Database model and specification of GermOnline Release 2.0, a cross-species community annotation knowledgebase on germ cell differentiation

Summary: GermOnline is a web-accessible relational database that enables life scientists to make a significant and sustained contribution to the annotation of genes relevant for the fields of mitosis, meiosis, germ line development and gametogenesis across species. This novel approach to genome annotation includes a platform for knowledge submission and curation as well as microarray data storage and visualization hosted by a global network of servers. Availability: The database is accessible at http://www.germonline.org/. For convenient world-wide access we have set up a network of servers in Europe (http://germonline.unibas.ch/; http://germonline.igh.cnrs.fr/), Japan (http://germonline.biochem.s.u-tokyo.ac.jp/) and USA (http://germonline.yeastgenome.org/). Supplementary information: Extended documentation of the database is available through the link ‘About GermOnline' at the website

Effects of cardiomyopathy-linked mutations K15N and R21H in tropomyosin on thin-filament regulation and pointed-end dynamics

Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Tropomyosin, together with the troponin complex, regulates muscle contraction and, along with tropomodulin and leiomodin, controls the uniform thin-filament lengths crucial for normal sarcomere structure and function. We used Förster resonance energy transfer to study effects of the tropomyosin mutations on the structure and kinetics of the cardiac troponin core domain associated with the Ca2+-dependent regulation of cardiac thin filaments. We found that the K15N mutation desensitizes thin filaments to Ca2+ and slows the kinetics of structural changes in troponin induced by Ca2+ dissociation from troponin, while the R21H mutation has almost no effect on these parameters. Expression of the K15N mutant in cardiomyocytes decreases leiomodin’s thin-filament pointed-end assembly but does not affect tropomodulin’s assembly at the pointed end. Our in vitro assays show that the R21H mutation causes a twofold decrease in tropomyosin’s affinity for F-actin and affects leiomodin’s function. We suggest that the K15N mutation causes DCM by altering Ca2+-dependent thin-filament regulation and that one of the possible HCM-causing mechanisms by the R21H mutation is through alteration of leiomodin’s function

Radiometer on a Chip

The radiometer on a chip (ROC) integrates whole wafers together to p rovide a robust, extremely powerful way of making submillimeter rece ivers that provide vertically integrated functionality. By integratin g at the wafer level, customizing the interconnects, and planarizing the transmission media, it is possible to create a lightweight asse mbly performing the function of several pieces in a more conventiona l radiometer

Real-World Concordance between Germline and Tumour <i>BRCA1/2</i> Status in Epithelial Ovarian Cancer

Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/ 2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/ 2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice ® companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/ 2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/ 2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice ® CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice ® CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged &lt; 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant. </p

Diamond Heat-Spreader for Submillimeter-Wave Frequency Multipliers

The planar GaAs Shottky diode frequency multiplier is a critical technology for the local oscillator (LO) for submillimeter- wave heterodyne receivers due to low mass, tenability, long lifetime, and room-temperature operation. The use of a W-band (75-100 GHz) power amplifier followed by a frequency multiplier is the most common for submillimeter-wave sources. Its greatest challenge is to provide enough input power to the LO for instruments onboard future planetary missions. Recently, JPL produced 800 mW at 92.5 GHz by combining four MMICs in parallel in a balanced configuration. As more power at W-band is available to the multipliers, their power-handling capability be comes more important. High operating temperatures can lead to degradation of conversion efficiency or catastrophic failure. The goal of this innovation is to reduce the thermal resistance by attaching diamond film as a heat-spreader on the backside of multipliers to improve their power-handling capability. Polycrystalline diamond is deposited by hot-filament chemical vapor deposition (CVD). This diamond film acts as a heat-spreader to both the existing 250- and 300-GHz triplers, and has a high thermal conductivity (1,000-1,200 W/mK). It is approximately 2.5 times greater than copper (401 W/mK) and 20 times greater than GaAs (46 W/mK). It is an electrical insulator (resistivity approx. equals 10(exp 15) Ohms-cm), and has a low relative dielectric constant of 5.7. Diamond heat-spreaders reduce by at least 200 C at 250 mW of input power, compared to the tripler without diamond, according to thermal simulation. This superior thermal management provides a 100-percent increase in power-handling capability. For example, with this innovation, 40-mW output power has been achieved from a 250-GHz tripler at 350-mW input power, while the previous triplers, without diamond, suffered catastrophic failures. This breakthrough provides a stepping-stone for frequency multipliers-based LO up to 3 THz. The future work for this design is to apply the high output power from both the 250 and 300 GHz to multiple chains in order to generate milliwatts at 2.3 THz. Using the first generation of results for this innovation, 40 mW of output power were produced from a 240-GHz tripler at 350-mW input power, and 27- mW output power was produced from a 300-GHz tripler at 408-mW input power. This is two times higher than the current state-of-the-art output power capability. A finite-element thermal simulation also shows that 30-microns thick diamond dropped the temperature of the anodes by at least 200 C

Herschel observations of deuterated water towards Sgr B2(M)

Observations of HDO are an important complement for studies of water, because they give strong constraints on the formation processes -- grain surfaces versus energetic process in the gas phase, e.g. in shocks. The HIFI observations of multiple transitions of HDO in Sgr~B2(M) presented here allow the determination of the HDO abundance throughout the envelope, which has not been possible before with ground-based observations only. The abundance structure has been modeled with the spherical Monte Carlo radiative transfer code RATRAN, which also takes radiative pumping by continuum emission from dust into account. The modeling reveals that the abundance of HDO rises steeply with temperature from a low abundance ($2.5\times 10^{-11}$) in the outer envelope at temperatures below 100~K through a medium abundance ($1.5\times 10^{-9}$) in the inner envelope/outer core, at temperatures between 100 and 200~K, and finally a high abundance ($3.5\times 10^{-9}$) at temperatures above 200~K in the hot core.Comment: A&A HIFI special issue, accepte

The Naturalistic Flight Deck System: An Integrated System Concept for Improved Single-Pilot Operations

This paper reviews current and emerging operational experiences, technologies, and human-machine interaction theories to develop an integrated flight system concept designed to increase the safety, reliability, and performance of single-pilot operations in an increasingly accommodating but stringent national airspace system. This concept, know as the Naturalistic Flight Deck (NFD), uses a form of human-centered automation known as complementary-automation (or complemation) to structure the relationship between the human operator and the aircraft as independent, collaborative agents having complimentary capabilities. The human provides commonsense knowledge, general intelligence, and creative thinking, while the machine contributes specialized intelligence and control, extreme vigilance, resistance to fatigue, and encyclopedic memory. To support the development of the NFD, an initial Concept of Operations has been created and selected normal and non-normal scenarios are presented in this document

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

All-Solid-State 2.45-to-2.78-THz Source

Sources in the THz range are required in order for NASA to implement heterodyne instruments in this frequency range. The source that has been demonstrated here will be used for an instrument on the SOFIA platform as well as for upcoming astrophysics missions. There are currently no electronic sources in the 2 3- THz frequency range. An electronically tunable compact source in this frequency range is needed for lab spectroscopy as well as for compact space-deployable heterodyne receivers. This solution for obtaining useful power levels in the 2 3- THz range is based on utilizing power-combined multiplier stages. Utilizing power combining, the input power can be distributed between different multiplier chips and then recombined after the frequency multiplication. A continuous wave (CW) coherent source covering 2.48 2.75 THz, with greater than 10 percent instantaneous and tuning bandwidth, and having l 14 W of output power at room temperature, has been demonstrated. This source is based on a 91.8 101.8-GHz synthesizer followed by a power amplifier and three cascaded frequency triplers. It demonstrates that purely electronic solid-state sources can generate a useful amount of power in a region of the electromagnetic spectrum where lasers (solid-state or gas) were previously the only available coherent sources. The bandwidth, agility, and operability of this THz source has enabled wideband, high-resolution spectroscopic measurements of water, methanol, and carbon monoxide with a resolution and signal-to-noise ratio unmatched by other existing systems, providing new insight in the physics of these molecules. Further - more, the power and optical beam quality are high enough to observe the Lamb-dip effect in water. The source frequency has an absolute accuracy better than 1 part in 1012, and the spectrometer achieves sub-Doppler frequency resolution better than 1 part in 108. The harmonic purity is better than 25 dB. This source can serve as a local oscillator for a variety of heterodyne systems, and can be used as a method for precision control of more powerful but much less frequency-agile quantum mechanical terahertz sources