Additional Signal Research Articles

Development of a one-shot dual aptamer-based fluorescence nanosensor for rapid, sensitive, and label-free detection of periostin

Periostin is associated with several diseases, including cancers. Therefore, monitoring blood periostin levels is a powerful tool for diagnosing various diseases and identifying their severity. However, conventional detection methods pose several challenges, including high costs. To address these issues, we developed a novel one-shot dual aptamer-based fluorescence nanosensor for detecting periostin. The proposed nanosensor facilitates rapid, label-free, and sensitive detection of periostin using gold nanoprobes constructed by rhodamine-b isothiocyanate, PL2trunc aptamer, and gold nanoparticles and silver nanoprobes fabricated by the PL5trunc aptamer and silver nanoparticles. The two nanoprobes form a core-satellite structure by interacting with periostin, and the nanosensor detects periostin through the fluorescence regenerated by the increased proximity between them. The nanosensor successfully detected periostin with remarkable detection limits of 106.68 pM in buffer and 463.3 pM in serum-spiked conditions within 30 min without additional washing or signal amplification processes. Considering serum periostin levels in various diseases, the proposed nanosensor provides a suitable method for identifying patients with various diseases and determining disease severity. Moreover, the platform can be helpful as a practical method for on-site medical diagnosis because it can be adapted to detect other biomarkers simply by replacing the aptamer with other detection probes.

O-131 BEYOND: a randomised controlled trial comparing efficacy and safety of individualised follitropin delta dosing in GnRH agonist versus antagonist protocols for first ovarian stimulation cycle

Abstract Study question How does a long GnRH agonist versus a GnRH antagonist protocol affect ovarian response when using individualised fixed daily follitropin delta dose for ovarian stimulation? Summary answer BEYOND trial data demonstrates that individualised follitropin delta dosing is safe and effective in a long GnRH agonist protocol in women with AMH ≤35 pmol/L. What is known already Efficacy and safety of a fixed daily dose of follitropin delta, individualised based on bodyweight and anti-Müllerian (AMH), have been established in RCTs using a GnRH antagonist protocol. Preliminary study data shows that individualised follitropin delta is efficacious when used with a long GnRH agonist protocol (RAINBOW trial). There is no comparative data for efficacy and safety of individualised follitropin delta in a long GnRH agonist versus an antagonist protocol. Study design, size, duration This was a randomised, controlled, open-label, multi-centre trial comparing efficacy and safety of individualised follitropin delta dosing in a long GnRH agonist versus an antagonist protocol in participants undergoing their first ovarian stimulation for IVF/ICSI conducted between May 2019 and February 2022. The primary endpoint was the number of oocytes retrieved. Important secondary endpoints included ongoing pregnancy rates and adverse drug reactions, with a special focus on OHSS. A total of 437 participants were randomised. Participants/materials, setting, methods Participants, 18–40 years old with AMH ≤35 pmol/L, were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway and Switzerland. The mean number of oocytes retrieved was compared between the agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. The analyses were based on all randomised subjects, using a multiple imputation method for randomised subjects withdrawing before start of stimulation. Main results and the role of chance Of the 437 randomised subjects, 202 and 204 initiated ovarian stimulation with follitropin delta in the agonist and antagonist groups, respectively. Baseline mean data were: age, 32.3±4.3 years; AMH, 16.6±7.8 pmol/L, respectively. The number of oocytes retrieved was statistically significantly higher in the agonist (11.1±5.9) versus antagonist (9.6±5.5) group, with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, p = 0.0185). The difference in number of oocytes retrieved was influenced by the patients’ age and ovarian reserve, with a greater difference observed in patients <35 years and patients with high ovarian reserve (AMH >15 pmol/L). Cycle cancellations (2.0% versus 3.4%) and transfer cancellations (13.7% versus 14.7%) were similar in both groups. Ongoing pregnancy rate (36.9% vs 29.1%; estimated difference: 7.74% [95% CI: –1.49; 16.97, p = 0.1002]) and other pregnancy outcomes were higher in the agonist versus antagonist protocol group, but the differences were not statistically significant. The most commonly reported adverse events (≥1% in either group) were similar in both groups (headache, OHSS, nausea, pelvic pain or discomfort, and abdominal pain). Incidence of early moderate/severe OHSS was low (1.5% versus 2.5%). Early pregnancy loss was similar between the groups (20% vs 24% of subjects with positive beta-hCG test, respectively). Limitations, reasons for caution Subjects with AMH >35 pmol/L were not enrolled. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/L (greater OHSS risk). OHSS incidence in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Wider implications of the findings In women with AMH ≤35 pmol/L, a fixed daily dose of follitropin delta (individualised according to bodyweight and AMH) showed similar efficacy when used in a long GnRH agonist protocol with no additional safety signals observed and no additional risk of OHSS versus follitropin delta used in an antagonist protocol. Trial registration number ClinicalTrials.gov identifier: NCT03809429; EudraCT number: 2017-002783-40

Dual-scale Contrastive Learning for multi-behavior recommendation

Multi-behavior recommendation (MBR) aims to improve the prediction of the target behavior (i.e., purchase) by exploiting multi-typed auxiliary behaviors, such as page view, cart and favorite. Recently, leveraging Graph Neural Networks (GNNs) to capture collaborative signals has been the mainstream paradigm for MBR. However, GNN-based MBR suffers from data sparsity in real-world scenarios and thus performs mediocrely. Excitingly, contrastive learning which can mine additional self-supervised signals from raw data, holds great potential to alleviate this problem. Naturally, we seek to exploit contrastive learning to enhance MBR, while two key challenges have yet to be addressed: (i) Difficult to learn reliable representations under different behaviors; (ii) Sparse supervised signals under target behavior. To tackle the above challenges, in this paper, we propose a novel Dual-Scale Contrastive Learning (DSCL) framework. Unlike traditional contrastive learning methods that artificially construct two views through data augmentation, we comprehensively consider two different views for MBR, including the collaborative view and the semantic view. Specifically, we regard the user–item graph as a collaborative view and the user–user graph as a semantic view. In particular, we develop two novel contrastive learning objectives at two scales. For the first challenge, we devise local-to-context contrastive learning within behaviors on collaborative view, which enhances the representation learning by incorporating potential neighbors into the contrastive learning from the graph topological space and the semantic space, respectively. As for the second challenge, we design local-to-local contrastive learning across behaviors on a semantic view, which has the benefit of capturing commonalities between different behaviors and integrating them into the target behavior to alleviate the sparse supervised signal problem of the target behavior. In addition, we also propose an adaptive weight network to efficiently customize the integration of all losses. Extensive experiments on three real-world benchmark datasets show that our proposed DSCL is significantly superior to various state-of-the-art recommendation methods.

Common and Distinct Genetic Architecture of Age at Diagnosis of Diabetes in South Indian and European Populations.

South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent. We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. We identified two signals near the TCF7L2 and CDKAL1 genes associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (rs7903146; P = 2.4 × 10-12, β = -0.436; SE 0.02) and chromosome 6p22.3 in CDKAL1 (rs9368219; P = 2.29 × 10-8; β = -0.053; SE 0.01) were directionally consistent across ethnic groups and present at similar frequencies; however, both loci harbored additional independent signals that were only present in the South Indian cohorts. A genome-wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; P = 3.255 × 10-8; β = 1.44; SE 0.25), specifically in the South Indian cohorts. Heritability estimates for the age at diagnosis were much stronger in South Indians than Europeans, and a polygenic risk score constructed based on South Indian GWAS explained ∼2% trait variance. Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.

Chromosomal mapping of ribosomal clusters and telomeric sequences (TTAGG) n in nine species of lobsters (Crustacea, Decapoda)

Lobsters are ubiquitous, economically important decapod crustaceans with apparently conflicting evolutionary relationships. Here, we describe the chromosomal location of the major (45S rDNA) and minor (5S rDNA) ribosomal gene families in four species of Astacidea and five of Achelata, using two-color FISH. The major ribosomal family is located in 4–16 sites per diploid chromosome set, with Nephrops norvegicus (Nephropidae) showing the highest number described so far in Decapoda. The 5S rDNA is located in two sites in eight species; only in the crayfish Procambarus clarkii the 5S FISH signals were detected in four sites together with additional weaker signals. Furthermore, in N. norvegicus the minor ribosomal genes are syntenic with one major ribosomal cluster. Moreover, we located by two-color FISH the pentanucleotide (TTAGG) n telomeric repeat in the Nephropidae studied, showing the occurrence of a colocalization with 45S ribosomal sequences in Homarus gammarus. The comparison of chromosomal locations of repetitive sequences in Mediterranean, Atlantic, and South African lobster species as well as in marine and freshwater ones provides information on chromosomal evolution and cytotaxonomy of Decapoda.

Developing AI enabled sensors and decision support for military operators in the field.

Wearable sensors enable down range data collection of physiological and cognitive performance of the warfighter. However, autonomous teams may find the sensor data impractical to interpret and hence influence real-time decisions without the support of subject matter experts. Decision support tools can reduce the burden of interpreting physiological data in the field and incorporate a systems perspective where noisy field data can contain useful additional signals. We present a methodology of how artificial intelligence can be used for modeling human performance with decision-making to achieve actionable decision support. We provide a framework for systems design and advancing from the laboratory to real world environments. The result is a validated measure of down-range human performance with a low burden of operation.

Rotor Position Estimation for Permanent Magnet Synchronous Machines using Electromotive Force and Anisotropy Using Extended-Kalman-Filter

In this paper a new rotor position observer for permanent magnet synchronous machines (PMSM) based on an Extended-Kalman-Filter (EKF) is presented. With this method, just one single EKF is sufficent to evaluate the position information from electromotive force (EMF) and anisotropy. Thus, the PMSM can be controlled for the entire speed range without a position sensor and without the need to switch or synchronize between different observers. The approach covers online estimation of permanent magnetic field and mechanical load. The resulting EKF-based rotor position estimator is embedded in the existing cascaded control concept of the PMSM without need of additional angle trackers or signal filters. The experimental validation for the position sensorless control shows optimized dynamic behaviour.

Fine-Tunable Emission Pulse Generation Circuit Based on p-Type Low-Temperature Poly-Si Thin-Film Transistors for Active Matrix Organic Light-Emitting Diode Displays

Active matrix organic light-emitting diode (AMOLED) displays have deployed the compensation techniques to cope with the luminance non-uniformity issues caused by variations on electrical characteristics of thin-film transistors (TFTs). While some compensation circuits require control signals of longer pulse widths than a line time, the luminance control as well as the higher bit depth representation have been also accomplished by adjusting the pulse widths. A proposed EM pulse generation circuit consists of 11 p-type low-temperature poly-Si (LTPS) TFTs and a one coupling capacitor. While previous tunable circuits could address pulse widths of either even or odd multiples of a line time, the proposed circuit can generate any multiples by changing phases of additional clock signals. In particular, the internal inverter is implemented with a load connected to the output of a previous stage’s inverter to reduce the power consumption over pulse widths. The coupling capacitor is also connected between two adjacent stages through one TFT, eliminating coupling noises on the output pulses. The proposed EM circuit is simulated at a line time of 3.8 <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu$</tex-math> </inline-formula> s for a 120 Hz <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\text{3840}$</tex-math> </inline-formula> <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\times $</tex-math> </inline-formula> <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\text{2160}$</tex-math> </inline-formula> display. The results ensure that pulse widths from three to 2160 lines are generated successfully without coupling noises and the small variation on power consumption from 1.23 to 0.33 mW is achieved at 30 stages for the whole range of pulse widths, compared to the large range from 1.26 to 76.91 mW with the inverter of a diode-connected load.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: T cells normally recognize bacterial proteins originating from the gut microbiome, including some that cross-react with normal host B cell-specific proteins. A peptide-based strategy designed to activate and expand such pre-existing memory CD8+ T cells recognizing and driving anti-tumor activity against B cell malignancies was developed. EO2463 includes 4 synthetically produced peptides corresponding to cytotoxic CD8 HLA-A2 restricted epitopes which exhibit molecular mimicry with the B cell antigens CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a helper CD4 peptide, UCP2, derived from hTERT. Memory CD8+ T cell clones can be detected in the peripheral blood of healthy donors recognizing the EO2463 mimic peptides; in vitro, such cells can kill target T2 cells loaded with mimic or human counterpart peptides. Methods: This first-in-human trial include HLA-A2+ patients (pts) with follicular lymphoma (FL) and marginal zone lymphoma (MZL). In the safety lead-in dose-finding part, EO2463 is administered subcutaneously every other week (w) × 4, followed by monthly administrations for a max of 12 months. After 6 w of EO2463 monotherapy, oral lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added, and if no complete remission (CR) at w 19, rituximab (375 mg/m2 IV, weekly × 4, followed by q4 w infusions × 4) is also added. The peptide-dose is evaluated in a 3-by-3 safety design, starting at 150 μg/peptide, max escalation to 300 μg. Results: Pts in the 1st (150 μg dose; 3 pts) and 2nd (300 μg dose; 3 pts) cohorts received EO2463 monotherapy without related grade ≥3 adverse events. Three more pts are being enrolled at the 300 μg dose, prior to starting expansion cohorts. Among the initial 6 pts, 5 had FL and 1 MZL; median number of prior therapies was 1 (range 1–4). Objective response rate 67%, including 50% CR (at w18, w18, w42), and 17% partial remission (at w18; ongoing treatment). On EO2463 monotherapy (at w6), 3 stable disease (including one metabolic response in 5 of 6 target lesions), 2 indeterminate responses (increased FDG uptake, no size change), 1 progressive disease. Combination therapy toxicity; grade 3 thrombocytopenia, rash, anemia, atrial fibrillation, bronchitis and sepsis (all n = 1); in addition, grade 4 neutropenia (n = 2). Expansion of specific CD8+ T cells against the mimic peptides and targeted B cell proteins was detected in 4/6 pts, including in 2 pts with no measurable B cells at baseline (prior anti-CD20). Immune response was maintained even following addition of rituximab. In vitro expanded EO2463 specific CD8+ T cells from pts with immune response can kill malignant HLA-A2 B cell lines. Conclusions: EO2463 is well tolerated as monotherapy, and without additional safety signals when combined with lenalidomide and rituximab. We find evidence of on-target immune activation, and preliminary complete response rate is encouraging. Expanded data to be presented. NCT04669171. Keywords: Combination Therapies, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. A. Pinto Consultant or advisory role: Scientific Advisory Boards (F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte-Italy) Honoraria: Speaking engagements – Educational Lectures (F. Hoffmann-La Roche AG, Incyte –Italy, Merck Sharp and Dohme, Servier Affaires Medicales, BMS-CELGENE) Other remuneration: Speaker's Bureau: Incyte-Italy, F. Hoffmann-La Roche AG S. D. Smith Consultant or advisory role: ADC Therapeutics, Astrazeneca, Beigene, Epizyme, Karyopharm, KITE pharma, Incyte, Numab Therapeutics, AG Abbvie, Coherus Biosciences, advisory board (spouse): Genentech Research funding: ADC Therapeutics, Astrazeneca, Ayala (spouse), Bayer, Beigene, Bristol Myers Squibb (spouse), De Novo Biopharma, Enterome, Genentech, Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp., MorphoSys, Nanjing Pharmaceuticals Co., Ltd., Portola Pharmaceuticals, Viracta Therapeutics L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau: EUSA Pharma, Novartis R. Merryman Consultant or advisory role: Genmab, Adaptive Biotechnologies, Bristol Myers Squibb, Abbvie, Inteillia, Epizyme, Alphasights Research funding: Merck, Bristol Myers Squibb, Genmab, Genentech/Roche S. Ansel Research funding: Bristol Myers Squibb, SeaGen, Takeda, Regeneron, AstraZeneca, Pfizer, Affimed and ADC Therapeutics. P. Armand Consultant or advisory role: Merck, BMS, ADC Therapeutics, Tessa, GenMab, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor, ATB Therapeutics Honoraria: Merck Research funding: Kite, Merck, BMS, Adaptive, Genentech, IGM P. L. Zinzani Consultant or advisory role: Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, ADC Therap., Incyte, Beigene Other remuneration: Speaker's Bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, Incyte, Beigene

Updated results from an ongoing phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via IT injection as monotherapy or combined with pembrolizumab in advanced solid tumors.

9535 Background: T3011 is a recombinant HSV-1 oncolytic virus expressing both IL-12 and anti-human PD-1 antibody. Upon injection, locally produced IL-12 induces IFN-γ production, enhances the oncolytic activity of NK cells and cytotoxic T lymphocytes, promotes anti-angiogenesis and inhibits tumor growth. PD-1 antibodies act as immune checkpoint inhibitors to augment tumor-killing activity of T-cells. Here we report the updated results from an open-label, dose escalation and expansion study of T3011 administered via intratumoral injection as monotherapy or in combination with intravenous pembrolizumab. Methods: Pts with pathologically confirmed recurrent or metastatic malignancy after failure of SOC were enrolled and received T3011 monotherapy (1*106-5*107 PFU/mL Q2W) or in combination with pembrolizumab (Lead-in T3011 1*106 PFU/mL Q2W monotherapy for 2 cycles followed by combination therapy Q3W). Pts with documented progression on T3011 monotherapy may cross over to receive combination therapy at the discretion of the investigator. The primary endpoints were safety and tolerability. Key secondary endpoints included confirmed ORR, DCR, DOR, PFS by investigator per RECIST1.1; OS; PD and PK. Results: As of 17 Jan 2023, 29 pts received T3011 alone or in combination with pembrolizumab, the median follow-up was 14.1 (1.2-27.6) months. No DLTs were reported. Any treatment-related adverse events (TRAEs) occurred in 75.9% (22/29) of pts (≥G3 in 10.3%). Treatment-related SAEs occurred in 3.4% (1/29). Most frequent TRAEs (≥10%) were pyrexia (27.6%), fatigue (20.7%) and chills, injection site pain, arthralgia, nausea, headache (10.3% each). No additional safety signals were observed with combination therapy. 12 advanced melanoma pts failing prior PD-1 or PD-1/CTLA-4 combination treatment received 5*107 PFU/mL of T3011 monotherapy. The confirmed ORR and DCR were 25.0% (3/12) and 33.3% (4/12), respectively. 12-month PFS rate was 36.4%. 6 of these pts were re-challenged with immunotherapy with T3011 (5*107 PFU/mL) combined with pembrolizumab after progressing on T3011 monotherapy, 1 pt achieved PR after 4 months lasting &gt; 8 months at data cutoff. 15 pts had tumor tissues for PD analysis. Increased CD8+ cells were observed in 46.7% (7/15) of all pts and 50% (5/10) of melanoma pts. It appeared to be more pronounced in pts with PR and SD, 66.7% (6/9) in all pts and 80% (4/5) in melanoma pts, respectively. Notably, the increment of CT8+ cells in 2 melanoma pts with PR was over 15 folds. Conclusions: Both T3011 IT monotherapy and combination therapy with pembrolizumab were safe and tolerable. The efficacy of T3011 in immune-resistant melanoma was encouraging. Our data suggest T3011 may modify the tumor microenvironment and overcome immune resistance. Clinical trial information: NCT04370587 .

A Nonintrusive Digital Current Sensing Method for DC–DC Converters With Wide Load Range

Current estimators for dc-dc converters reduce the requirement of current transducers (e.g. sense resistor, Hall sensor) which may be either expensive, invasive, and (or) require additional signal conditioning circuits. High-frequency inductor currents within dc-dc converters can be estimated instantaneously using voltage measurements taken at its terminals. The voltage measurement at the switching terminal of the inductor is assisted by a comparator, whose output state is related to the corresponding voltage magnitude. This paper presents a novel unified current estimation method in which a single comparator is required to detect the switch node status both in continuous and discontinuous modes of operation. The other measurements required for this method include sensing dc voltage magnitudes, which are essential measurements for a regulated dc-dc converter system; hence the proposed methodology can be easily integrated into existing digital control schemes. The proposed approach has been applied to first-order dc-dc converters and has been validated using a laboratory prototype of a digitally controlled boost converter system using an FPGA.

Setting Gendered Expectations? Recruiter Outreach Bias in Online Tech Training Programs

Competence development in digital technologies, analytics, and artificial intelligence is increasingly important to all types of organizations and their workforce. Universities and corporations are investing heavily in developing training programs, at all tenure levels, to meet the new skills needs. However, there is a risk that the new set of lucrative opportunities for employees in these tech-heavy fields will be biased against diverse demographic groups like women. Although much research has examined the experiences of women in science, technology, engineering, and mathematics (STEM) fields and occupations, less understood is the extent to which gender stereotypes influence recruiters’ perceptions and evaluations of individuals who are deciding whether to apply to STEM training programs. These behaviors are typically unobserved because they occur prior to the application interface. We address this question by investigating recruiters’ initial outreach decisions to more than 166,000 prospective students who have expressed interest in applying to a midcareer level online tech training program in business analytics. Using data on the recruiters’ communications, our results indicate that recruiters are less likely to initiate contact with female than male prospects and search for additional signals of quality from female prospects before contacting them. We also find evidence that recruiters are more likely to base initial outreach activities on prospect gender when they have higher workloads and limited attention. We conclude with a discussion of the implications of this research for our understanding of how screening and selection decisions prior to the application interface may undermine organizational efforts to achieve gender equality and diversity as well as the potential for demand-side interventions to mitigate these gender disparities. Funding: We gratefully acknowledge Harvard Business School and MIT Sloan School of Management for generously funding this work. Supplemental Material: The online appendix is available at https://doi.org/10.1287/orsc.2022.16499 .

Setting Gendered Expectations? Recruiter Outreach Bias in Online Tech Training Programs

Competence development in digital technologies, analytics, and artificial intelligence is increasingly important to all types of organizations and their workforce. Universities and corporations are investing heavily in developing training programs, at all tenure levels, to meet the new skills needs. However, there is a risk that the new set of lucrative opportunities for employees in these tech-heavy fields will be biased against diverse demographic groups like women. Although much research has examined the experiences of women in science, technology, engineering, and mathematics (STEM) fields and occupations, less understood is the extent to which gender stereotypes influence recruiters’ perceptions and evaluations of individuals who are deciding whether to apply to STEM training programs. These behaviors are typically unobserved because they occur prior to the application interface. We address this question by investigating recruiters’ initial outreach decisions to more than 166,000 prospective students who have expressed interest in applying to a midcareer level online tech training program in business analytics. Using data on the recruiters’ communications, our results indicate that recruiters are less likely to initiate contact with female than male prospects and search for additional signals of quality from female prospects before contacting them. We also find evidence that recruiters are more likely to base initial outreach activities on prospect gender when they have higher workloads and limited attention. We conclude with a discussion of the implications of this research for our understanding of how screening and selection decisions prior to the application interface may undermine organizational efforts to achieve gender equality and diversity as well as the potential for demand-side interventions to mitigate these gender disparities. Funding: We gratefully acknowledge Harvard Business School and MIT Sloan School of Management for generously funding this work. Supplemental Material: The online appendix is available at https://doi.org/10.1287/orsc.22.16499 .

Augmenting workload drives T-tubule assembly in developing cardiomyocytes.

Contraction of cardiomyocytes is initiated at subcellular elements called dyads, where L-type Ca2+ channels in t-tubules are located within close proximity to ryanodine receptors in the sarcoplasmic reticulum. While evidence from small rodents indicates that dyads are assembled gradually in the developing heart, it is unclear how this process occurs in large mammals. We presently examined dyadic formation in fetal and newborn sheep (Ovis aries), and the regulation of this process by fetal cardiac workload. By employing advanced imaging methods, we demonstrated that t-tubule growth and dyadic assembly proceed gradually during fetal sheep development, from 93days of gestational age until birth (147days). This process parallels progressive increases in fetal systolic blood pressure, and includes step-wise colocalization of L-type Ca2+ channels and the Na+/Ca2+ exchanger with ryanodine receptors. These proteins are upregulated together with the dyadic anchor junctophilin-2 during development, alongside changes in the expression of amphiphysin-2 (BIN1) and its partner proteins myotubularin and dynamin-2. Increasing fetal systolic load by infusing plasma or occluding the post-ductal aorta accelerated t-tubule growth. Conversely, reducing fetal systolic load with infusion of enalaprilat, an angiotensin converting enzyme inhibitor, blunted t-tubule formation. Interestingly, altered t-tubule densities did not relate to changes in dyadic junctions, or marked changes in the expression of dyadic regulatory proteins, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum. In conclusion, augmenting blood pressure and workload during normal fetal development critically promotes t-tubule growth, while additional signals contribute to dyadic assembly. KEY POINTS: T-tubule growth and dyadic assembly proceed gradually in cardiomyocytes during fetal sheep development, from 93days of gestational age until the post-natal stage. Increasing fetal systolic load by infusing plasma or occluding the post-ductal aorta accelerated t-tubule growth and hypertrophy. In contrast, reducing fetal systolic load by enalaprilat infusion slowed t-tubule development and decreased cardiomyocyte size. Load-dependent modulation of t-tubule maturation was linked to altered expression patterns of the t-tubule regulatory proteins junctophilin-2 and amphiphysin-2 (BIN1) and its protein partners. Altered t-tubule densities did not influence dyadic formation, indicating that distinct signals are responsible for maturation of the sarcoplasmic reticulum.

Stability Analysis of a One Degree of Freedom Robot Model With Sampled Digital Acceleration Feedback Controller in Turning and Milling

Abstract This study is interested in the stability of robots in machining. The goal is to improve the dynamic performance of robots using an additional acceleration signal fed back through the conventional built-in proportional-derivative controller provided by the manufacturer. The structure of the robot is modelled with a simple one degree-of-freedom lumped model and the control signals are fed back via a linear spring and damping. The time delays of the feedback controllers are considered as zero-order holds, which results in sawtooth-like time-periodic time delays. The resulting equation of motion is an advanced delay differential equation. The semidiscretization method is shown for such systems having multiple sampled digital delays and continuous delays. First, we establish the stable regions in the plane of the sampling delay and the gain of the acceleration signal without machining. Then, we show the possibility to improve stability in turning and milling using the additional acceleration feedback controller compared to the cases without any controller or using only the built-in proportional-derivative controller.

NMR sample optimization and backbone assignment of a stabilized neurotensin receptor

G protein-coupled receptors (GPCRs) are involved in a multitude of cellular signaling cascades and consequently are a prominent target for pharmaceutical drugs. In the past decades, a growing number of high-resolution structures of GPCRs has been solved, providing unprecedented insights into their mode of action. However, knowledge on the dynamical nature of GPCRs is equally important for a better functional understanding, which can be obtained by NMR spectroscopy. Here, we employed a combination of size exclusion chromatography, thermal stability measurements and 2D-NMR experiments for the NMR sample optimization of the stabilized neurotensin receptor type 1 (NTR1) variant HTGH4 bound to the agonist neurotensin. We identified the short-chain lipid di-heptanoyl-glycero-phosphocholine (DH7PC) as a promising membrane mimetic for high resolution NMR experiments and obtained a partial NMR backbone resonance assignment. However, internal membrane-incorporated parts of the protein were not visible due to lacking amide proton back-exchange. Nevertheless, NMR and hydrogen deuterium exchange (HDX) mass spectrometry experiments could be used to probe structural changes at the orthosteric ligand binding site in the agonist and antagonist bound states. To enhance amide proton exchange we partially unfolded HTGH4 and observed additional NMR signals in the transmembrane region. However, this procedure led to a higher sample heterogeneity, suggesting that other strategies need to be applied to obtain high-quality NMR spectra of the entire protein. In summary, the herein reported NMR characterization is an essential step toward a more complete resonance assignment of NTR1 and for probing its structural and dynamical features in different functional states.

Understanding the cellular and molecular mechanism of anti-CTLA4 mediated tumor rejection

Abstract Although the clinical success of checkpoint inhibitors treatment is significant to prolong the patient survival, there is a substantial gap in our understanding of their mechanism in patients due to several technical and ethical limitations. Recent work suggests that the therapeutic effect of anti-CTLA-4 antibodies may not only block CTLA-4 interaction with its ligands, but also selectively deplete intratumoral Tregs (the highest expresser of CTLA-4) through ADCC. This releases the immunosuppressive state of the tumor microenvironment, thereby, promoting the expansion of effector CD4 and CD8, and increasing the secretion of IFN-g and TNF to reject the tumors. We observed a rapid Treg reduction characterized with fragile phenotype as early as 24 hours after anti-CTLA4 treatment. Using FOXP3-DTR mice, we confirmed that Treg depletion is the major contributor against tumor progression as anti-CTLA4 effect was abrogated in the DT-treated mice, and Treg function was maintained in the FcR KO mice. This suggested that FcR engagement is responsible for the Treg weakness. We hypothesized that there might be additional signal being transmitted when anti-CTLA4 is engaging with FcR which is capable of inducing Treg reduction. We made this hypothesis when we found the important receptor CD25 expressed on the Treg was significantly decreased after engagement. This receptor can also sense surrounding IL2 to maintain Treg cell survival, function, and proliferation. Interestingly, the CD25 expression was not inhibited when lacking FcR to induce CTLA4 engagement. Hence, there is still a need to study the underlying mechanism to see why Treg cells express lower CD25 after CTLA4 engagement.

Visual Reinforcement Learning With Self-Supervised 3D Representations

A prominent approach to visual Reinforcement Learning (RL) is to learn an internal state representation using self-supervised methods, which has the potential benefit of improved sample-efficiency and generalization through additional learning signal and inductive biases. However, while the real world is inherently 3D, prior efforts have largely been focused on leveraging 2D computer vision techniques as auxiliary self-supervision. In this work, we present a unified framework for self-supervised learning of 3D representations for motor control. Our proposed framework consists of two phases: a <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">pretraining</i> phase where a deep voxel-based 3D autoencoder is pretrained on a large object-centric dataset, and a <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">finetuning</i> phase where the representation is jointly finetuned together with RL on in-domain data. We empirically show that our method enjoys improved sample efficiency compared to 2D representation learning methods. Additionally, our learned policies transfer zero-shot to a real robot setup with only approximate geometric correspondence, and successfully solve motor control tasks that involve grasping and lifting from <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">a single, uncalibrated RGB camera</i> . Code and videos are available at <uri xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">https://yanjieze.com/3d4rl/</uri> .

Suppression of Back-Tunneling Events in Hybrid Single-Electron Turnstiles by Source-Drain Bias Modulation

The accuracy of single-electron currents produced in hybrid turnstiles at high operation frequencies is, among other errors, limited by electrons tunneling in the wrong direction. Increasing the barrier transparency between the island and the leads, together with the source-drain bias, helps to suppress these events in a larger frequency range, although they lead to some additional errors. We experimentally demonstrate a driving scheme that suppresses tunneling in the wrong direction, thus extending the range of frequencies for generating accurate single-electron currents. The main feature of this approach is an additional ac signal applied to the bias with frequency twice that applied to the gate electrode. This allows additional modulation of the island chemical potential. By using this approach under certain parameters, we improve the single-electron current accuracy by one order of magnitude. Finally, we show through experimentally contrasted calculations that our method can improve accuracy even in devices for which the usual gate driving gives errors of the order of ${10}^{\ensuremath{-}3}$ at high frequencies and can bring them under $5\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}4}$.

Interpolated inverse discrete wavelet transforms in additive and non-additive spectral background corrections

We demonstrate the applicability of using interpolated inverse discrete wavelet transforms as a general tool for modeling additive or multiplicative background or error signals in spectra. Additionally, we propose an unsupervised way of estimating the optimal wavelet basis along with the model parameters. We apply the method to experimental Raman spectra of phthalocyanine blue, aniline black, naphthol red, pigment yellow 150, and pigment red 264 pigments to remove their additive background and to CARS spectra of adenosine phosphate, fructose, glucose, and sucrose to remove their multiplicative background signals.