bluuebunny/crossref_metadata_2025 huggingface dataset:
Klinische Anwendungsbeispiele einer Next-Generation-Sequencing-basierten Multi-Genpanel-Analyse
Authors: Enko Dietmar , Schaflinger Erich , Müller Daniel J.
Published: May 2023

Dieser Übersichtsartikel bietet einen Überblick über klinisch sinnvolle Anwendungsgebiete einer Next-Generation-Sequencing-basierten (NGS) Multi-Genpanel-Teststrategie in den Bereichen Onkologie, hereditärer Tumorsyndrome und Hämatologie. Bei soliden Tumoren (z.B. Lungenkarzinom, Kolonrektalkarzinom) trägt die Detektion somatischer Mutationen nicht nur zu einer besseren diagnostischen, sondern auch therapeutischen Stratifizierung der Betroffenen bei. Die zunehmende genetische Komplexität hereditärer Tumorsyndrome (z.B. Brust- und Ovarialkarzinom, Lynchsyndrom/Polypose) erfordert in betroffenen Familien eine Multi-Genpanel-Analyse von Keimbahnmutationen. Ein weiteres sinnvolles Indikationsgebiet einer Multi-Genpanel-Diagnostik und Prognoseabschätzung sind akute und chronische myeloische Erkrankungen. Die Kriterien der WHO-Klassifikation und des „European LeukemiaNet“-Prognosesystems der akuten myeloischen Leukämie können nur durch eine Multi-Genpanel-Teststrategie erfüllt werden.
Lebensqualität und Arbeitsfähigkeit nach unfallchirurgischer Rehabilitation – Ergebnisse der icfPROreha-Studie
Authors: Simmel Stefan , Kus Sandra , Oberhauser Cornelia , Coenen Michaela
Published: May 2023

Hintergrund Nicht nur die Schwere der Verletzung, sondern auch bio-psycho-soziale Faktoren haben einen Einfluss auf gesundheitsbezogene Lebensqualität und soziale Teilhabe nach schweren muskuloskelettalen Verletzungen.

Methode Multizentrische prospektive Längsschnittstudie mit Nacherhebungszeitraum bis zu 78 Wochen nach Entlassung aus der stationären unfallchirurgisch-orthopädischen Rehabilitation bei Patienten mit schweren muskuloskelettalen Verletzungen. Die Datenerfassung erfolgte mittels eines umfassenden Assessment-Tools. Lebensqualität wurde mit dem EQ-5D-5L erfasst, die Arbeitsfähigkeit mittels Selbstangaben der Patienten und einer Abfrage bei Kostenträgern. Analysen zum Zusammenhang zwischen Lebensqualität und Arbeitsfähigkeit, zur Veränderung der Lebensqualität im Verlauf im Vergleich zur deutschen Allgemeinbevölkerung und multivariate Analysen zur Prädiktion der Lebensqualität wurden durchgeführt.

Ergebnis Von 612 Studienteilnehmern (444 Männer (72,5%); M=48,5 Jahre; SD 12,0) kehrten 78 Wochen nach Entlassung aus der stationären Rehabilitation 502 (82,0%) an den Arbeitsplatz zurück. Die Lebensqualität verbessert sich im Verlauf der Rehabilitationsmaßnahme im Mittel deutlich von 50,18 auf 64,50 (visuelle Analogskala des EQ-5D-5L) und im weiteren Verlauf geringfügig auf 69,38 zu 78 Wochen nach Entlassung aus der stationären Rehabilitation. Der EQ-5D Index liegt unter den Normwerten der Allgemeinbevölkerung. 18 Aspekte zur Prädiktion der Lebensqualität 78 Wochen nach Entlassung aus der Rehabilitation wurden selektiert. Unter anderem haben Ruheschmerz und der Verdacht auf eine Angststörung bei Aufnahme einen sehr starken Effekt auf die Lebensqualität. Auch Kontextfaktoren wie Therapien nach der Akutversorgung und Selbstwirksamkeit haben einen Effekt auf die Lebensqualität 78 Wochen nach Entlassung aus der stationären Rehabilitation.

Schlussfolgerung Bio-psycho-soziale Faktoren haben einen großen Einfluss auf die langfristige Lebensqualität Unfallverletzter. Bereits bei der Entlassung aus der Akutklinik und mehr noch zu Beginn der stationären Rehabilitation können entscheidende Weichen gestellt werden, um eine bestmögliche Lebensqualität für die Betroffenen zu erreichen.
Concentric Cardiac Remodeling and Hypertrophy in Pregnant Individuals with Chronic Hypertension
Authors: Seagraves Elizabeth A. , Baraki Dana I. , Donaldson Thomas J. , Barake Carole , Brush John E. , Abuhamad Alfred Z. , Kawakita Tetsuya
Published: May 2023

Objective This study aimed to evaluate rates of superimposed preeclampsia in pregnant individuals with echocardiography-diagnosed cardiac geometric changes in the setting of chronic hypertension.

Study Design This was a retrospective study of pregnant individuals with chronic hypertension who delivered singleton pregnancies at 20 weeks' gestation or greater at a tertiary care center. Analyses were limited to individuals who had an echocardiogram during any trimester. Cardiac changes were categorized as normal morphology, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy according to the American Society of Echocardiography guidelines. Our primary outcome was early-onset superimposed preeclampsia defined as delivery at less than 34 weeks' gestation. Other secondary outcomes were also examined. Adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) were calculated, controlling for prespecified covariates.

Results Of the 168 individuals who delivered from 2010 to 2020, 57 (33.9%) had normal morphology, 54 (32.1%) had concentric remodeling, 9 (5.4%) had eccentric hypertrophy, and 48 (28.6%) had concentric hypertrophy. Non-Hispanic black individuals presented over 76% of the cohort. Rates of the primary outcome in individuals with normal morphology, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were 15.8, 37.0, 22.2, and 41.7%, respectively (p = 0.01). Compared with individuals with normal morphology, individuals with concentric remodeling were more likely to have the primary outcome (aOR: 3.28; 95% CI: 1.28–8.39), fetal growth restriction (crude OR: 2.98; 95% CI: 1.05–8.43), and iatrogenic preterm delivery <34 weeks' gestation (aOR: 2.72; 95% CI: 1.15–6.40). Compared with individuals with normal morphology, individuals with concentric hypertrophy were more likely to have the primary outcome (aOR: 4.16; 95% CI: 1.57–10.97), superimposed preeclampsia with severe features at any gestational age (aOR: 4.75; 95% CI: 1.94–11.62), iatrogenic preterm delivery <34 weeks' gestation (aOR: 3.60; 95% CI: 1.47–8.81), and neonatal intensive care unit admission (aOR: 4.82; 95% CI: 1.90–12.21).

Conclusion Concentric remodeling and concentric hypertrophy were associated with increased odds of early-onset superimposed preeclampsia.

Key Points
Kinetic or Thermodynamic Product? Case Studies on the Formation of Regioisomers of Tetraphenyladamantanes
Authors: Richert Clemens , Berking Tim , Frey Wolfgang
Published: May 2023

Tetraaryladamantanes (TAAs) with alkoxyphenyl groups are interesting synthetic targets because they can act as crystallization chaperones for liquid compounds. Their carbon framework is set up by Friedel–Crafts alkylation, using adamantane-1,3,5,7-tetraol and anisole derivatives as starting materials. One successful chaperone is 1,3,5,7-tetrakis(2-bromo-4-methoxyphenyl)adamantane (TBro). This compound was initially considered the thermodynamic product of alkyl­ation and its reaction towards strong Brønsted acid is reported. We now report that exposure of TBro to strong Brønsted acid leads to its regioisomer 1,3,5,7-tetrakis(4-bromo-2-methoxyphenyl)adamantane (iTBro) as the dominant product, obtained in a yield of 68%, far surpassing the 20% yield reported earlier for TBro. We also investigated the reactions of 3-iodo-, 3-chloro-, and 3-fluoroanisole to the corresponding TAAs and obtained yields of 66%, 26% and 52% for the main regioisomer. While 3-iodoanisole gave the same regioisomer as bromoanisole, 3-chloroanisole afforded complex mixtures and 3-fluoroanisole furnished 1,3,5,7-tetrakis(2-fluoro-4-methoxyphenyl)adamantane (TFM) in 52% yield as the main product. When mixtures of regioisomers were isomerized with an excess of triflic acid, the thermodynamic products were obtained in 76–91%. These results show how subtle effects govern the regioisomeric product distribution of aryladamantanes. They also help to make novel crystallization chaperones accessible in high yields.
Maternal–Fetal Results of COVID-19-Infected Pregnant Women Treated with Extracorporeal Membrane Oxygenation: A Descriptive Report
Authors: Alvarado-Socarras Jorge Luis , Quintero-Lesmes Doris C. , Martin Delia Theurel , Vasquez Raul , Monsalve Mary Mendoza , Cristancho Lizeth Mogollon , Rojas Leonardo Salazar , Martinez Jenifer Leon , Medina Carlos Riaño , Gomez Camilo Pizarro
Published: May 2023

Objective COVID-19 infection may produce severe pneumonia, mainly in the adult population. Pregnant women with severe pneumonia are at high risk of developing complications, and conventional therapy sometimes fails to reverse hypoxemia. Therefore, extracorporeal membrane oxygenation (ECMO) is an option in cases with refractory hypoxemic respiratory failure. This study aims to evaluate the maternal–fetal risk factors, clinical characteristics, complications, and outcomes of 11 pregnant or peripartum patients with COVID-19 treated with ECMO.

Study Design This is a retrospective descriptive study of 11 pregnant women undergoing ECMO therapy during the COVID-19 pandemic.

Results In our cohort, four patients underwent ECMO during pregnancy (36.3%) and 7 during the postpartum period. Initially, they started on venovenous ECMO, and three patients were required to change modality due to clinical conditions. In total, 4/11 pregnant women (36.3%) died. We established two periods that differed in the implementation of a standardized care model for reducing associated morbidities and mortality. Neurological complications were responsible for most deaths. Regarding fetal outcomes at early-stage pregnancies on ECMO (4), we report three stillbirths (75%), and one newborn (twin pregnancy) survived and had a favorable evolution.

Conclusion At later-stage pregnancies, all newborns survived, and we did not identify any vertical infection. ECMO therapy is an alternative for pregnant women with severe hypoxemic respiratory failure due to COVID-19, and may improve maternal and neonatal results. Regarding fetal outcomes, the gestational age played a definitive role. However, the main complications reported in our series and others are neurological. It is essential to develop novel, future interventions to prevent these complications.
Contemporary Trends in Cesarean Delivery Rates and Indications
Authors: Jaber Sara , Blanchard Christina T. , Lu Michelle Y. , Cozzi Gabriella D. , Casey Brian M. , Tita Alan T. , Kim Dhong-Jin , Szychowski Jeff M. , Subramaniam Akila
Published: May 2023

Objective This study aimed to describe cesarean delivery rates and indications at a single center in order to assess the impact of the guidelines published by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine on trends in labor management.

Study Design This is a retrospective cohort study of patients ≥23 weeks' gestation delivering at a single tertiary care referral center from 2013 to 2018. Demographic characteristics, mode of delivery, and main indication for cesarean delivery were ascertained by individual chart review. Cesarean delivery indications (mutually exclusive) were the following: repeat cesarean delivery, nonreassuring fetal status, malpresentation, maternal indications (e.g., placenta previa or genital herpes simplex virus), failed labor (any stage labor arrest), or other (i.e., fetal anomaly and elective). Polynomial (cubic) regression models were used to model rates of cesarean delivery and indications over time. Subgroup analyses further examined trends in nulliparous women.

Results Of the 24,637 patients delivered during the study period, 24,050 were included in the analysis; 7,835 (32.6%) had a cesarean delivery. The rates of overall cesarean delivery were significantly different over time (p < 0.001), declining to a minimum of 30.9% in 2014 and peaking at 34.6% in 2018. With regard to the overall cesarean delivery indications, there were no significant differences over time. When limited to nulliparous patients, the rates of cesarean delivery were also noted to be significantly different over time (p = 0.02) nadiring at 30% in 2015 from 35.4% in 2013 and then rising up to 33.9% in 2018. As for nulliparous patients, there was no significant difference in primary cesarean delivery indications over time except for nonreassuring fetal status (p = 0.049).

Conclusion Despite changes in labor management definitions and guidelines encouraging vaginal birth, the rates of overall cesarean delivery did not decrease over time. The indications for delivery, particularly failed labor, repeat cesarean delivery, and malpresentation have not significantly changed over time.

Key Points
A Dual Atrioventricular Approach to Repair Pseudoaneurysm after Mitral Valve Surgery
Authors: Fishberger Gregory , Bulard Blake , Lozonschi Lucian
Published: May 2023

Background Left ventricular pseudoaneurysm (LVPA) is an uncommon but potentially fatal complication following atrioventricular groove rupture.

Case Description We present a patient with a massive LVPA involving the lateral commissure and under the mitral P3 segment following coronary artery bypass grafting and mitral valve (MV) repair. MV replacement and arteriovenous pseudoaneurysm were repaired by dual approach via the left atrium with excision of the previously dehisced mitral ring to expose the defect and patch repair the atrioventricular defect through the pseudoaneurysm free wall.

Conclusion This is a rare case of a large subacute postoperative LVPA repaired by dual atrial–ventricular approach to treat a contained atrioventricular groove rupture.
Perspectives of U.S. Ophthalmology Residents and Medical Students on Ophthalmology Exposure during Medical School
Authors: Robles-Holmes Hailey , Kolli Ajay , Cox Victor , Nguyen Anne Xuan-Lan , Watane Arjun , Portney David , Ballouz Dena , Sridhar Jayanth
Published: May 2023

Introduction In recent decades, ophthalmology exposure in medical school has been increasingly reduced. In turn, medical students have expressed concern over their ophthalmic skills. Research investigating the status of ophthalmology education in U.S. undergraduate medical curricula is limited to institutional data devoid of the student or resident perspective. This study seeks to gain a better understanding of current ophthalmology education for U.S. medical students from the trainee point of view.

Methods A cross-sectional survey was distributed to current U.S. medical students interested in ophthalmology and U.S. ophthalmology residents. Demographic data, ophthalmology curriculum information, respondent learning preferences, and personal reflections were recorded. Thematic analysis and chi-square tests were utilized.

Results In total, 387/4,482 (8.6%) surveys were completed by respondents from 75 U.S. medical institutions. Most respondents were exposed to formal ophthalmology curriculum (63%), research (89%), mentorship (84%), and clinical experiences (87%) during medical school, and medical school curriculum was ranked the third most helpful resource for students to learn about ophthalmology. Yet, 29% of residents (n = 55) did not feel confident in their diagnostic ophthalmology skills based on their medical school exposure. Student and resident recommendations for improving ophthalmology education delivery commonly referenced nontraditional ophthalmology resources such as online videos (n = 83) to supplement traditional learning materials such as lectures (n = 56).

Discussion These findings suggest that primary ophthalmology exposure in medical school has shifted toward extracurricular activities such as research and clinical observation. Considering the increasing time demands placed on the medical education system, utilizing nontraditional educational materials to supplement current undergraduate medical education in ophthalmology may provide educators with a resource to improve learner confidence and resident preparedness.
Research on nonlinear response analysis of micro-cracks under vibro-acoustic modulation
Authors: Duan Xueliang , Zheng Huifeng , Du Wenjie , Ling Tianhao , Yao Runguang
Published: May 2023

In view of the complex nonlinear interaction mechanism between acoustic waves and damage in vibration sound modulation technology, this paper derives the kinematic equilibrium equation for linear elastic materials with cracks undergoing infinitesimal deformation using structural mechanics theory. The weak form of the equation is derived by applying the principle of virtual work to calculate the virtual work due to nonlinear changes in crack spacing. This paper also explains the physical origin of high harmonic and sideband signals in the system displacement solution. In addition, a three-dimensional contact model of micro-cracks is constructed to describe the nonlinear effect of contact sound on the crack surface caused by relevant displacement fields. To verify the correctness of the model, two indicators, the modulation index and the damage index, are used to evaluate the simulation results. The results indicate that the interface contact under micro-crack opening and closing motions causes additional nonlinear frequencies and that the nonlinear response increases with excitation amplitude while being relatively sensitive to micron-level cracks. Finally, experimental research is conducted, which confirms the theoretical derivation, and the reliability of the model has been verified.
Theoretical study on negative differential resistance in transition metal dichalcogenide planar heterostructures
Authors: Liu Dan-Na , Ke Sha-Sha , Yuan Rui-Yang , Guo Yong
Published: May 2023

Two types of WS2/MoX2/WS2 (X = S, Se) planar heterostructures driven by bias are theoretically proposed and studied, showing the pronounced negative differential resistance (NDR) effect. It is demonstrated that the maximum peak-to-valley ratio (mPVR) and current peak strongly depend on the temperature, and the enhanced mPVR can be realized by tuning the device length. In particular, type B (X = Se) has a more remarkable NDR effect than type A (X = S). Our work provides promising possibilities for designing and manufacturing future low-power electronic devices based on monolayer transition metal dichalcogenide planar heterostructures under low bias regime.
High efficiency radio frequency pulse generation in a nonlinear corrugated coaxial transmission line with ferrite saturated by permanent magnets
Authors: Priputnev P. , Romanchenko I. , Maltsev S. , Sobyanin R. , Konev V.
Published: May 2023

The work on the development of a generator of high-power, high-frequency pulses based on a nonlinear transmission line with saturated ferrite is presented. A feature of the generator is that the ferrite rings are saturated in the field of permanent magnets, unlike traditional generators with a solenoid wrapped around the transmission line. Due to the changed structure of the inner conductor, which is a corrugated conductor, the line has spatial dispersion. The paper demonstrates the generation of high-frequency pulses with a duration of up to 6 ns and a center frequency of 2.7 GHz. This pulse duration with a frequency above 2 GHz was not previously observed in traditional nonlinear transmission line geometry. The maximal peak power achieved was 70 MW for an incident voltage pulse of 90 kV. The energy efficiency of video pulse energy conversion into radio pulse was 6% [G. Kataev, Electromagnetic Shock Waves (Sov. Radio, Moscow, 1963)]. The paper discusses the performance of RF and microwave NiZn ferrites for the purposes of radio pulse generation.
Exciton diffusion in amorphous organic semiconductors: Reducing simulation overheads with machine learning
Authors: Wechwithayakhlung Chayanit , Weal Geoffrey R. , Kaneko Yu , Hume Paul A. , Hodgkiss Justin M. , Packwood Daniel M.
Published: May 2023

Simulations of exciton and charge hopping in amorphous organic materials involve numerous physical parameters. Each of these parameters must be computed from costly ab initio calculations before the simulation can commence, resulting in a significant computational overhead for studying exciton diffusion, especially in large and complex material datasets. While the idea of using machine learning to quickly predict these parameters has been explored previously, typical machine learning models require long training times, which ultimately contribute to simulation overheads. In this paper, we present a new machine learning architecture for building predictive models for intermolecular exciton coupling parameters. Our architecture is designed in such a way that the total training time is reduced compared to ordinary Gaussian process regression or kernel ridge regression models. Based on this architecture, we build a predictive model and use it to estimate the coupling parameters which enter into an exciton hopping simulation in amorphous pentacene. We show that this hopping simulation is able to achieve excellent predictions for exciton diffusion tensor elements and other properties as compared to a simulation using coupling parameters computed entirely from density functional theory. This result, along with the short training times afforded by our architecture, shows how machine learning can be used to reduce the high computational overheads associated with exciton and charge diffusion simulations in amorphous organic materials.
In silico design and validation of a time-varying PID controller for an artificial pancreas with intraperitoneal insulin delivery and glucose sensing
Authors: Dalla Libera Alberto , Toffanin Chiara , Drecogna Martina , Galderisi Alfonso , Pillonetto Gianluigi , Cobelli Claudio
Published: May 2023

Type 1 diabetes (T1D) is a chronic autoimmune disease featured by the loss of beta cell function and the need for lifetime insulin replacement. Over the recent decade, the use of automated insulin delivery systems (AID) has shifted the paradigm of treatment: the availability of continuous subcutaneous (SC) glucose sensors to guide SC insulin delivery through a control algorithm has allowed, for the first time, to reduce the daily burden of the disease as well as to abate the risk for hypoglycemia. AID use is still limited by individual acceptance, local availability, coverage, and expertise. A major drawback of SC insulin delivery is the need for meal announcement and the peripheral hyperinsulinemia that, over time, contributes to macrovascular complications. Inpatient trials using intraperitoneal (IP) insulin pumps have demonstrated that glycemic control can be improved without meal announcement due to the faster insulin delivery through the peritoneal space. This calls for novel control algorithms able to account for the specificities of IP insulin kinetics. Recently, our group described a two-compartment model of IP insulin kinetics demonstrating that the peritoneal space acts as a virtual compartment and IP insulin delivery is virtually intraportal (intrahepatic), thus closely mimicking the physiology of insulin secretion. The FDA-accepted T1D simulator for SC insulin delivery and sensing has been updated for IP insulin delivery and sensing. Herein, we design and validate—in silico—a time-varying proportional integrative derivative controller to guide IP insulin delivery in a fully closed-loop mode without meal announcement.
Comparing the kinetics of ionized and neutral atoms from single and multi-element laser-produced plasmas
Authors: Kautz Elizabeth J. , Phillips Mark C. , Diwakar Prasoon K. , Zelenyuk Alla , Harilal Sivanandan S.
Published: May 2023

Kinetics of ion and neutral atom emission features were compared for nanosecond laser-produced plasmas generated from several metal targets (i.e., Al, Ti, Zr, Nb, Ta) and an alloy containing all of these as principal alloying elements. Plasmas were produced by focusing 6 ns, 1064 nm pulses from an Nd:YAG laser on the targets of interest in a vacuum. A Faraday cup was used for collecting ion temporal features while spatially and temporally resolved emission spectroscopy was used for measuring the optical time of flight of various neutral atomic transitions. Our results highlight that most probable ion and atom velocities decay with increasing atomic mass. Trends for ions from the alloy target represent a weighted average where all ions contribute. For both ions and atoms, velocities decrease with increasing heat of vaporization and melting temperature, consistent with the thermal mechanisms that contribute to nanosecond laser ablation. Kinetic energies for neutral atoms from pure metal targets have some variability with atomic mass, whereas kinetic energies for atoms from the alloy target are more similar. These more similar kinetic energies observed for neutral atoms in the multi-element plasma may be attributed to collisions between species from all elements in the Knudsen layer.
Implicit solvent approach based on generalized Born and transferable graph neural networks for molecular dynamics simulations
Authors: Katzberger Paul , Riniker Sereina
Published: May 2023

Molecular dynamics simulations enable the study of the motion of small and large (bio)molecules and the estimation of their conformational ensembles. The description of the environment (solvent) has, therefore, a large impact. Implicit solvent representations are efficient but, in many cases, not accurate enough (especially for polar solvents, such as water). More accurate but also computationally more expensive is the explicit treatment of the solvent molecules. Recently, machine learning has been proposed to bridge the gap and simulate, in an implicit manner, explicit solvation effects. However, the current approaches rely on prior knowledge of the entire conformational space, limiting their application in practice. Here, we introduce a graph neural network based implicit solvent that is capable of describing explicit solvent effects for peptides with different compositions than those contained in the training set.
Noise-to-energy conversion in a nanometer-scale dot observed with electron counting statistics
Authors: Chida Kensaku , Fujiwara Akira , Nishiguchi Katsuhiko
Published: May 2023

We converted Gaussian-distributed voltage noise applied to an electron reservoir into the non-equilibrium free energy of a nanometer-scale dot connected to the reservoir via an energy barrier. Counting statistics of single-electron motion into and out of the dot through the energy barrier allows us to quantitatively analyze the energy transported into the dot as well as changes in the internal energy and effective temperature of the dot in this noise-induced non-equilibrium steady state (NESS). By analyzing the transition rates of electrons moving into and out of the dot, we confirmed that the rectification effect caused by the asymmetry with respect to the direction of electron motion is the origin of the increase in the internal energy of the dot. The information on energy transport in a nanometer-scale dot in the noise-induced NESS obtained in this study with electron counting statistics clarifies the relationship between the non-equilibrium dynamics of a nanodevice and noise applied to it. This study provides us with the means to evaluate device operation using noise as a resource.
Deep learning collective variables from transition path ensemble
Authors: Ray Dhiman , Trizio Enrico , Parrinello Michele
Published: May 2023

The study of the rare transitions that take place between long lived metastable states is a major challenge in molecular dynamics simulations. Many of the methods suggested to address this problem rely on the identification of the slow modes of the system, which are referred to as collective variables. Recently, machine learning methods have been used to learn the collective variables as functions of a large number of physical descriptors. Among many such methods, Deep Targeted Discriminant Analysis has proven to be useful. This collective variable is built from data harvested from short unbiased simulations in the metastable basins. Here, we enrich the set of data on which the Deep Targeted Discriminant Analysis collective variable is built by adding data from the transition path ensemble. These are collected from a number of reactive trajectories obtained using the On-the-fly Probability Enhanced Sampling flooding method. The collective variables thus trained lead to more accurate sampling and faster convergence. The performance of these new collective variables is tested on a number of representative examples.
Structural design and optimization of subwavelength grating polarizers for short infrared-wavelengths
Authors: Yuan Wentao , Pan Xiaohang , Tian Shuoqiu , Chen Yifang
Published: May 2023

Subwavelength grating (SWG) is currently the major component being applied in polarimetric detections in infrared wavelengths, owing to its unique advantages in miniaturized dimensions, integrability with the exiting planar focal plane array of photoelectronic detectors, and compatibility with semiconductor technology. However, the obstacle hindering the applications of the SWGs polarizer is the limited polarization performance of both the transmittance and the extinction ratio, despite substantial efforts have been reported. It has been well understood that SWG with short pitch and high aspect ratio is the solution for achieving high performance, which is a daunting challenge to nanofabrication. To overcome the technical bottleneck for highly dense gratings with high aspect ratio, this work proposed a structure with the metallic grating parasitically grown on the sidewalls of replicated dielectric lines/spaces by electron beam lithography, followed by an angled evaporation process of metal. Numerical simulations by a finite-difference time-domain method were carried out to optimize the structural dimensions for achieving both high transmittances and extinction ratios. Electron beam lithography together with angled depositions of an aluminum (Al) film was applied to fabricate the proposed SWG polarizers with the aspect ratio as high as 13:1. Optical characterizations demonstrated enhanced polarization performances in short infrared wavelengths from 1050 up to 1600 nm. The developed SWG polarizer and the fabrication technique possess advantages in the simplified process, lift off free and wafer scale prospect.
Measurement of minority carrier diffusion length in p-GaN using electron emission spectroscopy (EES)
Authors: Ho Wan Ying , Chow Yi Chao , Nakamura Shuji , Peretti Jacques , Weisbuch Claude , Speck James S.
Published: May 2023

Electron emission spectroscopy was performed on metalorganic chemical vapor deposition grown p-n−-n+ junctions with p-thicknesses ranging from 50 to 300 nm, doped with [Mg] = 3.5 × 1019 cm−3. By measuring the decreasing emitted electron intensity from a cesiated p-GaN surface with increasing p-thickness, we were able to extract the minority carrier diffusion length of electron in p-type GaN, Le = 26 ± 3 nm. The measured value is in good agreement with literature reported values. The extrapolated electron current at the n− region–p-GaN interface is in reasonable agreement with the simulated electron current at the interface.
Parallel array of planar Hall effect sensors for high resolution magnetometry
Authors: Nhalil Hariharan , Schultz Moty , Amrusi Shai , Grosz Asaf , Klein Lior
Published: May 2023

We introduce a planar Hall effect magnetometer in the form of a parallel array of permalloy-based elliptical sensors. The number of ellipses in the array and other fabrication parameters are optimized with the support of numerical simulations. We obtain equivalent magnetic noise (EMN) of 16 pT/Hz at 100 Hz, 25 pT/Hz at 10 Hz, 98 pT/Hz at 1 Hz, and 470 pT/Hz at 0.1 Hz. The exceptional EMN without the use of magnetic flux concentrators highlights the advantages of the design. The presented magnetometer, characterized by its simplicity, affordability, and ability to operate at room temperature, is anticipated to be useful for applications requiring pT resolution.
High density fabrication process for single flux quantum circuits
Authors: Yohannes D. , Renzullo M. , Vivalda J. , Jacobs A. C. , Yu M. , Walter J. , Kirichenko A. F. , Vernik I. V. , Mukhanov O. A.
Published: May 2023

We implemented, optimized, and fully tested a superconducting Josephson junction fabrication process over multiple runs tailored for integrated digital circuits that are used for control and readout of superconducting qubits operating at millikelvin temperatures. This process was optimized for highly energy efficient rapid single flux quantum (ERSFQ) circuits with critical currents reduced by a factor of ∼10 as compared to those operated at 4.2 K. Specifically, it implemented Josephson junctions with 10 μA unit critical current fabricated with 10 μA/μm2 critical current density. In order to circumvent the substantial size increase in the SFQ circuit inductors, we employed an NbN high kinetic inductance layer with 8.5 pH/sq sheet inductance. Similarly, to maintain the small size of junction resistive shunts, we used a non-superconducting PdAu alloy with 4.0 Ω/sq sheet resistance. For integration with quantum circuits in a multi-chip module, 5 and 10 μm height bump processes were also optimized. To keep the fabrication process in check, we developed and thoroughly tested a comprehensive process control monitor chip set.
General exponential basis set parametrization: Application to time-dependent bivariational wave functions
Authors: Højlund Mads Greisen , Zoccante Alberto , Christiansen Ove
Published: May 2023

We present equations of motion (EOMs) for general time-dependent wave functions with exponentially parameterized biorthogonal basis sets. The equations are fully bivariational in the sense of the time-dependent bivariational principle and offer an alternative, constraint-free formulation of adaptive basis sets for bivariational wave functions. We simplify the highly non-linear basis set equations using Lie algebraic techniques and show that the computationally intensive parts of the theory are, in fact, identical to those that arise with linearly parameterized basis sets. Thus, our approach offers easy implementation on top of existing code in the context of both nuclear dynamics and time-dependent electronic structure. Computationally tractable working equations are provided for single and double exponential parametrizations of the basis set evolution. The EOMs are generally applicable for any value of the basis set parameters, unlike the approach of transforming the parameters to zero at each evaluation of the EOMs. We show that the basis set equations contain a well-defined set of singularities, which are identified and removed by a simple scheme. The exponential basis set equations are implemented in conjunction with the time-dependent modals vibrational coupled cluster (TDMVCC) method, and we investigate the propagation properties in terms of the average integrator step size. For the systems we test, the exponentially parameterized basis sets yield slightly larger step sizes compared to the linearly parameterized basis set.
Quantification of van der Waals forces in bimodal and trimodal AFM
Authors: Santos Sergio , Gadelrab Karim , Elsherbiny Lamiaa , Drexler Xaver , Olukan Tuza , Font Josep , Barcons Victor , Chiesa Matteo
Published: May 2023

The multifrequency formalism is generalized and exploited to quantify attractive forces, i.e., van der Waals interactions, with small amplitudes or gentle forces in bimodal and trimodal atomic force microscopy (AFM). The multifrequency force spectroscopy formalism with higher modes, including trimodal AFM, can outperform bimodal AFM for material property quantification. Bimodal AFM with the second mode is valid when the drive amplitude of the first mode is approximately an order of magnitude larger than that of the second mode. The error increases in the second mode but decreases in the third mode with a decreasing drive amplitude ratio. Externally driving with higher modes provides a means to extract information from higher force derivatives while enhancing the range of parameter space where the multifrequency formalism holds. Thus, the present approach is compatible with robustly quantifying weak long range forces while extending the number of channels available for high resolution.
Biomass partitioning and ionomics of Macadamia with high manganese and low phosphorus concentrations
Authors: Zhao Xin , Lyu Yang , Dong Qianqian , He Xiyong , Yue Hai , Yang Liping , Tao Liang , Gong Lidan , Zheng Hongxu , Wen Sijie , Lambers Hans , Shen Jianbo
Published: May 2023

Knowledge of the ionome of plant organs helps us understand a plant’s nutritional status. However, the ionome of Macadamia (Proteaceae), which is an important nut-producing tree, remains unknown. We aimed to characterise the allocation of biomass and nutrient-partitioning patterns in three macadamia genotypes. We excavated 15 productive trees (three cultivars at 21 years of age; two cultivars at 16 years of age) in an orchard. Biomass, nutrient concentrations, and contents of roots, stems, branches, and leaves were analysed. Dry weight of roots, stems, branches and leaves accounted for 14–20%, 19–30%, 36–52%, and 12–18% of total plant weight, respectively. No significant difference was found in the total biomass among the cultivars at the same age. Compared with most crop plants, macadamia had low phosphorus (P) concentrations in all organs (<1 g kg−1), and low leaf zinc (Zn) concentration (8 mg kg−1). In contrast, macadamia accumulated large amounts of manganese (Mn), with a 20-fold higher leaf Mn concentration than what is considered sufficient for crop plants. Leaves exhibited the highest nutrient concentrations, except for iron and Zn, which exhibited the highest concentrations in roots. The organ-specific ionomics of Macadamia is characterised by low P and high Mn concentrations, associated with adaptation to P-impoverished habitats.
Impact of regulatory T cell therapy on immune cell composition and fetal survival rate in abortion prone mice
Authors: Idali F. , Golshahi H. , Katouzian L. , Notash Haghighat F. , Rezaii-nia S. , Jeddi-Tehrani M.
Published: May 2023

Context Implantation of fertilised eggs and survival of a semi-allogenic embryo rely on the interactions between the cells and molecules preparing the uterus. We investigated the effect of regulatory T cell (Treg) therapy on the mechanism of local immune tolerance of mice prone to spontaneous abortion. Methods Naive T cells were stimulated in vitro with 17β-oestradiol (E2), progesterone (P4) and TGF-β1 for 96 h to generate induced Tregs (iTreg). The iTregs were injected into DBA/2-mated pregnant CBA/J female mice (abortion prone model). On day 14 of pregnancy, mice were killed and decidual and placental tissues were collected for cellular composition analysis. Results Abortion prone mice (PBS treated) showed significantly lower survival rates (P < 0.0001), increased CD3+CD8+ (P < 0.05), lower IDO+ (P < 0.05) and increased natural killer cells (uNK) cell numbers (P < 0.001) in the uterus, as well increased NK cells in the placenta (P < 0.05) than in normal pregnant mice (CBA/J × BALB/c). Adoptive transfer of iTregs increased fetal survival in abortion-prone mice (P < 0.01) and histopathological evaluation revealed a significantly decreased number of uNK cells in the uterus of TGF-β1-, E2- and P4-iTregs (P < 0.05, P < 0.0001 and P < 0.05, respectively) than in the PBS treated group. In the placenta, we found significantly lower numbers of uNK cells from TGF-β1-, E2- and P4-iTregs than in the PBS treated group (P < 0.05, P < 0.05 and P < 0.01, respectively). Conclusions We propose that modulation of uterine NK cell activity through immunotherapy using Treg cells should be given more attention as an immunological strategy in the treatment of recurrent miscarriage.
Shifts in mutation spectra enhance access to beneficial mutations
Authors: Sane Mrudula , Diwan Gaurav D. , Bhat Bhoomika A. , Wahl Lindi M. , Agashe Deepa
Published: May 2023

Biased mutation spectra are pervasive, with wide variation in the magnitude of mutational biases that influence genome evolution and adaptation. How do such diverse biases evolve? Our experiments show that changing the mutation spectrum allows populations to sample previously undersampled mutational space, including beneficial mutations. The resulting shift in the distribution of fitness effects is advantageous: Beneficial mutation supply and beneficial pleiotropy both increase, while deleterious load reduces. More broadly, simulations indicate that reducing or reversing the direction of a long-term bias is always selectively favored. Such changes in mutation bias can occur easily via altered function of DNA repair genes. A phylogenetic analysis shows that these genes are repeatedly gained and lost in bacterial lineages, leading to frequent bias shifts in opposite directions. Thus, shifts in mutation spectra may evolve under selection and can directly alter the outcome of adaptive evolution by facilitating access to beneficial mutations.
Redox states in the endoplasmic reticulum directly regulate the activity of calcium channel, inositol 1,4,5-trisphosphate receptors
Authors: Fujii Shohei , Ushioda Ryo , Nagata Kazuhiro
Published: May 2023

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are one of the two types of tetrameric ion channels that release calcium ion (Ca
2+
) from the endoplasmic reticulum (ER) into the cytosol. Ca
2+
released via IP3Rs is a fundamental second messenger for numerous cell functions. Disturbances in the intracellular redox environment resulting from various diseases and aging interfere with proper calcium signaling, however, the details are unclear. Here, we elucidated the regulatory mechanisms of IP3Rs by protein disulfide isomerase family proteins localized in the ER by focusing on four cysteine residues residing in the ER lumen of IP3Rs. First, we revealed that two of the cysteine residues are essential for functional tetramer formation of IP3Rs. Two other cysteine residues, on the contrary, were revealed to be involved in the regulation of IP3Rs activity; its oxidation by ERp46 and the reduction by ERdj5 caused the activation and the inactivation of IP3Rs activity, respectively. We previously reported that ERdj5 can activate the sarco/endoplasmic reticulum Ca
2+
-ATPase isoform 2b (SERCA2b) using its reducing activity [Ushioda et al.,
Proc. Natl. Acad. Sci. U.S.A.
 
113
, E6055–E6063 (2016)]. Thus, we here established that ERdj5 exerts the reciprocal regulatory function for IP3Rs and SERCA2b by sensing the ER luminal Ca
2+
concentration, which contributes to the calcium homeostasis in the ER.
Molecular mechanism of fatty acid activation of FFAR1
Authors: Kumari Punita , Inoue Asuka , Chapman Karen , Lian Peng , Rosenbaum Daniel M.
Published: May 2023

FFAR1 is a G-protein-coupled receptor (GPCR) that responds to circulating free fatty acids to enhance glucose-stimulated insulin secretion and release of incretin hormones. Due to the glucose-lowering effect of FFAR1 activation, potent agonists for this receptor have been developed for the treatment of diabetes. Previous structural and biochemical studies of FFAR1 showed multiple sites of ligand binding to the inactive state but left the mechanism of fatty acid interaction and receptor activation unknown. We used cryo–electron microscopy to elucidate structures of activated FFAR1 bound to a G
q
mimetic, which were induced either by the endogenous FFA ligand docosahexaenoic acid or γ-linolenic acid and the agonist drug TAK-875. Our data identify the orthosteric pocket for fatty acids and show how both endogenous hormones and synthetic agonists induce changes in helical packing along the outside of the receptor that propagate to exposure of the G-protein-coupling site. These structures show how FFAR1 functions without the highly conserved “DRY” and “NPXXY” motifs of class A GPCRs and also illustrate how the orthosteric site of a receptor can be bypassed by membrane-embedded drugs to confer full activation of G protein signaling.
Osteolectin increases bone elongation and body length by promoting growth plate chondrocyte proliferation
Authors: Zhang Jingzhu , Du Liming , Davis Bethany , Gu Zhimin , Lyu Junhua , Zhao Zhiyu , Xu Jian , Morrison Sean J.
Published: May 2023

Osteolectin is a recently identified osteogenic growth factor that binds to Integrin α11 (encoded byItga11), promoting Wnt pathway activation and osteogenic differentiation by bone marrow stromal cells. WhileOsteolectinandItga11are not required for the formation of the skeleton during fetal development, they are required for the maintenance of adult bone mass. Genome-wide association studies in humans reported a single-nucleotide variant (rs182722517) 16 kb downstream ofOsteolectinassociated with reduced height and plasma Osteolectin levels. In this study, we tested whether Osteolectin promotes bone elongation and found thatOsteolectin-deficient mice have shorter bones than those of sex-matched littermate controls. Integrin α11 deficiency in limb mesenchymal progenitors or chondrocytes reduced growth plate chondrocyte proliferation and bone elongation. Recombinant Osteolectin injections increased femur length in juvenile mice. Human bone marrow stromal cells edited to contain the rs182722517 variant produced less Osteolectin and underwent less osteogenic differentiation than that of control cells. These studies identify Osteolectin/Integrin α11 as a regulator of bone elongation and body length in mice and humans.
Efficient precise integration of large DNA sequences with 3′-overhang dsDNA donors using CRISPR/Cas9
Authors: Han Wenjie , Li Zhigang , Guo Yijun , He Kaining , Li Wenqing , Xu Caoling , Ge Lishuang , He Miao , Yin Xue , Zhou Junxiang , Li Chengxu , Yao Dongbao , Bao Jianqiang , Liang Haojun
Published: May 2023

CRISPR/Cas9 genome-editing tools have tremendously boosted our capability of manipulating the eukaryotic genomes in biomedical research and innovative biotechnologies. However, the current approaches that allow precise integration of gene-sized large DNA fragments generally suffer from low efficiency and high cost. Herein, we developed a versatile and efficient approach, termed LOCK (
L
ong dsDNA with 3′-
O
verhangs mediated
C
RISPR
K
nock-in), by utilizing specially designed 3′-overhang double-stranded DNA (odsDNA) donors harboring 50-nt homology arm. The length of the 3′-overhangs of odsDNA is specified by the five consecutive phosphorothioate modifications. Compared with existing methods, LOCK allows highly efficient targeted insertion of kilobase-sized DNA fragments into the mammalian genomes with low cost and low off-target effects, yielding >fivefold higher knock-in frequencies than conventional homologous recombination-based approaches. This newly designed LOCK approach based on homology-directed repair is a powerful tool suitable for gene-sized fragment integration that is urgently needed for genetic engineering, gene therapies, and synthetic biology.
Collective property rights lead to secondary forest growth in the Brazilian Amazon
Authors: Baragwanath Kathryn , Bayi Ella , Shinde Nilesh
Published: May 2023

Forests serve a crucial role in our fight against climate change. Secondary forests provide important potential for conservation of biodiversity and climate change mitigation. In this paper, we explore whether collective property rights in the form of indigenous territories (ITs) lead to higher rates of secondary forest growth in previously deforested areas. We exploit the timing of granting of property rights, the geographic boundaries of ITs and two different methods, regression discontinuity design and difference-in-difference, to recover causal estimates. We find strong evidence that indigenous territories with secure tenure not only reduce deforestation inside their lands but also lead to higher secondary forest growth on previously deforested areas. After receiving full property rights, land inside ITs displayed higher secondary forest growth than land outside ITs, with an estimated effect of 5% using our main RDD specification, and 2.21% using our difference-in-difference research design. Furthermore, we estimate that the average age of secondary forests was 2.2 y older inside ITs with secure tenure using our main RDD specification, and 2.8 y older when using our difference-in-difference research design. Together, these findings provide evidence for the role that collective property rights can play in the push to restore forest ecosystems.