devices beside other potential applications for terahertz domain.

Directed Evolution of Reprogramming Factors by Cell Selection and Sequencing.

Directed biomolecular evolution is widely used to tailor and enhance enzymes, fluorescent proteins, and antibodies but has hitherto not been applied in the reprogramming of mammalian cells. Here, we describe a method termed directed evolution of reprogramming factors by cell selection and sequencing (DERBY-seq) to identify artificially enhanced and evolved reprogramming transcription factors. DERBY-seq entails pooled screens with libraries of positionally randomised genes, cell selection based on phenotypic readouts, and genotyping by amplicon sequencing for candidate identification. We benchmark this approach using pluripotency reprogramming with libraries based on the reprogramming factor SOX2 and the reprogramming incompetent endodermal factor SOX17. We identified several SOX2 variants outperforming the wild-type protein in three- and four-factor cocktails. The most effective variants were discovered from the SOX17 library, demonstrating that this factor can be converted into a highly potent inducer of pluripotency with a range of diverse modifications. We propose DERBY-seq as a broad-based approach to discover reprogramming factors for any donor/target cell combination applicable to direct lineage reprogramming in vitro and in vivo.

A Metamaterial Analog of the Ising Model.

The interaction between microscopic particles is always a fascinating and intriguing area of science. Direct interrogation of such interactions is often difficult. Structured electromagnetic systems offer a rich toolkit for mimicking and reproducing the key dynamics that govern the microscopic interactions, and thus provides an avenue to explore and interpret the microscopic phenomena. In particular, metamaterials offer the freedom to artificially tailor light-matter coupling and to control the interaction between unit cells in the metamaterial array. Here, a terahertz metamaterial that mimics spin-related interactions of microscopic particles in a 2D lattice via complex electromagnetic multipoles scattered within the metamaterial array is demonstrated. Fano resonances featured by distinct mode properties due to strong nearest-neighbor interactions are discussed, which draw parallels with the 2D Ising model. Interestingly, a phase transition from single Fano resonance to hyperfine splitting of the Fano spectrum is observed by manipulating the 2D interactions without applying external magnetic or electric fields, which provides a potential multispectral platform for applications in super-resolution imaging, biosensing, and selective thermal emission. The dynamic approach to reproduce static interaction between microscopic particles will enable more profound significance in exploring the unknown physical world by the macroscopic analogs.