An integrated vertex model of the mesoderm invagination during the embryonic development of Drosophila.

The mesoderm invagination of the Drosophila embryo is known as an archetypal morphogenic process. To explore the roles of the active cellular forces and the regulation of these forces, we developed an integrated vertex model that combines the regulation of morphogen expression with cell movements and tissue mechanics. Our results suggest that a successful furrow formation requires an apical tension gradient, decreased basal tension, and increased lateral tension, which corresponds to apical constriction, basal expansion, and apicobasal shortening respectively. Our model also considers the mechanical feedback which leads to an ectopic twist expression with external compression as observed in experiments. Our model predicts that ectopic invagination could happen if an external compressive gradient is applied.

[Radiographic study of relationship between medial cuneiform obliquity and simple hallux valgus].

OBJECTIVE: To investigate the relationship between hallux valgus and the indicators associated with medial cuneiform obliquity measured on feet weight-bearing anteroposterior X-ray films. METHODS: Based on the feet weight-bearing anteroposterior X-ray films taken between January 2018 and February 2021 and met the criteria, the hallux valgus angle (HVA), intermetatarsal angle (IMA), metatarsus adductus angle (MAA), metatarsus cuneiform angle (MCA), distal medial cuneiform angle (DMCA), and proximal metatarsal articular angle (PMAA) were measured and the morphology of the first tarsometatarsal (TMT) were recorded. According to the HVA, the X-ray films were divided into normal group (HVA<15°) and hallux valgus group (HVA≥15°). The gender, age, sides, IMA, MAA, MCA, DMCA, PMAA, and the morphology of TMT were compared between groups. The influencing factors of HVA and IMA were analyzed by multivariate linear regression analysis. RESULTS: X-ray films of 534 patients (679 feet) met the selection criteria and were included in the study. There were 220 males and 314 females, with an average age of 36 years (mean, 18-82 years). There were 154 cases (168 feet) in the normal group and 403 cases (511 feet) in the hallux valgus group. There were significant differences in gender and age between groups ( P<0.05), and no significant difference in the side ( P>0.05). The IMA, MAA, and MCA in the hallux valgus group were significantly bigger than those in the normal group ( P<0.05); the difference in DMCA between the two groups was not significant ( P>0.05). The TMT morphology of the two groups was mainly curved, and the difference in morphology classification was not significant ( P>0.05). PMAA measurement showed that there were 3 kinds of metatarsal shapes: adductive metatarsal, neutral metatarsal, and abductive metatarsal, the difference in metatarsal shapes between groups was not significant ( P>0.05). The PMAA of abductive metatarsal was significantly bigger in normal group than in hallux valgus group ( P<0.05), there was no significant difference in PMAA of adductive metatarsal between groups ( P>0.05). Multivariate linear regression analysis showed that age, MCA, and DMCA were the influencing factors of HVA ( P<0.05), and age, MAA, MCA, and DMCA were the influencing factors of IMA ( P<0.05). CONCLUSION: The medial cuneiform obliquity is relatively constant and the DMCA can not be used as the characteristic angle to quantify hallux valgus. The morphology of TMT has no relationship with hallux valgus, while MAA, MCA, and PMAA are all factors to be considered, and MCA can be used as the characteristic angle to quantify hallux valgus.

Follow-up of SARS-CoV-2 positive subgroup from the Asymptomatic novel CORonavirus iNFection study.

A nested longitudinal study within theAsymptomatic novel CORonavirus iNFfection study followed participants with positive nasopharyngeal swab to query for development of symptoms and assess duration of positive reverse transcription-polymerase chain reaction (RT-PCR) test results. Of the 91 participants initially testing positive, 86 participated in follow-up approximately 14 days after study enrollment; of those 86 participants, 19 (22.1%) developed at least one symptom at any time after the initial positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. The median number of days to symptom development after their initial positive test result was 6 (range 1-29 days). No participants reported a SARS-CoV-2-related hospitalization. The most frequently reported symptoms were fatigue or muscle aches (10.5%), headache (9.3%), fever (5.8%), and shortness of breath (5.8%). Of the 78 participants who submitted a nasopharyngeal swab for repeat RT-PCR testing, 17 (21.8%) remained positive at Day 14, 4 of which continued to test positive at Day 28. These findings reinforce the probable role of silent SARS-CoV-2 infections in community transmission, and that reliance on symptom development will miss a large proportion of infections. Broad testing programs not limited to individuals presenting with symptoms are critical for identifying persons with SARS-CoV-2 infection and ultimately slowing transmission.

Continuously tunable true-time delay lines based on a one-dimensional grating waveguide for beam steering in phased array antennas.

In this paper, we propose integrated one-dimensional (1D) grating waveguide-based true-time delay (TTD) lines on a silicon-on-insulator (SOI) platform. Through optimizing the structure of the proposed waveguide, a time delay of 77.23 ps/mm can be readily achieved in a wavelength tuning range from 1540.20 nm to 1558.97 nm. Compared to conventional photonic crystal waveguide-based TTDs, the proposed waveguide occupies 70% less chip surface and has much lower propagation loss when compared with 2D photonic crystal devices. Therefore, a larger time delay can be achieved on-chip. To facilitate low loss coupling from strip waveguides to 1D grating waveguides and vice versa, a novel step taper is designed and shows a coupling efficiency of over 78%. Based on the 1D grating waveguide, a 1×4 beam steering module is designed and simulated. A wide beam steering angle from -67.84° to 67.84° for the X-band four-element phased array antenna with an array pitch size of 1.25 cm is obtained.

Broadband tunable filter based on the loop of multimode Bragg grating.

A broadband tunable silicon filter has been demonstrated on silicon-on-insulator platform. The device is based on the loop of multimode anti-symmetric waveguide Bragg grating. A wide bandwidth tunability about 1.455 THz (0.117-1.572 THz) is achieved. The device, functions like a ring, can realize the bandwidth tunable of the drop port and the through port. And, its feature has simultaneous wavelength tuning and no free space ranges limitation. A high out-of-band contrast of 30 dB is achieved with a bandwidth of 1.572 THz (Δλ = 13 nm). The out-of-band contrast is 18 dB at the minimum bandwidth 0.117 THz (Δλ = 1.0 nm).

Graphene-based nonvolatile terahertz switch with asymmetric electrodes.

We propose a nonvolatile terahertz (THz) switch which is able to perform the switching with transient stimulus. The device utilizes graphene as its floating-gate layer, which changes the transmissivity of THz signal by trapping the tunneling charges. The conventional top-down electrode configuration is replaced by a left-right electrode configuration, so THz signals could transmit through this device with the transmissivity being controlled by voltage pulses. The two electrodes are made of metals with different work functions. The resultant asymmetrical energy band structure ensures that both electrical programming and erasing are viable. With the aid of localized surface plasmon resonances in graphene ribbon arrays, the modulation depth is 89% provided that the Femi level of graphene is tuned between 0 and 0.2 eV by proper voltage pulses.

Silicon lateral-apodized add-drop filter for on-chip optical interconnection.

A lateral-apodized add-drop filter is demonstrated in a multimode asymmetric waveguide Bragg grating. This design utilizes two individual superposed gratings with the same sidewall corrugation depth. The strong side lobes of the grating filter are efficiently suppressed by mapping the target apodization profile into lateral shifts between the periods of the two gratings. Compared with other apodized technology, this device is easier to be realized. Experimental results show that the side-lobes suppression ratio can reach 18.5 dB, and a bandwidth of 9.5 nm is achieved by a large corrugation width of 150 nm. The insertion loss at the drop port is only 0.8 dB, and the extinction ratio is up to 24 dB at the through port.

Broad bandwidth and large fabrication tolerance polarization beam splitter based on multimode anti-symmetric Bragg sidewall gratings.

A novel polarization beam splitter based on an anti-symmetric sidewall Bragg grating in a multimode silicon-on-insulator strip waveguide is demonstrated. Anti-symmetric spatially periodic refractive-index perturbations are designed for strong coupling between the fundamental (TE0) and the first-order transverse electric modes (TE1), while not for transfer magnetic modes. An adiabatic coupler is cascaded at the input-port, so as to drop the TE1 reflection. The Bragg grating has a compact length of ∼20 µm (55 periods). The polarization isolations of the through- and drop-ports at the wavelength of 1557 nm are 34 and 31 dB, respectively. A broad bandwidth of 64 nm and a large fabrication tolerance of 80 nm for polarization isolation over 20 dB are also achieved.

Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.

Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.

Group-Based Trajectory Modeling of Healthcare Financial Charges in Inflammatory Bowel Disease: A Comprehensive Phenotype.

OBJECTIVES: Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory gastrointestinal conditions with variable disease courses often requiring significant healthcare expenditures. We aimed to identify disease trajectory patterns based on longitudinal financial expenditures and to assess the association of classic disease activity parameters with financial charges. METHODS: This was an analysis of a consented, prospective, natural history IBD registry (2009-2013) from a tertiary IBD center of 2,203 patients and their associated medical charges excluding pharmacy expenses. We applied group-based trajectory modeling to longitudinal healthcare financial charges to determine patterns of charges. We assessed the association between charge patterns and disease activity, quality of life, healthcare utilization, and medication requirement. RESULTS: The final model included 1,600 IBD patients with 5-year charges. We identified six distinct trajectories over the study period. Consistently High charges were associated with Crohn's disease (66.0% Consistently High patients, P<0.01), perianal involvement (22.6%, P<0.01), ulcerative colitis extent (89.7% extensive, P=0.01), prior IBD surgery (52.5%, P<0.01), and depression/anxiety (36.2%, P<0.01). Compared with other trajectories, Consistently High charges had higher 5-year disease activity indices (Harvey-Bradshaw P<0.01; ulcerative colitis activity index P<0.01), elevated C-reactive protein rates (72.3%, P<0.01), IBD surgery (64.5%, P<0.01), hospitalization (97.2%, P<0.01), corticosteroid (70.9%, P<0.01) and antitumor necrosis factor requirement (50.4%, P<0.01), and worse quality of life (P<0.01). Annual trends in parameters were reflected in temporal changes in financial charges. The majority of financial burden stemmed from inpatient care. CONCLUSIONS: Healthcare financial charges represent a novel phenotype in IBD that reflect trends in classic disease activity parameters and allow for subgroup identification of temporal disease trajectories.

Silicon band-rejection and band-pass filter based on asymmetric Bragg sidewall gratings in a multimode waveguide.

A silicon photonic wire filter based on an asymmetric sidewall Bragg grating in a multimode silicon-on-insulator strip waveguide is demonstrated. The operating principle is based on the contra-directional coupling between the transverse electric fundamental (TE0) and first-order (TE1) modes, which is enabled by the asymmetric spatially periodic refractive-index perturbations. An asymmetric Y-junction is cascaded at the input port of the filter so as to drop the Bragg reflection. Compared with conventional Bragg grating-based filters, this device eliminates the back reflection at the input port and the 6 dB inherent insertion loss at the drop port; moreover, a narrow 3 dB bandwidth can be obtained with a large critical dimension as a result of the weak coupling strength between the TE0 and TE1 modes inside the multimode waveguide. Experimental results show that a bandwidth of ∼2.8 nm is achieved by a large corrugation width of 150 nm. The insertion loss at the drop port is -2.1 dB, and the extinction ratio is -33 dB at the through port.

Correction to "Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator".

[This corrects the article DOI: 10.1021/ml5003635.].

LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1.

Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCF-Fbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity.

Mitochondrial Redox Opto-Lipidomics Reveals Mono-Oxygenated Cardiolipins as Pro-Apoptotic Death Signals.

While opto-genetics has proven to have tremendous value in revealing the functions of the macromolecular machinery in cells, it is not amenable to exploration of small molecules such as phospholipids (PLs). Here, we describe a redox opto-lipidomics approach based on a combination of high affinity light-sensitive ligands to specific PLs in mitochondria with LC-MS based redox lipidomics/bioinformatics analysis for the characterization of pro-apoptotic lipid signals. We identified the formation of mono-oxygenated derivatives of C18:2-containing cardiolipins (CLs) in mitochondria after the exposure of 10-nonylacridine orange bromide (NAO)-loaded cells to light. We ascertained that these signals emerge as an immediate opto-lipidomics response, but they decay long before the commencement of apoptotic cell death. We found that a protonophoric uncoupler caused depolarization of mitochondria and prevented the mitochondrial accumulation of NAO, inhibited the formation of C18:2-CL oxidation product,s and protected cells from death. Redox opto-lipidomics extends the power of opto-biologic protocols to studies of small PL molecules resilient to opto-genetic manipulations.

Precessing cylinders at the second and third resonance: turbulence controlled by geostrophic flow.

We investigate, via both asymptotic analysis and direct numerical simulation, precessionally driven flow of a homogeneous fluid confined in fluid-filled circular cylinders that rotate rapidly about their symmetry axis and precess about a different axis and that are marked by radius-height aspect ratios Γ=1.045945 and Γ=1.611089. At these radius-height aspect ratios, the Poincaré force resonates directly with the two special inertial modes that have the simplest vertical structure. An asymptotic analytical solution in closed form describing weakly precessing flow is derived in the mantle frame of reference for asymptotically small Ekman numbers, showing quantitative agreement with the result of direct nonlinear numerical simulation. Our numerical simulation makes use of a finite-element method with the three-dimensional tetrahedralization of a cylindrical cavity that allows the construction of dense nodes in the vicinity of the bounding surface of the cavity for resolving the thin viscous boundary layer. It is found that axisymmetric geostrophic flow in the alternating eastward and westward direction can be generated and maintained by nonlinear and viscous effects in the viscous boundary layer. It is also found that, when the precessing rate is moderate and, consequently, the geostrophic flow is weak, nonlinear interaction between the resonant inertial mode and the nonesonant inertial modes driven by the Poincaré force and the boundary-layer influx leads to strongly turbulent flow with irregular temporal-spatial fluctuation. When the cylinders are strongly precessing such that the geostrophic flow becomes predominant, however, the effect of the geostrophic flow controls/stabilizes its nonlinear dynamics, leading to weakly turbulent flow that can be largely described by a dominant quasisteady geostrophic component and a weak nonaxisymmetric component localized in the region where the geostrophic flow is weak.

On-chip microwave signal generation based on a silicon microring modulator.

A photonic-assisted microwave signal generator based on a silicon microring modulator is demonstrated. The microring cavity incorporates an embedded PN junction that enables a microwave signal to modulate the lightwave circling inside. The DC component of the modulated light is trapped in the cavity, while the high-order sideband components are able to exit the cavity and then generate microwave signals at new frequencies in a photodetector. In our proof-of-concept experiment, a 10 GHz microwave signal is converted to a 20 GHz signal in the optical domain with an electrical harmonic suppression ratio of 22 dB. An analytic model is also established to explain the operation mechanism, which agrees well with the measured data.

Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator.

Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2 and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl-phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body γ-irradiation.

A mitochondrial pathway for biosynthesis of lipid mediators.

The central role of mitochondria in metabolic pathways and in cell-death mechanisms requires sophisticated signalling systems. Essential in this signalling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin (CL), is oxidized by the intermembrane-space haemoprotein, cytochrome c. We show that a number of oxygenated CL species undergo phospholipase A2-catalysed hydrolysis and thus generate multiple oxygenated fatty acids, including well-known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway, which includes the oxidation of polyunsaturated CLs and accumulation of their hydrolysis products (oxygenated linoleic, arachidonic acids and monolysocardiolipins), is activated in vivo after acute tissue injury.

Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids.

Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency.

Design of a high voltage stimulator chip for a stroke rehabilitation system.

This paper describes the design of an 8-channel high voltage stimulator chip for rehabilitation of stroke patients through surface stimulation, which requires high stimulation currents and high compliance voltage. The chip gets stimulation control data through its Serial Peripheral Interface (SPI), and can accordingly generate biphasic stimulation currents with different amplitudes, duration, frequencies and polarities independently for each channel. The current driver is implemented with thick oxide devices with a supply voltage up to 90V. The chip is designed in a 0.35εm X-FAB high voltage process.