Pulse interaction induced systematic errors in dual comb spectroscopy.

Systematic errors are observed in dual comb spectroscopy when pulses from the two sources travel in a common fiber before interrogating the sample of interest. When sounding a molecular gas, these errors distort both the line shapes and retrieved concentrations. Simulations of dual comb interferograms based on a generalized nonlinear Schrodinger equation highlight two processes for these systematic errors. Self-phase modulation changes the spectral content of the field interrogating the molecular response but affects the recorded spectral baseline and absorption features differently, leading to line intensity errors. Cross-phase modulation modifies the relative inter-pulse delay, thus introducing interferogram sampling errors and creating a characteristic asymmetric distortion on spectral lines. Simulations capture the shape and amplitude of experimental errors which are around 0.1% on spectral transmittance residuals for 10 mW of total average power in 10 meters of common fiber, scaling up to above 0.6% for 20 mW and 60 m.

Increasing severity of medical outcomes and associated substances in cases reported to United States poison centers.

INTRODUCTION: Poison centers provide free expert recommendations on the treatment of a wide variety of toxicological emergencies. Prior studies have called attention to the increasing complexity of cases reported to poison centers. We aimed first, to evaluate the trends in medical outcome severity, over a 15-year period in both the adult and pediatric populations. Second, we described the most frequently reported substances associated with major effect or death. METHODS: This is a retrospective review of exposures reported to the National Poison Data System from 1 January 2007 through 31 December 2021. All closed cases, for human exposures, reported during the study period were included. We assessed trends in frequencies and rates of medical outcomes and level of care received, among the adult (age greater than 19 years) and pediatric (age 19 years and younger) populations by reason for exposure. RESULTS: During the study period, the number of adult unintentional exposures resulting in major effect (37.4 percent) and death (65.3 percent) increased. The number of adult intentional exposures resulting in death increased by 233.9 percent and those resulting in a major effect increased by 133.1 percent. The rates of exposures resulting in major effect and death increased among both intentional and unintentional adult exposures. The number of pediatric unintentional exposures resulting in a major effect increased by 76.6 percent and the number of pediatric intentional exposures resulting in death and major effect increased by 122.7 and 190.1 percent, respectively. Moderate, major effect, and death rates increased in pediatric unintentional exposures and moderate and major effect rates increased in pediatric intentional exposures. CONCLUSIONS: We found a worsening severity of medical outcomes in adult and pediatric cases reported to poison centers. Poison centers are increasingly managing complex cases. Monitoring trends in which substances are associated with severe outcomes is imperative for future strategic prevention efforts.

Precision Doppler shift measurements with a frequency comb calibrated laser heterodyne radiometer.

We report precision atmospheric spectroscopy of CO2 using a laser heterodyne radiometer (LHR) calibrated with an optical frequency comb. Using the comb calibrated LHR, we record spectra of atmospheric CO2 near 1572.33 nm with a spectral resolution of 200 MHz, using sunlight as a light source. The measured CO2 spectra exhibit frequency shifts by approximately 11 MHz over the course of the 5-h measurement, and we show that these shifts are caused by Doppler effects due to wind along the spectrometer line of sight. The measured frequency shifts are in excellent agreement with an atmospheric model, and we show that our measurements track the wind-induced Doppler shifts with a relative frequency precision of 2 MHz (3 m·s-1) for a single 10 s measurement, improving to 100 kHz (15 cm·s-1) after averaging (equivalent to a fractional precision of a few parts in 1010). These results demonstrate that frequency comb calibrated LHR enables precision velocimetry that can be of use in applications ranging from climate science to astronomy.

Androgen receptor nucleocytoplasmic trafficking - A one-way journey.

The androgen receptor (AR) is a key regulator of the growth and proliferation of prostate cancer. The majority of lethal castration-resistant prostate cancer (CRPC) growth is still dependent on AR activity. The AR need to be in the nucleus to exert its biological action as a transcription factor. As such, defining the mechanisms that regulate the subcellular localization of AR are important. Previously it was believed that AR was imported into the nucleus in a ligand-dependent manner and subsequently exported out of the nucleus upon ligand withdrawal. Recent evidence has challenged this decades-old paradigm and showed that the AR is degraded, not exported, in the nucleus. This review discusses the current understanding of how AR nucleocytoplasmic localization is regulated by import and through nuclear degradation.

Suspected Suicide Attempts by Self-Poisoning Among Persons Aged 10-19 Years During the COVID-19 Pandemic - United States, 2020-2022.

The World Health Organization declared COVID-19 a global pandemic on March 11, 2020 (1). As strategies to mitigate the pandemic were implemented, concerns were raised that the containment efforts through quarantine and social distancing practices were negatively affecting the mental and physical health of children and adolescents (2). Suicide is a growing public health problem in the United States. In 2020, suicide was the second leading cause of death among persons aged 10-14 years and the third leading cause among those aged 15-24 years (3). The National Poison Data System (NPDS) database was used to examine trends in suspected suicide attempts by self-poisoning among persons aged 10-19 years before and during the COVID-19 pandemic. Compared with 2019 (prepandemic), during 2021, the overall rate of suspected suicide attempts by self-poisoning increased by 30.0% (95% CI = 28.6%-30.9%), rates among children aged 10-12 years, adolescents aged 13-15 years, and females increased 73.0% (67.4%-80.0%), 48.8% (46.7%-50.9%), and 36.8% (35.4%-38.2%), respectively, and these trends continued into the third quarter of 2022. Substances most frequently involved in overdoses were acetaminophen, ibuprofen, sertraline, fluoxetine, and diphenhydramine. Acetaminophen-involved overdoses increased 71% (67.4%-74.9%) in 2021 and 58.0% (54.5%-61.6%) in 2022. Diphenhydramine-involved overdoses increased 24.2% (19.9%-28.7%) in 2021 and 35.8% (31.2%-40.5%) in 2022. A comprehensive public health approach to suicide prevention, focused on children and adolescents and involving a partnership between families, school teachers, mental health professionals, and public health leadership is needed. The 9-8-8 Suicide and Crisis Lifeline provides crisis support for persons experiencing mental health-related distress and assists community members who are concerned about persons experiencing a mental health crisis.

The Sting of a White Flannel Moth Caterpillar (Norape ovina).

The purpose of this report is to describe a case of urticarial dermatitis, or erucism, caused by the white flannel moth caterpillar (Norape ovina) in central Virginia. Many caterpillars are known to cause erucism, with the puss caterpillar (Megalopyge opercularis) being the most reported culprit in the United States. White flannel moth caterpillars are expected to cause erucism as they belong to the same family as the puss caterpillar (Megalopygidae) and have similar venom-containing hairs, but no reports of the reaction or clinical course have been documented in the medical literature. A subject was stung by a white flannel moth caterpillar after it fell on his neck while clearing brush with a machete. The subject experienced immediate pain and developed a raised, erythematous rash where the caterpillar had fallen. The rash, referred to as erucism, was painful for 1 d and improved slowly over the course of 2 wk, but a small area of discoloration remained 2.5 mo after contact. Symptoms were managed by the subject at home and no medications were administered. The white flannel moth caterpillar inflicts erucism similar to that caused by the more commonly mentioned puss caterpillar. If only local symptoms are sustained from contact with a white flannel moth caterpillar, it can be safely and effectively managed with over-the-counter medications similar to the management for erucism induced by other caterpillar species. Irrigation and removal of urticating hairs with adhesive tape may help reduce the pain and is recommended, though not performed in this case.

(+)-JJ-74-138 is a Novel Noncompetitive Androgen Receptor Antagonist.

Identification of novel androgen receptor (AR) antagonists may lead to urgently needed new treatments for patients with prostate cancer resistant to current AR antagonists. AR is presently the main target for treating prostate cancer. Clinically approved AR antagonists compete with dihydrotestosterone (DHT) for binding to the ligand-binding domain (LBD) of AR, and patients eventually develop resistance to these treatments. One approach to overcoming resistance is to discover compounds that inhibit AR in alternative ways. Our lab previously identified a small molecule, JJ-450, that is capable of inhibiting AR lacking LBD. To optimize the efficacy of this class of inhibitors, we developed structural analogues of JJ-450 and identified (+)-JJ-74-138 as a promising candidate. Here, we show that (+)-JJ-74-138 is more potent than JJ-450 in the inhibition of androgen-independent AR activity in enzalutamide-resistant LN95 cells. Further studies showed (+)-JJ-74-138 inhibition of castration-resistant PSA expression in all tested castration-resistant prostate cancer (CRPC) cells. (+)-JJ-74-138 inhibited mRNA expression of AR and ARv7 target genes and reduced AR level in the nucleus in the absence of androgens. Also, this analogue noncompetitively inhibited androgen-stimulated AR activity in C4-2, LN95, and 22Rv1 CRPC cells. At low dosages, (+)-JJ-74-138 inhibited the proliferation of enzalutamide-resistant AR-positive LN95 and 22Rv1 cells, but not AR-negative PC3 and DU145 cells. A surface plasmon resonance assay detected (+)-JJ-74-138 binding to AR and a chromatin immunoprecipitation assay indicated (+)-JJ-74-138 inhibited AR binding to androgen response elements. In addition, (+)-JJ-74-138 inhibited 22Rv1 xenograft tumor growth. Our observations suggest that (+)-JJ-74-138 is a novel noncompetitive AR antagonist capable of inhibiting enzalutamide-resistant CRPC.

Mechanisms and targeting of proteosome-dependent androgen receptor degradation in prostate cancer.

The androgen receptor (AR) remains to be a key target for the treatment of prostate cancer, including the majority of castration-resistant prostate cancer (CRPC). AR is stabilized in CRPC and the ubiquitin-proteasome system (UPS) plays a major role in AR degradation. Targeting AR for degradation provides a potential approach to overcome the resistance of CRPC to current AR antagonists, including the next generation AR signaling inhibitors. Different types of AR degraders have been developed, including the proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), and novel AR degraders, with several AR PROTACs currently in clinical trials. The present mini-review discusses the regulation of AR degradation by the UPS, the potential role of a novel nuclear degradation signal in AR, and different types of AR degraders.

The classical and updated models of androgen receptor nucleocytoplasmic trafficking.

This mini-review covers the classical model of androgen receptor (AR) nucleocytoplasmic trafficking and provides an overview of new data that updates the existing paradigm. The classical model of androgen receptor trafficking involves AR translocating to the nucleus in the presence of androgens and subsequently being exported back to the cytoplasm following the withdrawal of androgens. New data challenges and updates the fate of nuclear AR. In the updated model, the AR can be imported into the nucleus in the absence of androgens and nuclear AR is degraded, not exported. Further, androgens can enhance AR nuclear import and inhibit AR degradation in the nucleus; androgen withdrawal causes nuclear AR degradation, but not export. Enhanced androgen-independent AR nuclear localization and AR nuclear stability may be a hallmark of castration-resistant prostate cancer (CRPC). Further characterization of AR trafficking may aid in the development of new therapies for patients with CRPC.

Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer.

Nuclear localization of the androgen receptor (AR) is necessary for its activation as a transcription factor. Defining the mechanisms regulating AR nuclear localization in androgen-sensitive cells and how these mechanisms are dysregulated in castration-resistant prostate cancer (CRPC) cells is fundamentally important and clinically relevant. According to the classical model of AR intracellular trafficking, androgens induce AR nuclear import and androgen withdrawal causes AR nuclear export. The present study has led to an updated model that AR could be imported in the absence of androgens, ubiquitinated, and degraded in the nucleus. Androgen withdrawal caused nuclear AR degradation, but not export. In comparison with their parental androgen-sensitive LNCaP prostate cancer cells, castration-resistant C4-2 cells exhibited reduced nuclear AR polyubiquitination and increased nuclear AR level. We previously identified 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (CPPI) in a high-throughput screen for its inhibition of androgen-independent AR nuclear localization in CRPC cells. The current study shows that CPPI is a competitive AR antagonist capable of enhancing AR interaction with its E3 ligase MDM2 and degradation of AR in the nuclei of CRPC cells. Also, CPPI blocked androgen-independent AR nuclear import. Overall, these findings suggest the feasibility of targeting androgen-independent AR nuclear import and stabilization, two necessary steps leading to AR nuclear localization and activation in CRPC cells, with small molecule inhibitors.

Cepstral analysis for baseline-insensitive absorption spectroscopy using light sources with pronounced intensity variations.

This paper presents a data-processing technique that improves the accuracy and precision of absorption-spectroscopy measurements by isolating the molecular absorbance signal from errors in the baseline light intensity (Io) using cepstral analysis. Recently, cepstral analysis has been used with traditional absorption spectrometers to create a modified form of the time-domain molecular free-induction decay (m-FID) signal, which can be analyzed independently from Io. However, independent analysis of the molecular signature is not possible when the baseline intensity and molecular response do not separate well in the time domain, which is typical when using injection-current-tuned lasers [e.g., tunable diode and quantum cascade lasers (QCLs)] and other light sources with pronounced intensity tuning. In contrast, the method presented here is applicable to virtually all light sources since it determines gas properties by least-squares fitting a simulated m-FID signal (comprising an estimated Io and simulated absorbance spectrum) to the measured m-FID signal in the time domain. This method is insensitive to errors in the estimated Io, which vary slowly with optical frequency and, therefore, decay rapidly in the time domain. The benefits provided by this method are demonstrated via scanned-wavelength direct-absorption-spectroscopy measurements acquired with a distributed-feedback (DFB) QCL. The wavelength of a DFB QCL was scanned across the CO P(0,20) and P(1,14) absorption transitions at 1 kHz to measure the gas temperature and concentration of CO. Measurements were acquired in a gas cell and in a laminar ethylene-air diffusion flame at 1 atm. The measured spectra were processed using the new m-FID-based method and two traditional methods, which rely on inferring (instead of rejecting) the baseline error within the spectral-fitting routine. The m-FID-based method demonstrated superior accuracy in all cases and a measurement precision that was ≈1.5 to 10 times smaller than that provided using traditional methods.

Baseline-free quantitative absorption spectroscopy based on cepstral analysis.

The accuracy of quantitative absorption spectroscopy depends on correctly distinguishing molecular absorption signatures in a measured transmission spectrum from the varying intensity or 'baseline' of the light source. Baseline correction becomes particularly difficult when the measurement involves complex, broadly absorbing molecules or non-ideal transmission effects such as etalons. We demonstrate a technique that eliminates the need to account for the laser intensity in absorption spectroscopy by converting the measured transmission spectrum of a gas sample to a modified form of the time-domain molecular free induction decay (m-FID) using a cepstral analysis approach developed for audio signal processing. Much of the m-FID signal is temporally separated from and independent of the source intensity, and this portion can be fit directly with a model to determine sample gas properties without correcting for the light source intensity. We validate the new approach in several complex absorption spectroscopy scenarios and discuss its limitations. The technique is applicable to spectra obtained with any absorption spectrometer and provides a fast and accurate approach for analyzing complex spectra.

Broadband dual-frequency comb spectroscopy in a rapid compression machine.

We demonstrate fiber mode-locked dual-frequency comb spectroscopy for broadband, high-resolution measurements in a rapid compression machine (RCM). We apply an apodization technique to improve the short-term signal-to-noise-ratio (SNR), which enables broadband spectroscopy at combustion-relevant timescales. We measure the absorption on 24345 individual wavelength elements (comb teeth) between 5967 and 6133 cm-1 at 704 µs time resolution during a 12 ms compression of a CH4-N2 mixture. We discuss the effect of the apodization technique on the absorption spectra, and apply an identical effect to the spectral model during fitting to recover the mixture temperature. The fitted temperature is compared against an adiabatic model, and found to be in good agreement with expected trends. This work demonstrates the potential of DCS to be used as an in situ diagnostic tool for broadband, high-resolution measurements in engine-like environments.

Spectrally-broad coherent anti-Stokes Raman scattering hyper-microscopy utilizing a Stokes supercontinuum pumped at 800 nm.

We demonstrate spectral-focusing based coherent anti-Stokes Raman scattering (SF-CARS) hyper-microscopy capable of probing vibrational frequencies from 630 cm-1 to 3250 cm-1 using a single Ti:Sapphire femtosecond laser operating at 800 nm, and a commercially-available supercontinuum-generating fibre module. A broad Stokes supercontinuum with significant spectral power at wavelengths between 800 nm and 940 nm is generated by power tuning the fibre module using atypically long and/or chirped ~200 fs pump pulses, allowing convenient access to lower vibrational frequencies in the fingerprint spectral region. This work significantly reduces the instrumental and technical requirements for multimodal CARS microscopy, while expanding the spectral capabilities of an established approach to SF-CARS.

Idiopathic eruptive macular pigmentation: a case of 21 years' duration.

Idiopathic eruptive macular pigmentation is a rare condition characterized by asymptomatic pigmented macules involving the neck, trunk, and proximal portions of the extremities. Age at onset usually varies from 1 to 20 years. The lesions usually appear abruptly and remit spontaneously over months to years. An unusual case of a 24-year-old woman with idiopathic eruptive macular pigmentation lasting 21 years was characterized by several periods of spontaneous resolution followed by recurrences.