Search

Background: Many studies have documented the effect of reducing spectral information for speech perception in listeners with normal hearing and hearing impairment. While it is understood that more spectral bands are needed for unilateral cochlear implant listeners to perform well on more challenging listening tasks such as speech perception in noise, it is unclear how reducing the number of spectral bands or electrodes in cochlear implants influences the ability to localize sound or understand speech with spatially separate noise sources. Purpose: The purpose of this study was to measure the effect of reducing the number of electrodes for patients with bilateral cochlear implants on spatial hearing tasks. Research Design: Performance on spatial hearing tasks was examined as the number of bilateral electrodes in the speech processor was deactivated equally across ears and the full frequency spectrum was reallocated to a reduced number of active electrodes. Program parameters (i.e., pulse width, stimulation rate) were held constant among the programs and set identically between the right and left cochlear implants so that only the number of electrodes varied. Study Sample: Nine subjects had used bilateral Nucleus or Advanced Bionics cochlear implants for at least 12mo prior to beginning the study. Only those subjects with full insertion of the electrode arrays with all electrodes active in both ears were eligible to participate. Data Collection and Analysis: Two test measures were utilized to evaluate the effect of reducing the number of electrodes, including a speech-perception-in-noise test with spatially separated sources and a sound source localization test. Results: Reducing the number of electrodes had different effects across individuals. Three patterns emerged: (1) no effect on localization (two of nine subjects), (2) at least two to four bilateral electrodes were required for maximal performance (five of nine subjects), and (3) performance gradually decreased across conditions as electrode number was reduced (two of nine subjects). For the test of speech perception in spatially separated noise, performance was affected as the number of electrodes was reduced for all subjects. Two categories of performance were found: (1) at least three or four bilateral electrodes were needed for maximum performance (five of seven subjects) and (2) as the number of electrodes were reduced, performance gradually decreased across conditions (two of seven subjects). Conclusion: Large individual differences exist in determining maximum performance using bilateral electrodes for localization and speech perception in noise. For some bilateral cochlear implant users, as few as three to four electrodes can be used to obtain maximal performance on localization and speech-in-noise tests. However, other listeners show a gradual decrement in performance on both tasks when the number of electrodes is reduced. [ABSTRACT FROM AUTHOR]

Evidence-based practice (EBP) has been widely embraced in many health-care fields as a way of maintaining currency of knowledge and state-of-the-art treatment recommendations in an age of information abundance and rapid scientific progress. Although the principles of EBP are slowly entering the specialties of communication disorders, they are not well known or extensively employed as yet. In this article, the rationale for EBP is presented and differences between EBP and traditional practice are highlighted. The five-step process of EBP is described: defining the problem, searching for evidence, critically appraising the evidence, formulating a recommendation, and assessing the outcome. Critical appraisal calls for determination of the validity, clinical significance, and applicability of evidence. Each of these topics is explored with emphasis placed on the application of EBP to hearing rehabilitation. Finally some suggestions are offered for researchers and practitioners to facilitate a transition to EBP in amplification provision. [ABSTRACT FROM AUTHOR]

This paper provides an overview of the measurement of hearing aid fitting outcomes in real life using self-report methods. Three topics are addressed: (1) why we should measure real-life outcomes; (2) seven different types of self-report outcome data; and (3) issues to consider in self-report outcome measurement. It is stressed that self-report data provide a unique view of the way that clients function and feel in their daily lives with regard to their hearing health. Self-report outcome data are multidimensional, and the different domains are only moderately correlated. When these types of data are gathered, it is essential to control relevant variables to safeguard validity and reliability. [ABSTRACT FROM AUTHOR]

AbstractHormones mediate sexual dimorphism by regulating sex-specific patterns of gene expression, but it is unclear how much of this regulation involves sex-specific hormone levels versus sex-specific transcriptomic responses to the same hormonal signal. Moreover, transcriptomic responses to hormones can evolve, but the extent to which hormonal pleiotropy in gene regulation is conserved across closely related species is not well understood. We addressed these issues by elevating testosterone levels in juvenile females and males of three Sceloporus lizard species before sexual divergence in circulating testosterone and then characterizing transcriptomic responses in the liver. In each species, more genes were responsive to testosterone in males than in females, suggesting that early developmental processes prime sex-specific transcriptomic responses to testosterone later in life. However, overall transcriptomic responses to testosterone were concordant between sexes, with no genes exhibiting sex-by-treatment interactions. By contrast, hundreds of genes exhibited species-by-treatment interactions, particularly when comparing distantly related species with different patterns of sexual dimorphism, suggesting evolutionary lability in gene regulation by testosterone. Collectively, our results indicate that early organizational effects may lead to sex-specific differences in the magnitude, but not the direction, of transcriptomic responses to testosterone and that the hormone-genome interface accrues regulatory changes over evolutionary time.

A comprehensive understanding of when and how 5f orbitals participate in complex chemical bonding is important for a variety of applications. The actinides are unique in that they possess 5f orbitals and can access high oxidation states, which make them attractive for use in catalysis. Fundamental studies of actinide-ligand interactions offer a mechanism to examine the activation of the 5f orbitals so that the selectivity of 5f orbitals can be assessed. A previous study examined the reaction of Pu + + CO 2 and determined that the reaction efficiency is restricted by a barrier, namely, promotion from the Pu + ground-state configuration, 5f 6 7s, to a reactive-state configuration, 5f 5 6d 2 . The present study illustrates the benefit of activation of Pu's 5f orbitals when studying the reaction of Pu + + NO. In this reaction, PuO + forms in an exothermic, barrierless process. The 5f orbitals can and do participate in forming a linear intermediate, [N-Pu-O] + , and this drives the exothermic reaction. Understanding the conditions under which 5f orbitals are active in chemical bonding is the key to exploiting the actinides' selective catalytic capabilities.

Batborne henipaviruses, such as Nipah and Hendra viruses, represent a major threat to global health due to their propensity for spillover, severe pathogenicity, and high mortality rate in human hosts. Coupled with the absence of approved vaccines or therapeutics, work with the prototypical species and uncharacterized, emergent species is restricted to high biocontainment facilities. There is a scarcity of such specialized spaces for research, and often, the scope and capacity of research, which can be conducted at BSL-4, is limited. Therefore, there is a pressing need for innovative life-cycle modeling systems to enable comprehensive research within lower biocontainment settings. This work showcases tetracistronic, transcription, and replication-competent minigenomes for the Nipah, Hendra, and Cedar viruses, which encode viral proteins facilitating budding, fusion, and receptor binding. We validate the functionality of all encoded viral proteins and demonstrate a variety of applications to interrogate the viral life cycle. Notably, we found that the Cedar virus replicase exhibits remarkable promiscuity, efficiently driving replication and transcription of minigenomes from all tested henipaviruses. We also apply this technology to Ghana virus (GhV), an emergent species that has so far not been isolated in culture. We demonstrate that the reported sequence of GhV is incomplete, but that this missing sequence can be substituted with analogous sequences from other henipaviruses. The use of our GhV system establishes the functionality of the GhV replicase and identifies two antivirals that are highly efficacious against the GhV polymerase., Importance: Henipaviruses are recognized as significant global health threats due to their high mortality rates and lack of effective vaccines or therapeutics. Due to the requirement for high biocontainment facilities, the scope of research which may be conducted on henipaviruses is limited. To address this challenge, we developed innovative tetracistronic, transcription, and replication-competent minigenomes. We demonstrate that these systems replicate key aspects of the viral life cycle, such as budding, fusion, and receptor binding, and are safe for use in lower biocontainment settings. Importantly, the application of this system to the Ghana virus revealed that its known sequence is incomplete; however, substituting the missing sequences with those from other henipaviruses allowed us to overcome this challenge. We demonstrate that the Ghana virus replicative machinery is functional and can identify two orally efficacious antivirals effective against it. Our research offers a versatile system for life-cycle modeling of highly pathogenic henipaviruses at low biocontainment., Competing Interests: The authors declare no conflict of interest.

Interference removal in inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) is strongly dependent on the gas selected for use within the collision/reaction cell. There has been little investigation on the effects that reaction gas impurities may have on the resulting spectra. The reactivity of 60 elements was evaluated using nitric oxide (NO 99.5%) with and without a gas purifier to reduce H 2 O impurities to <100 pptV. Experiments were performed using V, Ce, Tl and Th to investigate the effects of purified NO at various flowrates (0.22-1.49 mL min -1 ). Purified NO was shown to significantly mitigate oxy-hydride interferences, improve total ion sensitivity (notable at high gas flows), and shift product distributions advantageously. The reduction in oxy-hydride species results in a product distribution favoring the major expected products, where signals were shown to increase by an order of magnitude. Reduced background and increased signal for the major expected products provides avenues for improving various analytical applications of ICP-MS/MS.

Small-molecule antivirals can be used as chemical probes to stabilize transitory conformational stages of viral target proteins, facilitating structural analyses. Here, we evaluate allosteric pneumo- and paramyxovirus polymerase inhibitors that have the potential to serve as chemical probes and aid the structural characterization of short-lived intermediate conformations of the polymerase complex. Of multiple inhibitor classes evaluated, we discuss in-depth distinct scaffolds that were selected based on well-understood structure-activity relationships, insight into resistance profiles, biochemical characterization of the mechanism of action, and photoaffinity-based target mapping. Each class is thought to block structural rearrangements of polymerase domains albeit target sites and docking poses are distinct. This review highlights validated druggable targets in the paramyxo- and pneumovirus polymerase proteins and discusses discrete structural stages of the polymerase complexes required for bioactivity., Competing Interests: R.M.C. and R.K.P. are co-inventors on patent filings covering composition and method of use of GHP-88309 and its analogs for antiviral therapy. R.K.P. is a co-inventor on patent filings covering composition and method of use of AVG-233 and ERDRP-0519 and their analogs for antiviral therapy. This paper could affect their personal financial status. R.K.P. reports contract testing from Enanta Pharmaceuticals, Atea Pharmaceuticals, and Icosagen Biosciences and research support from Gilead Sciences, outside of the described work.

The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission., (© 2024. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread in the population. We recently reported the production of bovine colostrum-derived antibodies that can neutralize the virus. These have been formulated into a nasal spray. The immunoglobulin preparation is capable of blocking interaction of the trimeric spike protein (Tri S) of SARS-CoV-2 with the cellular receptor angiotensin-converting enzyme 2 (ACE2), entry of a pseudovirus carrying the Tri S into ACE2 over-expressing human embryonic kidney (HEK) cells, and entry of the virus into live Vero E6 cells. Using an ELISA assay, we demonstrate here that this holds true for different SARS-CoV-2 variants of concern. Using the ferret transmission model, we show that the nasal spray formulation of anti-SARS-CoV-2 immunoglobulins efficiently blocks transmission of SARS-CoV-2 from infected to uninfected ferrets. The results indicate that the use of the nasal spray in humans can add an effective additional layer of protection against the virus, and might be applicable for other viruses of the upper respiratory tract., Competing Interests: The drug product used in this study is marketed and sold in Estonia since 2021. This study was supported by the funding from Enterprise Estonia grant number 2014-2020.4.02.21-0317. The use of bovine colostrum as a prophylactic agent against SARS-CoV-2 has been patented (US patent application no 63/160,833). Work at Georgia State University for this study was carried out under a contract agreement from Icosagen. R.K.P. reports research contract testing from Enanta Pharmaceuticals and Atea Pharmaceuticals, and research support from Gilead Sciences, outside of the described work. R.M.C. reports consulting for Merck & Co, outside of the described work., (© 2024 The Authors.)

Background: Preoperative opioid users experience worse outcomes and higher complication rates compared to opioid-naïve patients following shoulder arthroplasty. This study evaluates the effects of socioeconomic status, as measured by the Distressed Communities Index (DCI), on pre- and postoperative opioid use and its influence on clinical outcomes such as readmission and revision surgery., Methods: A retrospective review of patients who underwent primary shoulder arthroplasty (Current Procedural Terminology code 23472) from 2014 to 2022 at a single academic institution was performed. Exclusion criteria included arthroplasty for fracture, active malignancy, and revision arthroplasty. Demographics, Charlson Comorbidity Index, DCI, and clinical outcomes including 90-day readmission and revision surgery were collected. Patients were classified according to the DCI score of their zip code. Using the Prescription Drug Monitoring Program database, patient pre- and postoperative opioid use in morphine milligram equivalents was gathered., Results: Individuals from distressed communities used more opioids within 90 days preoperatively compared to patients from prosperous, comfortable, mid-tier, and at-risk populations, respectively. Patients from distressed communities also used significantly more opioids within 90 days postoperatively compared with prosperous, comfortable, and mid-tier, respectively. Of patients from distressed communities, 35.1% developed prolonged opioid use (filling prescriptions >30 days after surgery), significantly more than all other cohorts. Among all patients, 3.5% were readmitted within 90 days and were more likely to be prolonged opioid users (38.9 vs. 21.3%, P < .001). Similarly, 1.5% of patients underwent revision surgery. Those who underwent revision were significantly more likely to be prolonged opioid users (38.2 vs. 21.7%, P = .002)., Conclusions: Shoulder arthroplasty patients from distressed communities use more opioids within 90 days before and after their surgery and are more likely to become prolonged opioid users, placing them at risk for readmission and revision surgery. Identifying patients at an increased risk for excess opioid use is essential to employ appropriate strategies that minimize the detrimental effects of prolonged use following surgery., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Proximal humerus bone loss in shoulder arthroplasty is a difficult problem with limited treatment options. It most commonly occurs in the setting of a previously failed shoulder arthroplasty; however, it is occasionally encountered in cases of primary shoulder arthroplasty. Reconstruction of the proximal humerus is essential for soft tissue tension for implant stability and maximizing function. The purpose of this study was to analyze the clinical and functional outcomes of the allograft prosthetic composite (APC) technique for the management of proximal humeral bone loss in shoulder arthroplasty., Methods: A retrospective review was performed of all patients who underwent primary or revision shoulder arthroplasty using an APC technique with a reverse shoulder arthroplasty prosthesis for the management of proximal humerus bone loss. Data collected included demographic variables, previous shoulder surgeries, indication for APC, type of allograft utilized, fixation technique, and reoperation and revision rates. Patients were contacted by phone and/or email survey to obtain the latest patient-reported functional outcome scores., Results: We identified 14 patients who underwent shoulder arthroplasty using the APC technique with a reverse shoulder arthroplasty prosthesis. One (7.1%) was performed as a primary arthroplasty, and 13 (92.9%) were performed as revision arthroplasties. The indications for APC were instability (21.4%), periprosthetic fracture (21.4%), periprosthetic joint infection (14.3%), humeral component loosening (14.3%), rotator cuff failure (14.3%), fracture sequelae (7.1%), and failed hemiarthroplasty (7.1%). In terms of allograft type, 10 (71.4%) were performed with proximal femur allograft and 4 (28.6%) with proximal humerus allograft. There were 6 patients (42.9%) who sustained postoperative complications, 5 patients (35.7%) had instability, and 1 (7.1%) patient had postoperative wound drainage. All patients with a complication required a revision arthroplasty., Conclusion: The APC technique used to address proximal humerus bone loss in shoulder arthroplasty has a high complication rate with fair patient-reported functional outcome scores. Most of the postoperative complications and reoperations are related to implant instability., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

All eukaryotes share a common ancestor from roughly 1.5 - 1.8 billion years ago, a single-celled, swimming microbe known as LECA, the Last Eukaryotic Common Ancestor. Nearly half of the genes in modern eukaryotes were present in LECA, and many current genetic diseases and traits stem from these ancient molecular systems. To better understand these systems, we compared genes across modern organisms and identified a core set of 10,092 shared protein-coding gene families likely present in LECA, a quarter of which are uncharacterized. We then integrated >26,000 mass spectrometry proteomics analyses from 31 species to infer how these proteins interact in higher-order complexes. The resulting interactome describes the biochemical organization of LECA, revealing both known and new assemblies. We analyzed these ancient protein interactions to find new human gene-disease relationships for bone density and congenital birth defects, demonstrating the value of ancestral protein interactions for guiding functional genetics today.

The effect of ion kinetic energy on gas phase ion reactivity with ICP-MS/MS was investigated in order to explore tuning strategies for interference removal. The collision/reaction gases CO 2 , N 2 O and O 2 were used to observe the ion product distribution for 48 elements using an Agilent tandem ICP-MS (ICP-MS/MS) as a function of reaction gas flow rate (pressure) and ion kinetic energy. The kinetic energy of the incident ion was varied by adjusting the octopole bias (V oct ). The three gases all form oxides (MO + ) as the primary product with differing reaction enthalpies that result in distinct differences in the ion energies required for reaction with product ion distributions that vary with Voct. Consequently, by varying the ion kinetic energy (i.e., V oct ), differences in interference reactivity can be used to achieve maximum separation. Three practical application examples were reported to demonstrate how the ion kinetic energy can be varied to achieve the ideal ion product distribution for interference resolution: CO 2 for the removal of 238 U in Pu analyses, CO 2 for the removal of 40 Ar 16 O vs. 56 Fe, and O 2 for the removal of Sm in Eu analyses, analogous to Pu/Am. The results demonstrate how the starting ion energy defined by V oct is an important factor to fully leverage the utility of any given reaction gas to remove interferences in the mass spectrum using ICP-MS/MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Online and real-time analysis of a chemical process is a major analytical challenge that can drastically change the way the chemical industry or chemical research operates. With in situ analyses, a new and powerful understanding of chemistry can be gained; however, building robust tools for long-term monitoring faces many challenges, including compensating for instrument drift, instrument replacement, and sensor or probe replacement. Accounting for these changes by recollecting calibration data and rebuilding quantification models can be costly and time-consuming. Here, methods to overcome these challenges are demonstrated with an application of Raman spectroscopy to monitoring hydrogen isotopes with varied speciation within dynamic gas streams. Specifically, chemical data science tools such as chemometric modeling are leveraged along with several examples of calibration transfer approaches. Furthermore, the optimization of instrument and sensor cell parameters for targeted gas-phase analyses is discussed. While the particular focus on hydrogen is highly beneficial within the nuclear energy sector, mechanisms built and demonstrated here are widely applicable to optical spectroscopy monitoring in numerous other chemical systems that can be leveraged in other processes.

Understanding the reactivity of metal cations with various reaction gases in inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) is important to determine the best gas to use for a given analyte/interference pair. In this study, nitric oxide (NO) was investigated as the reaction gas following previous experimental designs. The reactions with 50 elements were investigated to examine periodic trends in reactivity, validate theoretical modeling of reaction enthalpies as a method to screen reactant gases, and provide a baseline data set for potential in-line gas separation methods. ICP-MS/MS studies involving actinides are typically limited to Th, U, and Pu, with analyses of Np and Am rarely reported in the literature. To date, only two previous methods have investigated the use of NO in ICP-MS/MS analyses. To showcase the utility of NO, a method was developed to measure 239 Pu in the presence of environmental matrix constituent and other actinides, like what could be expected from postdetonation debris, with no chemical separation prior to analysis. 239 Pu + was reacted to form 239 Pu 16 O + , eliminating interferences derived from the sample matrix by measuring the 239 Pu + intensity at m / z = 255 ( 239 Pu 16 O + ). To validate NO for 238 U 1 H + interference removal in environmental matrices, standard reference materials were diluted to 1 mg/g of solution and spiked to 0.05 pg/g of 239 Pu and 1 μg/g 238 U (Pu/U = 5 × 10 -8 ). Measured 239 Pu concentrations were within 6% of the spiked value. These results demonstrate that reliable 239 Pu measurements can be made at levels relevant to nuclear forensics without the need for extensive chemical matrix separation prior to analysis.

Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease., (© 2024. The Author(s).)

Pre-existing or rapidly emerging resistance of influenza viruses to approved antivirals makes the development of novel therapeutics to mitigate seasonal influenza and improve preparedness against future influenza pandemics an urgent priority. We have recently identified the chain-terminating broad-spectrum nucleoside analog clinical candidate 4'-fluorouridine (4'-FlU) and demonstrated oral efficacy against seasonal, pandemic, and highly pathogenic avian influenza viruses in the mouse and ferret model. Here, we have resistance-profiled 4'-FlU against a pandemic A/CA/07/2009 (H1N1) (CA09). In vitro viral adaptation yielded six independently generated escape lineages with distinct mutations that mediated moderate resistance to 4'-FlU in the genetically controlled background of recombinant CA09 (recCA09). Mutations adhered to three distinct structural clusters that are all predicted to affect the geometry of the active site of the viral RNA-dependent RNA polymerase (RdRP) complex for phosphodiester bond formation. Escape could be achieved through an individual causal mutation, a combination of mutations acting additively, or mutations functioning synergistically. Fitness of all resistant variants was impaired in cell culture, and all were attenuated in the mouse model. Oral 4'-FlU administered at lowest-efficacious (2 mg/kg) or elevated (10 mg/kg) dose overcame moderate resistance when mice were inoculated with 10 LD50 units of parental or resistant recCA09, demonstrated by significantly reduced virus load and complete survival. In the ferret model, invasion of the lower respiratory tract by variants representing four adaptation lineages was impaired. Resistant variants were either transmission-incompetent, or spread to untreated sentinels was fully blocked by therapeutic treatment of source animals with 4'-FlU., Competing Interests: MGN is a coinventor on patent WO 2019/1736002 covering composition of matter and use of 4’-FlU (EIDD-2749) and its analogs as an antiviral treatment. This study could affect his personal financial status. RKP reports contract testing from Enanta Pharmaceuticals and Atea Pharmaceuticals, and research support from Gilead Sciences, outside of the described work. ALG reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen and Hologic, research support from Gilead, outside of the described work. All other authors declare that they have no competing interests., (Copyright: © 2024 Lieber et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In non-avian reptiles, the onset of sexual dimorphism of the major structures of the urogenital tract varies temporally relative to gonadal differentiation, more so than in other amniote lineages. In the current study, we used tonic-release implants to investigate the effects of exogenous testosterone (T) on postnatal development of the urogenital tract in juvenile Eastern Fence Lizards (Sceloporus undulatus) to better understand the mechanisms underlying the ontogeny of sexual differentiation in reptiles. We examined gonads, mesonephric kidneys and ducts (male reproductive tract primordia), paramesonephric ducts (oviduct primordia), sexual segments of the kidneys (SSKs), and hemiphalluses to determine which structures were sexually dimorphic independent of T treatment and which structures exhibited sexually dimorphic responses to T. To better understand tissue-level responsiveness to T treatment, we also characterized androgen receptor (AR) expression by immunohistochemistry. At approximately 4 months after hatching in control animals, gonads were well differentiated but quiescent; paramesonephric ducts had fully degenerated in males; mesonephric kidneys, mesonephric ducts, and SSKs remained sexually undifferentiated; and hemiphalluses could not be everted in either sex. Exogenous T caused enlargement, regionalization, and secretory activity of the mesonephric ducts and SSKs in both sexes; enlargement and regionalization of the oviducts in females; and enlargement of male hemipenes. The most responsive tissues exhibited moderate but diffuse staining for AR in control lizards and intense nuclear staining in T-treated lizards, suggestive of autoregulation of AR. The similarity between sexes in the responsiveness of the mesonephric ducts and SSK to T indicates an absence of sexually dimorphic organizational effects in these structures prior to treatment, which was initiated approximately 2 months after hatching. In contrast, the sex-specific responses in oviducts and hemipenes indicate that significant organization and/or differentiation had taken place prior to treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Morbilliviruses such as measles virus (MeV) are responsible for major morbidity and mortality worldwide, despite the availability of an effective vaccine and global vaccination campaigns. MeV belongs to the mononegavirus order of viral pathogens that store their genetic information in non-segmented negative polarity RNA genomes. Genome replication and viral gene expression are carried out by a virus-encoded RNA-dependent RNA polymerase (RdRP) complex that has no immediate host cell analog. To better understand the organization and regulation of the viral RdRP and mechanistically characterize antiviral candidates, biochemical RdRP assays have been developed that employ purified recombinant polymerase complexes and synthetic RNA templates to monitor the initiation of RNA synthesis and RNA elongation in vitro. In this article, we will discuss strategies for the efficient expression and preparation of mononegavirus polymerase complexes, provide detailed protocols for the execution and optimization of RdRP assays, evaluate alternative options for the choice of template and detection system, and describe the application of the assay for the characterization of inhibitor candidates. Although MeV RdRP assays are the focus of this article, the general strategies and experimental approaches are readily transferable to related viruses in the mononegavirus order., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

f-Block chemistry offers an opportunity to test current knowledge of chemical reactivity. The energy dependence of lanthanide cation (Ln + = Ce + , Pr + , Nd + -Eu + ) and actinide cation (An + = Th + , U + -Am + ) oxidation reactions by CO 2 , was observed by inductively coupled plasma tandem mass spectrometry. This reaction is commonly spin-unallowed because the neutral reactant (CO 2 , 1 Σ+g) and product (CO, 1 Σ + ) require the metal and metal oxide cations to have the same spin state. Correlation of the promotion energy ( E p ) to the first state with two free d-electrons with the reaction efficiency indicates that spin conservation is not a primary factor in the reaction rate. The E p likely influences the reaction rate by partially setting the crossing between the ground and reactive states. Comparison of Ln + and An + congener reactivity indicates that the 5f-orbitals play a small role in the An + reactions.

Phenotypic sexual dimorphism often involves the hormonal regulation of sex-biased expression for underlying genes. However, it is generally unknown whether the evolution of hormonally mediated sexual dimorphism occurs through upstream changes in tissue sensitivity to hormone signals, downstream changes in responsiveness of target genes, or both. Here, we use comparative transcriptomics to explore these possibilities in 2 species of Sceloporus lizards exhibiting different patterns of sexual dichromatism. Sexually dimorphic S. undulatus develops blue and black ventral coloration in response to testosterone, while sexually monomorphic S. virgatus does not, despite exhibiting similar sex differences in circulating testosterone levels. We administered testosterone implants to juveniles of each species and used RNAseq to quantify gene expression in ventral skin. Transcriptome-wide responses to testosterone were stronger in S. undulatus than in S. virgatus, suggesting species differences in tissue sensitivity to this hormone signal. Species differences in the expression of genes for androgen metabolism and sex hormone-binding globulin were consistent with this idea, but expression of the androgen receptor gene was higher in S. virgatus, complicating this interpretation. Downstream of androgen signaling, we found clear species differences in hormonal responsiveness of genes related to melanin synthesis, which were upregulated by testosterone in S. undulatus, but not in S. virgatus. Collectively, our results indicate that hormonal regulation of melanin synthesis pathways contributes to the development of sexual dimorphism in S. undulatus, and that changes in the hormonal responsiveness of these genes in S. virgatus contribute to the evolutionary loss of ventral coloration., (© The Author(s) 2023. Published by Oxford University Press on behalf of The American Genetic Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The SARS-CoV-2 main protease (M pro ) has been proven to be a highly effective target for therapeutic intervention, yet only one drug currently holds FDA approval status for this target. We were inspired by a series of publications emanating from the Jorgensen and Anderson groups describing the design of potent, non-peptidic, competitive SARS-CoV-2 M pro inhibitors, and we saw an opportunity to make several design modifications to improve the overall pharmacokinetic profile of these compounds without losing potency. To this end, we created a focused virtual library using reaction-based enumeration tools in the Schrödinger suite. These compounds were docked into the M pro active site and subsequently prioritized for synthesis based upon relative binding affinity values calculated by FEP+. Fourteen compounds were selected, synthesized, and evaluated both biochemically and in cell culture. Several of the synthesized compounds proved to be potent, competitive M pro inhibitors with improved metabolic stability profiles., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Human activities are rapidly changing ecosystems around the world. These changes have widespread implications for the preservation of biodiversity, agricultural productivity, prevalence of zoonotic diseases, and sociopolitical conflict. To understand and improve the predictive capacity for these and other biological phenomena, some scientists are now relying on observatory networks, which are often composed of systems of sensors, teams of field researchers, and databases of abiotic and biotic measurements across multiple temporal and spatial scales. One well-known example is NEON, the US-based National Ecological Observatory Network. Although NEON and similar networks have informed studies of population, community, and ecosystem ecology for years, they have been minimally used by organismal biologists. NEON provides organismal biologists, in particular those interested in NEON's focal taxa, with an unprecedented opportunity to study phenomena such as range expansions, disease epidemics, invasive species colonization, macrophysiology, and other biological processes that fundamentally involve organismal variation. Here, we use NEON as an exemplar of the promise of observatory networks for understanding the causes and consequences of morphological, behavioral, molecular, and physiological variation among individual organisms., Competing Interests: All authors declare that they have no conflict of interest, although one coauthor (Dr. S.H. Paull) is employed by Battelle Ecology, which manages NEON., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Therapeutic options against SARS-CoV-2 are underutilized. Two oral drugs, molnupiravir and paxlovid (nirmatrelvir/ritonavir), have received emergency use authorization. Initial trials suggested greater efficacy of paxlovid, but recent studies indicated comparable potency in older adults. Here, we compare both drugs in two animal models; the Roborovski dwarf hamster model for severe COVID-19-like lung infection and the ferret SARS-CoV-2 transmission model. Dwarf hamsters treated with either drug survive VOC omicron infection with equivalent lung titer reduction. Viral RNA copies in the upper respiratory tract of female ferrets receiving 1.25 mg/kg molnupiravir twice-daily are not significantly reduced, but infectious titers are lowered by >2 log orders and direct-contact transmission is stopped. Female ferrets dosed with 20 or 100 mg/kg nirmatrelvir/ritonavir twice-daily show 1-2 log order reduction of viral RNA copies and infectious titers, which correlates with low nirmatrelvir exposure in nasal turbinates. Virus replication resurges towards nirmatrelvir/ritonavir treatment end and virus transmits efficiently (20 mg/kg group) or partially (100 mg/kg group). Prophylactic treatment with 20 mg/kg nirmatrelvir/ritonavir does not prevent spread from infected ferrets, but prophylactic 5 mg/kg molnupiravir or 100 mg/kg nirmatrelvir/ritonavir block productive transmission. These data confirm reports of similar efficacy in older adults and inform on possible epidemiologic benefit of antiviral treatment., (© 2023. Springer Nature Limited.)