The structural mechanism of dimeric DONSON in replicative helicase activation.

The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.

Atypical Clinical presentation of a patient with Monkeypox.

Presentation The Monkeypox virus is spreading in the European continent. A 36-year-old Irish man presented with a cellulitis lesion on the nose, spreading to the cheeks and upper lip. Atypical clinical features of the evolving outbreak are posing a community and healthcare risk to its management. Diagnosis Real-time PCR assay of the lesion swab revealed Monkeypox virus. The biochemical and hematological blood indices were normal, except for C-Reactive Protein, which was higher than normal. Treatment The patient was put on 750 mg intravenous Acyclovir, 15mg/kg twice a day of Vancomycin and 2g/day Ceftriaxone infusion. Discussion Cellulitis lesions are an atypical clinical feature of Monkeypox virus infection. Its management, using antibiotics and antiviral drugs, treated the infection and confined the spread of the virus around the patient's nose.

Cubic-wavelength mode volume photonic crystal nanobeam cavities in a monolithic CMOS platform.

We report on the design, fabrication, and experimental characterization of photonic crystal (PhC) nanobeam cavities with the smallest footprint, largest intrinsic quality factor, and smallest mode volume to be demonstrated to date in a monolithic CMOS platform. Two types of cavities were designed, with opposite spatial mode symmetries. The opposite mode symmetry, combined with evanescent coupling, allows the nanobeam cavities to be used in reflectionless topologies, desirable in complex photonic integrated circuits (PICs). The devices were implemented and fabricated in a 45 nm monolithic electronics-photonics CMOS platform optimized for silicon photonics (GlobalFoundries 45CLO) and do not require any post-processing. Quality factors exceeding 100 000 were measured for both devices, the highest, to the best of our knowledge, among fully cladded PhC nanobeam cavities in any silicon-on-insulator (SOI) platform. Additionally, the ability of the cavities to confine light into small mode volumes, of the order of (λ/n)3, was confirmed experimentally using near-field scanning optical microscopy (NSOM). These types of cavities are an important step toward realizing ultra-low energy active devices required for the next generation of integrated optical links beyond the current microring resonator-based links and other CMOS PICs.

Polarization-insensitive 1D grating coupler based on a zero-birefringence subwavelength corelet waveguide.

Grating coupler devices provide efficient, foundry-compatible vertical fiber-to-chip coupling solutions in integrated photonic platforms. However, standard grating coupler designs are highly polarization sensitive, which hinders their adoption. We present a new, to the best of our knowledge, type of 1D polarization-insensitive grating coupler (PIGC) that is based on a zero-birefringence subwavelength "corelet" waveguide. We demonstrate a PIGC for coupling in the telecommunications O-band in a 45-nm-node monolithic silicon-on-insulator (SOI) CMOS electronic-photonic platform, with measured insertion losses of 6.7 and 6.1 dB to transverse electric and transverse magnetic polarizations, respectively, and a ±1-dB polarization dependent loss bandwidth of 73 nm.

Multiple roles of Pol epsilon in eukaryotic chromosome replication.

Pol epsilon is a tetrameric assembly that plays distinct roles during eukaryotic chromosome replication. It catalyses leading strand DNA synthesis; yet this function is dispensable for viability. Its non-catalytic domains instead play an essential role in the assembly of the active replicative helicase and origin activation, while non-essential histone-fold subunits serve a critical function in parental histone redeposition onto newly synthesised DNA. Furthermore, Pol epsilon plays a structural role in linking the RFC-Ctf18 clamp loader to the replisome, supporting processive DNA synthesis, DNA damage response signalling as well as sister chromatid cohesion. In this minireview, we discuss recent biochemical and structural work that begins to explain various aspects of eukaryotic chromosome replication, with a focus on the multiple roles of Pol epsilon in this process.

Combined hereditary thrombophilias are responsible for poor placental vascularization development and low molecular weight heparins (LMWH) prevent adverse pregnancy outcomes in these patients.

BACKGROUND: Even though thrombophilias are associated with negative pregnancy outcomes (PO), there is not a consensus of when thrombophilias should be screened for, or how they affect placental vascularization during pregnancy. Therefore, the main aim of this study was to discover inherited thrombophilias (IHT) in the first trimester in women with otherwise no indications for thrombophilia screening, based on their vascularization parameters. LMWH treatment in improvement of placental vascularization and PO was also assessed. Finally, the classification of thrombophilias based on observed obstetric risks was proposed. METHODS: Women were included in study based on their poor gestational sac and later utero-placental juncture vascularization signal and screening for inherited thrombophilias. LMWH were then initiated and Resistance index of Uterine artery (RIAU) was followed alongside PO (preterm birth, preeclampsia, placental abruption, intrauterine growth reduction). Study group consisted of women with combined inherited thrombophilias. Control group consisted of patients with inherited thrombophilias who have received LMWH therapy since pregnancy beginning. FINDINGS: Out of 219 women, 93 had IHT, and 43 had combined IHT. All pregnancies both in both groups ended up with live births. Vaginal birth was more present in the control group (p < .001), and all women in study group delivered by CS. Premature birth was present in 8.4% of patients in control group, and in 32.55% of the patients in the study (p < .001). PE wasn't noted, and only 1 case of PA in control group. In the control group, 6.5% patients had IUGR, and 32.55% in the study group (p < .05). Based on RIAU and PO, thrombophilia categories were established: S (severe), MO (moderate), MI (mild) and L (low). Higher risk thrombophilias had higher RIAU later in the pregnancy, earlier pregnancy termination and Intrauterine Growth Reduction (IUGR). CONCLUSIONS: Thrombophilias should be considered and screened when poor vascularization is noted early in the pregnancy with Doppler sonography. Intervention with LMWH prevents adverse PO in these patients.

Optical isolation using microring modulators.

Optical isolators, while commonplace in bulk and fiber optical systems, remain a key missing component in integrated photonics. Isolation using magneto-optic materials has been difficult to integrate into complementary metal-oxide-semiconductor (CMOS) fabrication platforms, motivating the use of other paths to effective non-reciprocity such as temporal modulation. We demonstrate a non-reciprocal element comprising a pair of microring modulators and a microring phase shifter in an active silicon photonic process, which, in combination with standard bandpass filters, yields an isolator on-chip. Isolation up to 13 dB is measured with a 3 dB bandwidth of 2 GHz and insertion loss of 18 dB. We also show transmission of a 4 Gbps optical data signal through the isolator while retaining a wide-open eye diagram. This compact design, in combination with increased modulation efficiency, could enable modulator-based isolators to become a standard 'black-box' component in integrated photonics CMOS foundry platform component libraries.

Reflectionless dual standing-wave microcavity resonator units for photonic integrated circuits.

We propose a novel photonic circuit element configuration that emulates the through-port response of a bus coupled traveling-wave resonator using two standing-wave resonant cavities. In this "reflectionless resonator unit", the two constituent cavities, here photonic crystal (PhC) nanobeams, exhibit opposite mode symmetries and may otherwise belong to a single design family. They are coupled evanescently to the bus waveguide without mutual coupling. We show theoretically, and verify using FDTD simulations, that reflection is eliminated when the two cavities are wavelength aligned. This occurs due to symmetry-induced destructive interference at the bus coupling region in the proposed photonic circuit topology. The transmission is equivalent to that of a bus-coupled traveling-wave (e.g. microring) resonator for all coupling conditions. We experimentally demonstrate an implementation fabricated in a new 45 nm silicon-on-insulator complementary metal-oxide semiconductor (SOI CMOS) electronic-photonic process. Both PhC nanobeam cavities have a full-width half-maximum (FWHM) mode length of 4.28 µm and measured intrinsic Q's in excess of 200,000. When the resonances are tuned to degeneracy and coalesce, transmission dips of the over-coupled PhC nanobeam cavities of -16 dB and -17 dB nearly disappear showing a remaining single dip of -4.2 dB, while reflection peaks are simultaneously reduced by 10 dB, demonstrating the quasi-traveling-wave behavior. This photonic circuit topology paves the way for realizing low-energy active devices such as modulators and detectors that can be cascaded to form wavelength-division multiplexed links with smaller power consumption and footprint than traveling wave, ring resonator based implementations.

Integrated optical isolators using electrically driven acoustic waves.

We propose and investigate the performance of integrated photonic isolators based on non-reciprocal mode conversion facilitated by unidirectional, traveling acoustic waves. A triply-guided waveguide system on-chip, comprising two optical modes and an electrically-driven acoustic mode, facilitates the non-reciprocal mode conversion and is combined with spatial mode filters to create the isolator. The co-guided and co-traveling arrangement enables isolation with no additional optical loss, without magnetic-optic materials, and with low power consumption. The approach is theoretically evaluated with simulations predicting over 20 dB of isolation and 2.6 dB of insertion loss with a 370 GHz optical bandwidth and 1 cm device length. The isolator uses only 1 mW of electrical drive power, an improvement of 1-3 orders of magnitude over the state of the art. The electronic drive and lack of magneto-optic materials suggest the potential for straightforward integration with drive circuits, including in monolithic CMOS electronic-photonic platforms, enabling a fully contained 'black box' optical isolator with two optical ports and DC electrical power.

Mode multiplexer for guided optical and acoustic waves.

Integrated acousto-optic (AO) devices utilize the strong overlap of acoustic and optical fields in a waveguide to facilitate efficient photon-phonon (Brillouin) interactions. For example, acoustic waves offer a lossless modulation mechanism for light. "Brillouin active" photonic platforms are currently being developed that may see optical, acoustic, and AO waveguide circuits on the same chip, where guided light and sound come together in active interaction regions. A key missing component for such a platform is a device that can multiplex modes across these two physical domains. We propose and describe a new class of optical and acoustic components, the "acoustic-optical mode multiplexer" (AOMM), a device that takes respective optical and acoustic waveguides as input ports and couples their excited guided modes into a single, joint output waveguide. We show an example suspended silicon-silicon dioxide design that combines two optical modes and a spatially separate acoustic mode into a single, co-guided output port with low insertion loss down to 0.3 dB for both optical and acoustic modes, and reflection below -20dB and -11dB, respectively. The AOMM may enable new, efficient integrated AO devices, such as isolators and circulators, where the acoustic wave generation and opto-acoustic interaction are separated.

Compact multi-million Q resonators and 100 MHz passband filter bank in a thick-SOI photonics platform.

We demonstrate ring and racetrack resonators with Qs of 3.8 to 7.5 million and 100 MHz bandwidth racetrack resonator filters, implemented in a thick silicon-on-insulator foundry platform that features a 3 µm thick device layer. We show that special racetrack resonators (with weakly guiding straight sections that transition to strongly confining bends) implemented in this platform can be preferable to rings for applications such as integrated microwave-photonic signal processing that require filters with sub-GHz bandwidth, tens of GHz of free spectral range (FSR), and a compact footprint for dense system-on-chip integration. We demonstrate ring resonators with 7.5×106 intrinsic Q, but limited FSR of 5.1 GHz and a taxing footprint of 21mm2 due to a large 2.6 mm bend-loss-limited radius. In comparison, we demonstrate two racetrack resonator designs with intrinsic Qs of 3.8×106 and 4.3×106, larger respective FSRs of 11.6 GHz and 7.9 GHz, and less than 1/20th the area of the ring resonator. Using racetrack resonators, we implemented a four-channel, 100 MHz wide passband filter bank with 4.2 to 5.4 dB insertion loss to drop ports.

Microtubule Nucleation Properties of Single Human γTuRCs Explained by Their Cryo-EM Structure.

The γ-tubulin ring complex (γTuRC) is the major microtubule nucleator in cells. The mechanism of its regulation is not understood. We purified human γTuRC and measured its nucleation properties in a total internal reflection fluorescence (TIRF) microscopy-based real-time nucleation assay. We find that γTuRC stably caps the minus ends of microtubules that it nucleates stochastically. Nucleation is inefficient compared with microtubule elongation. The 4 Å resolution cryoelectron microscopy (cryo-EM) structure of γTuRC, combined with crosslinking mass spectrometry analysis, reveals an asymmetric conformation with only part of the complex in a "closed" conformation matching the microtubule geometry. Actin in the core of the complex, and MZT2 at the outer perimeter of the closed part of γTuRC appear to stabilize the closed conformation. The opposite side of γTuRC is in an "open," nucleation-incompetent conformation, leading to a structural asymmetry explaining the low nucleation efficiency of purified human γTuRC. Our data suggest possible regulatory mechanisms for microtubule nucleation by γTuRC closure.

Triply resonant coupled-cavity electro-optic modulators for RF to optical signal conversion.

We propose an on-chip triply resonant electro-optic modulator architecture for RF-to-optical signal conversion and provide a detailed theoretical analysis of the optimal "circuit-level" device geometries and their performance limits. The designs maximize the RF-optical conversion efficiency through simultaneous resonant enhancement of the RF drive signal, a continuous-wave (CW) optical pump, and the generated optical sideband. The optical pump and sideband are resonantly enhanced in respective supermodes of a two-coupled-cavity optical resonator system, while the RF signal can be enhanced in addition by an LC circuit formed by capacitances of the optical resonator active regions and (integrated) matching inductors. We show that such designs can offer 15-50 dB improvement in conversion efficiency over conventional microring modulators. In the proposed configurations, the photon lifetime (resonance linewidth) limits the instantaneous RF bandwidth of the electro-optic response but does not limit its central RF frequency. The latter is set by the coupling strength between the two coupled cavities and is not subject to the photon lifetime constraint inherent to conventional singly resonant microring modulators. This feature enables efficient operation at high RF carrier frequencies without a reduction in efficiency commonly associated with the photon lifetime limit and accounts for 10-30 dB of the total improvement. Two optical configurations of the modulator are proposed: a "basic" configuration with equal Q-factors in both supermodes, most suitable for narrowband RF signals, and a "generalized" configuration with independently tailored supermode Q-factors that supports a wider instantaneous bandwidth. A second significant 5-20 dB gain in modulation efficiency is expected from RF drive signal enhancement by integrated LC resonant matching, leading to the total expected improvement of 15-50 dB. Previously studied triply-resonant modulators, with coupled longitudinal [across the free spectral range (FSR)] modes, have large resonant mode volume for typical RF frequencies, which limits the interaction between the optical and RF fields. In contrast, the proposed modulators support maximally tightly confined resonant modes, with strong coupling between the mode fields, which increases and maintains high device efficiency across a range of RF frequencies. The proposed modulator architecture is compact, efficient, capable of modulation at high RF carrier frequencies and can be applied to any cavity design or modulation mechanism. It is also well suited to moderate Q, including silicon, implementations, and may be enabling for future CMOS RF-electronic-photonic systems on chip.

Publisher Correction: Integrating photonics with silicon nanoelectronics for the next generation of systems on a chip.

In this Letter, owing to an error during the production process, the author affiliations were listed incorrectly. Affiliation number 5 (Colleges of Nanoscale Science and Engineering, State University of New York (SUNY)) was repeated, and affiliation numbers 6-8 were incorrect. In addition, the phrase "two oxide thickness variants" should have been "two gate oxide thickness variants". These errors have all been corrected online.

Integrating photonics with silicon nanoelectronics for the next generation of systems on a chip.

Electronic and photonic technologies have transformed our lives-from computing and mobile devices, to information technology and the internet. Our future demands in these fields require innovation in each technology separately, but also depend on our ability to harness their complementary physics through integrated solutions1,2. This goal is hindered by the fact that most silicon nanotechnologies-which enable our processors, computer memory, communications chips and image sensors-rely on bulk silicon substrates, a cost-effective solution with an abundant supply chain, but with substantial limitations for the integration of photonic functions. Here we introduce photonics into bulk silicon complementary metal-oxide-semiconductor (CMOS) chips using a layer of polycrystalline silicon deposited on silicon oxide (glass) islands fabricated alongside transistors. We use this single deposited layer to realize optical waveguides and resonators, high-speed optical modulators and sensitive avalanche photodetectors. We integrated this photonic platform with a 65-nanometre-transistor bulk CMOS process technology inside a 300-millimetre-diameter-wafer microelectronics foundry. We then implemented integrated high-speed optical transceivers in this platform that operate at ten gigabits per second, composed of millions of transistors, and arrayed on a single optical bus for wavelength division multiplexing, to address the demand for high-bandwidth optical interconnects in data centres and high-performance computing3,4. By decoupling the formation of photonic devices from that of transistors, this integration approach can achieve many of the goals of multi-chip solutions 5 , but with the performance, complexity and scalability of 'systems on a chip'1,6-8. As transistors smaller than ten nanometres across become commercially available 9 , and as new nanotechnologies emerge10,11, this approach could provide a way to integrate photonics with state-of-the-art nanoelectronics.

Optimal design of a microring cavity optical modulator for efficient RF-to-optical conversion.

The efficiency of optical sideband generation with a microring resonator modulator as a function of modulator parameters is studied taking into account the photon dynamics inside the resonator. The best achievable modulation efficiency is determined for any choice of the resonator intrinsic quality factor, and analytic solutions for the optimum modulator parameters, namely the coupling coefficient and the detuning between the frequencies of the input laser light and the microring resonance, are provided. This analysis is carried out both for a narrowband RF signal, in which case the modulator is optimized for the center frequency of this signal, and for wideband signals, when high conversion efficiency over a wide range of RF frequencies is desired. The obtained results are expected to be useful coherent optical links, direct detection RF receivers, and optical wavelength converters.

Acoustic Waveguide Eigenmode Solver Based on a Staggered-Grid Finite-Difference Method.

A numerical method of solving for the elastic wave eigenmodes in acoustic waveguides of arbitrary cross-section is presented. Operating under the assumptions of linear, isotropic materials, it utilizes a finite-difference method on a staggered grid to solve for the acoustic eigenmodes (field and frequency) of the vector-field elastic wave equation with a given propagation constant. Free, fixed, symmetry, and anti-symmetry boundary conditions are implemented, enabling efficient simulation of acoustic structures with geometrical symmetries and terminations. Perfectly matched layers are also implemented, allowing for the simulation of radiative (leaky) modes. The method is analogous to that in eigenmode solvers ubiquitously employed in electromagnetics to find waveguide modes, and enables design of acoustic waveguides as well as seamless integration with electromagnetic solvers for optomechanical device design. The accuracy of the solver is demonstrated by calculating eigenfrequencies and mode shapes for common acoustic modes across four orders of magnitude in frequency in several simple geometries and comparing the results to analytical solutions where available or to numerical solvers based on more computationally expensive methods. The solver is utilized to demonstrate a novel type of leaky-guided acoustic wave that couples simultaneously to two independent radiation channels (directions) with different polarizations - a 'bi-leaky' mode.

Pregnancy and delivery in a woman with severe haemophilia A.

: Severe form of haemophilia in women is an extremely rare condition. Owing to the rarity of the disease there are no precise recommendations concerning the optimal management of pregnancy and delivery in these patients. We are reporting the clinical course and management of a 30-year-old woman with a severe form of haemophilia A (factor VIII <1 IU/dl) during her first pregnancy and delivery. Antepartum, she was treated on demand by FVIII concentrate and she delivered at 37 weeks of gestation by cesarean section. In postpartal period an excellent control of bleeding was obtained by regularly administering FVIII concentrate for several days as well by concomitant use of tranexamic acid and oral contraceptive pills in the next 6 weeks.