bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a Bulking Agent on the Protein:Carbohydrate Ratio, Bioconversion, and Cost-effectiveness of a Larval Diet for Anastrepha ludens (Diptera: Tephritidae)
Authors: Aceituno-Medina Marysol , Hernández Emilio , Rincón-Betancurt Olivia , García-Fajardo Luz Verónica , Diego-García Elia
Published: February 2022

Although the bulking agent is categorized as ‘inert’, it could modify protein bioavailability and nutritional quality. In this study, the main goal was to determine if the bulking agent modified the protein:carbohydrate (P:C) ratio and bioconversion from diet biomass to larval biomass of Anastrepha ludens. The diet was altered only by modifying the type of bulking agent (corncob powder, coconut fiber, carrot fiber, oatmeal) added without changing the composition and concentration of the other components in the formulation. This allowed reclassification of the food matrices according to P:C ratios of 1:30, 1:35, 1:64, and 1:93. A food matrix with a high P:C ratio promoted a high protein and carbohydrate content in the larval hemolymph and immediately influenced the life-history traits of the larva or delayed them in the adult. The present study indicated a positive relationship between the P:G+T (glucose+trehalose) ratio in the larval hemolymph and the P:C ratio in the larval diet. Our results highlight the importance of including the optimum and real P:C ratio in whole fresh larval diets, since considering only the theoretical concentration of the formulation is not enough to understand the variation in key life-history traits. In addition, the bioconversion index should be included as an indicator of the efficacy of larval diets for mass rearing insects. A diet with high cost-effectiveness should be evaluated by taking into account flying flies as the end product of the mass rearing process to enhance operational SIT programs.
Mating Competitiveness ofBactrocera dorsalis(Diptera: Tephritidae) Males From a Genetic Sexing Strain: Effects of Overflooding Ratio and Released Females
Authors: Shelly Todd E , Manoukis Nicholas C
Published: February 2022

The oriental fruit fly, Bactrocera dorsalis (Hendel), is a global pest that infests a range of fruit and vegetables. Males are attracted to methyl eugenol, and control is often achieved by the Male Annihilation Technique, where methyl eugenol + insecticide dispensers are deployed to eliminate males, preclude matings, and reduce population growth. The Sterile Insect Technique (SIT) has also been used to control B. dorsalis. The SIT involves the release of mass-reared, sterilized males to achieve matings with wild females, who then produce inviable eggs. Two key elements of SIT include the overflooding ratio achieved (sterile: wild males) and the strain type utilized, namely bisexual or genetically sexed (allowing male-only releases). Here, we describe the effects of these two factors on the mating competitiveness of a males from a genetic sexing strain of B. dorsalis, termed DTWP. Mating success was scored for DTWP versus wild males in field cages at ratios of 1:2, 1:1, 2:1, and 10:1 both when DTWP females were or were not concurrently released with DTWP males. Close correspondence was found between observed numbers of matings of particular male–female combinations and expected numbers based on the numbers of flies released of each sex and each strain. As a result, the proportion of total matings achieved by the DTWP across the eight treatments showed a corresponding increase with overflooding ratio. At a given ratio, DTWP males had a higher relative mating success when DTWP females were absent rather than present, although the reason for this was unclear.
Enhancement of antiproliferative potential of metformin against melanoma mice B16 cells using an optimized liposomal drug delivery system
Authors: Magdy Shrouk , Fathalla Zeinab , Alaaeldin Eman , Abdel-Aziz Rasha T A , Mansour Heba F
Published: February 2022

Objective

Metformin-loaded liposomes were optimized for enhanced antiproliferative activity against melanoma.

Methods

Box–Behnken design and response surface methodology were employed to optimize entrapment efficiency, ex-vivo permeation and vesicle size. The optimized formulation was prepared by both the lipid hydration method and the modified injection method for comparison. Different concentrations of Pluronic F127 were employed for modification. Selected Pluronic-modified formulation (lipid molar concentration 55 mmol, cholesterol 30% and drug loading 52.9 mg) was characterized for morphology, entrapment efficiency, permeation and vesicle size.

Results

The optimized formulation resulted in entrapment efficiency of 41.7 ± 0.01%, vesicle size of 1.405 ± 0.061 µm and percentage of permeation was 67 ± 5.5%. The improved cytotoxic effect of the selected formulation against melanoma mice B16 cell line compared with metformin solution was determined using MTT assay. Compared with the corresponding drug solution, the Pluronic-modified optimized liposomes displayed a highly efficient cytotoxic effect as evidenced by significant lowering in IC50 −887.3 ± 23.2 and 26.71 ± 0.69 μg/ml, respectively, P < 0.0001.

Conclusion

This study introduces an optimized liposomal formulation with enhanced cytotoxic effect against melanoma B16 cell line.
Research progress on the pharmacy of tetramethylpyrazine and its pharmacological activity in cardiovascular and cerebrovascular diseases
Authors: Zhang Yafang , He Linfeng , Ma Cheng , Wang Cheng , Zhou Honglin , Guo Chaocheng , Gong Lihong , Wan Yan , Peng Cheng , Li Yunxia
Published: February 2022

Objectives

The role and mechanism of tetramethylpyrazine (TMP) in cardio-cerebrovascular diseases (CCVDs), as well as the research of its new formulations are reviewed, which provides a new strategy for the clinical application of TMP.

Methods

We searched the databases including PubMed, Web of Science, Google Scholar and CNKI for relevant literature from 1991 to 2021 by searching for the keywords “TMP”, “ligustrazine”, “cardiovascular disease” and “nanoformulation”. The inclusion criteria are as follows: (1) the literature is an experimental article, (2) the article studies cardiovascular and cerebrovascular-related diseases and (3) the article also includes the pharmacy research of TMP. A total of 160 articles were screened.

Key findings

TMP has various pharmacological effects in the treatment of many CCVDs, such as atherosclerosis, myocardium, cerebral ischemia, reperfusion injury and hypertension. Its protective effects are mainly related to its anti-platelet activity, protection of endothelial cells, and anti-inflammation, anti-oxidant and anti-apoptotic effects. In addition to pharmacological activity studies, the information of the new formulations is also significant for the further development and utilization of TMP.

Conclusions

Above all, TMP can protect cardio-cerebro vessels, and preparing new formulations can improve its bioavailability, indicating that TMP has broad prospects in the treatment of CCVDs.
Bronchopleural fistula due to cavitary pneumonia after SARS-CoV-2 infection treated with open thoracostomy
Authors: Belyayev Leonid A , Foroushani Sophia M , Wiener Daniel C , Branch-Elliman Westyn , Marshall M Blair , Khalil Hassan A
Published: February 2022

Severe coronavirus disease of 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes substantial parenchymal damage in some patients. There is a paucity of literature describing the surgical management COVID-19 associated bronchopleural fistula after failure of medical therapy. We present the case of a 59-year-old woman with SARS-CoV-2 pneumonia, secondary bacterial pneumonia with bronchopleural fistula and radiographic and clinical evidence of disease refractory to medical therapy. After a course of culture-driven antimicrobial therapy and failure to improve following drainage with tube thoracostomy, she was treated successfully with Clagett open thoracostomy. After resolution of the bronchopleural fistula, the thoracostomy was closed and she was discharged home. In cases of severe COVID-19 complicated by bronchopleural fistula with parenchymal destruction, a tailored approach involving surgical management when indicated can lead to acceptable outcomes without significant morbidity.
Priming of camalexin accumulation in induced systemic resistance by beneficial bacteria against Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000
Authors: Nguyen Ngoc Huu , Trotel-Aziz Patricia , Villaume Sandra , Rabenoelina Fanja , Clément Christophe , Baillieul Fabienne , Aziz Aziz
Published: February 2022

Plants harbor various beneficial microbes that modulate their innate immunity, resulting in induced systemic resistance (ISR) against a broad range of pathogens. Camalexin is an integral part of Arabidopsis innate immunity, but the contribution of its biosynthesis in ISR is poorly investigated. We focused on camalexin accumulation primed by two beneficial bacteria, Pseudomonas fluorescens and Bacillus subtilis, and its role in ISR against Botrytis cinerea and Pseudomonas syringae Pst DC3000. Our data show that colonization of Arabidopsis thaliana roots by beneficial bacteria triggers ISR against both pathogens and primes plants for enhanced accumulation of camalexin and CYP71A12 transcript in leaf tissues. Pseudomonas fluorescens induced the most efficient ISR response against B. cinerea, while B. subtilis was more efficient against Pst DC3000. Analysis of cyp71a12 and pad3 mutants revealed that loss of camalexin synthesis affected ISR mediated by both bacteria against B. cinerea. CYP71A12 and PAD3 contributed significantly to the pathogen-triggered accumulation of camalexin, but PAD3 does not seem to contribute to ISR against Pst DC3000. This indicated a significant contribution of camalexin in ISR against B. cinerea, but not always against Pst DC3000. Experiments with Arabidopsis mutants compromised in different hormonal signaling pathways highlighted that B. subtilis stimulates similar signaling pathways upon infection with both pathogens, since salicylic acid (SA), but not jasmonic acid (JA) or ethylene, is required for ISR camalexin accumulation. However, P. fluorescens-induced ISR differs depending on the pathogen; both SA and JA are required for camalexin accumulation upon B. cinerea infection, while camalexin is not necessary for priming against Pst DC3000.
Adjustment Disorder in U.S. Service Members: Factors Associated With Early Separation
Authors: Morgan Maria A , O’Gallagher Kevin , Kelber Marija Spanovic , Garvey Wilson Abigail L , Belsher Bradley E , Evatt Daniel P
Published: February 2022

Introduction

Adjustment disorder (AD) is a time-delimited disorder characterized by excessive emotional distress or impaired functioning in response to an identifiable stressor. Although it is commonly diagnosed in mental health settings, its impact on occupational, social and other areas of functioning is not well understood. As a subthreshold disorder that is frequently diagnosed in conjunction with other physical and mental health disorders, the extent of its contribution to functional impairment may be obscured. During military service, research suggests AD is frequently diagnosed in early-service trainees. To help elucidate the relationship between AD and functional outcome, we explored 2 factors that may be associated with the rate of separation from service in U.S. active duty service members (SMs) with an AD diagnosis: previous mental health diagnoses and time in service when SMs receive an incident AD diagnosis (IADx).

Materials and Methods

Twenty-thousand SMs with an IADx were grouped by whether or not this was their first mental health diagnosis received in the military. To assess functional impairment, the 2 groups were compared on rate of separation. Those without prior diagnoses were then stratified into 5 groups based on length of time from military entrance to receipt of IADx and were further analyzed for separation rates. The Cox model was used to determine hazard ratios and create survival curves. The study was determined to be “not human subjects research.”

Results

Nearly half (46.4%) of SMs with an IADx previously had received a mental health diagnosis and had an increased risk of separation [hazard ratio = 1.25 (95% confidence interval: 1.207-1.286)]. Of SMs with IADx as their first diagnosis, 19.3% were diagnosed during the first 6 months of service and had the highest risk of separating [hazard ratio = 1.48 (1.381-1.589)], with a 60% probability of separating within 2 years of diagnosis. Those receiving it during the second 6 months of service (16.2%), second year (20.1%), or third year (18.2%) had approximately a 47% probability of separating within 2 years.

Conclusions

Previous mental health diagnoses and time in service when diagnosed appear to be important factors associated with functional impairment for SMs with AD. Nearly half of those with an IADx had previously received diagnoses for mood, anxiety, and other disorders and were at higher risk of separation following IADx. Our findings are based on diagnoses entered in electronic health records, so we cannot identify the nature of the stressor that precipitated AD. Nonetheless, early IADx predicted the fastest rate of separation, and it may be an opportune time for interventions to reduce its impact on functional outcomes.
Trapping of H ii regions in Population III star formation
Authors: Jaura Ondrej , Glover Simon C O , Wollenberg Katharina M J , Klessen Ralf S , Geen Sam , Haemmerlé Lionel
Published: February 2022

Radiative feedback from massive Population III (Pop III) stars in the form of ionizing and photodissociating photons is widely believed to play a central role in shutting off accretion on to these stars. Understanding whether and how this occurs is vital for predicting the final masses reached by these stars and the form of the Pop III stellar initial mass function. To help us better understand the impact of UV radiation from massive Pop III stars on the gas surrounding them, we carry out high-resolution simulations of the formation and early evolution of these stars, using the arepo moving-mesh code coupled with the innovative radiative transfer module sprai. Contrary to most previous results, we find that the ionizing radiation from these stars is trapped in the dense accretion disc surrounding them. Consequently, the inclusion of radiative feedback has no significant impact on either the number or the total mass of protostars formed during the 20 kyr period that we simulate. We show that the reason that we obtain qualitatively different results from previous studies of Pop III stellar feedback lies in how the radiation is injected into the simulation. H ii region trapping only occurs if the photons are injected on scales smaller than the local scale height of the accretion disc, a criterion not fulfilled in previous 3D simulations of this process. Finally, we speculate as to whether outflows driven by the magnetic field or by Lyman-α radiation pressure may be able to clear enough gas away from the star to allow the H ii region to escape from the disc.
High-throughput screening of cell-free riboswitches by fluorescence-activated droplet sorting
Authors: Tabuchi Takeshi , Yokobayashi Yohei
Published: February 2022

Cell-free systems that display complex functions without using living cells are emerging as new platforms to test our understanding of biological systems as well as for practical applications such as biosensors and biomanufacturing. Those that use cell-free protein synthesis (CFPS) systems to enable genetically programmed protein synthesis have relied on genetic regulatory components found or engineered in living cells. However, biological constraints such as cell permeability, metabolic stability, and toxicity of signaling molecules prevent development of cell-free devices using living cells even if cell-free systems are not subject to such constraints. Efforts to engineer regulatory components directly in CFPS systems thus far have been based on low-throughput experimental approaches, limiting the availability of basic components to build cell-free systems with diverse functions. Here, we report a high-throughput screening method to engineer cell-free riboswitches that respond to small molecules. Droplet-sorting of riboswitch variants in a CFPS system rapidly identified cell-free riboswitches that respond to compounds that are not amenable to bacterial screening methods. Finally, we used a histamine riboswitch to demonstrate chemical communication between cell-sized droplets.
Radiation dose to circumscribed brain regions and neurocognitive function in patients with meningioma
Authors: Sekely Angela , Tsang Derek S , Mabbott Donald , Kongkham Paul , Zadeh Gelareh , Zakzanis Konstantine K , Edelstein Kim
Published: February 2022

Background

Although radiation (RT) is standard treatment for many brain tumors, it may contribute to neurocognitive decline. The objective of this study was to investigate associations between RT dose to circumscribed brain regions and specific neurocognitive domains in patients with meningioma.

Methods

We undertook a retrospective study of 40 patients with meningioma who received RT and underwent an in-depth clinical neurocognitive assessment. Radiation dosimetry characteristics were delineated based on treatment planning computerized tomography co-registered with contrast-enhanced 3D T1-weighted magnetic resonance imaging. Principal components analysis was applied to organize neurocognitive test scores into factors, and multivariate multiple linear regression models were undertaken to examine if RT dose to circumscribed brain regions is associated with specific neurocognitive outcomes.

Results

Radiation dose to brain regions was associated with neurocognitive functions across a number of domains. High dose to the parietal-occipital region was associated with slower visuomotor processing speed (mean dose, β = −1.100, P = .017; dose to 50% of the region [D50], β = −0.697, P = .049). In contrast, high dose to the dorsal frontal region was associated with faster visuomotor processing speed (mean dose, β = 0.001, P = .036).

Conclusions

These findings suggest that RT delivered to brain regions (ie, parietal-occipital areas) may contribute to poor neurocognitive outcomes. Given that modern radiotherapy techniques allow for precise targeting of dose delivered to brain regions, prospective trials examining relations between dose and neurocognitive functions are warranted to confirm these preliminary results.
Targeted synthesis of zeolites from calculated interaction between zeolite structure and organic template
Authors: Wu Qinming , Luan Huimin , Xiao Feng-Shou
Published: February 2022

Zeolites, a class of silica-based porous materials, have been widely employed in the chemical industry for uses such as sorption, separation, catalysis and ion exchange. Normally, the synthesis of zeolites is performed in the presence of organic templates via a trial-and-error route, which is labor-intensive and empirical. In recent years, theoretical simulation from the interaction between a zeolite structure and an organic template has been used to guide the synthesis of zeolites, which is time-saving. In this review, recent progress in the targeted synthesis of zeolites from interaction between a zeolite structure and an organic template are briefly outlined including the design of new templates for zeolite synthesis, preparation of zeolites with new composition, development of novel routes for zeolite synthesis, synthesis of intergrowth zeolites, generation of novel zeolite structures, control of zeolite morphology and modulation of aluminum distribution in zeolites. These targeted syntheses reveal that the minimum energy principle from the theoretical simulation is key for guiding zeolite crystallization. This review will be important for zeolite researchers for rationally synthesizing zeolites and effectively designing new zeolite structures.
Recovery of sinus rhythm by tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy with atrial arrhythmias
Authors: Isotani Yoshitaka , Amiya Eisuke , Ishida Junichi , Ishizuka Masato , Hatano Masaru , Nakanishi Koki , Daimon Masao , Komuro Issei
Published: February 2022

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening infiltrative disease in elderly patients. Atrial arrhythmias (AAr) are common in patients with ATTR-CM. However, AAr treatment in these patients is challenging. In this case, a patient diagnosed with wild-type ATTR-CM suffered atrial fibrillation (AF) for ~1 year, according to the data of his self-monitoring and regular electrocardiogram. This AF reverted to normal sinus rhythm a few months after the initiation of tafamidis without administering an antiarrhythmic drug. Tafamidis may be beneficial as alternative antiarrhythmic therapy in patients with ATTR-CM.
Taming the temperature: Sagebrush songbirds modulate microclimate via nest-site selection
Authors: Scherr Tayler M , Chalfoun Anna D
Published: February 2022

Understanding species’ responses to temperature via behavior, and the factors affecting the extent of behavioral responses, is a critical and timely endeavor given the rapid pace at which the climate is changing. The young of altricial songbirds are particularly sensitive to temperature, and parents may modulate temperatures at nests via selection of nest sites, albeit to a largely unknown extent. We examined whether sagebrush-obligate songbirds, that reproduce within an open ecosystem with wide temperature fluctuations and span a range of body sizes, selected their nest sites on the basis of temperature. We further investigated whether nest predation risk and ambient conditions modulated temperature-based choices. We placed temperature loggers at nest sites and in unused but available nest niches and nest shrubs along a known predation-risk gradient and used nearby weather stations to determine ambient temperatures. The two smaller-bodied birds, Brewer’s Sparrow (Spizella breweri) and Sagebrush Sparrow (Artemisiospiza nevadensis), selected nest shrubs and niches that were warmer and less variable relative to unused sites whereas the larger bodied species, Sage Thrashers (Oreoscoptes montanus), did not. Brewer’s Sparrows and Sage Thrashers dampened selection for warmer nest sites when temperatures experienced during the nest-site prospecting period were warmer. None of the three species altered nest-site selection with respect to temperature in response to ambient temperature variability or our index of nest predation risk. The microhabitat characteristics that most influenced temperatures at nests varied across species. Our results suggest that songbirds can modulate temperatures at nests to some extent, and such responses can vary depending on the conditions experienced prior to nest initiation. Responses also varied across species, likely reflecting different physiological tolerances. The extent to which breeding birds will be able to continue to proximately influence temperature via nest-site choices likely will depend on the extent and rate of future climatic shifts.
A Feature Selection Approach Guided an Early Prediction of Anthocyanin Accumulation Using Massive Untargeted Metabolomics Data in Mulberry
Authors: Yu Cui , Dong Zhaoxia , Jemaa Essemine , Zhu Zhixian , Mo Rongli , Li Yong , Deng Wen , Hu Xingming , Zhang Cheng , Han Guangming
Published: February 2022

Identifying the early predictive biomarkers or compounds represents a pivotal task for guiding a targeted agricultural practice. Despite the various available tools, it remains challenging to define the ideal compound combination and thereby elaborate an effective predictive model fitting that. Hence, we employed a stepwise feature selection approach followed by a maximum relevance and minimum redundancy (MRMR) on the untargeted metabolism in four mulberry genotypes at different fruit developmental stages (FDSs). Thus, we revealed that 7 out of 226 differentially abundant metabolites (DAMs) explained up to 80% variance of anthocyanin based on linear regression model and stepwise feature selection approach accompanied by an MRMR across the genotypes over the FDSs. Among them, the phosphoenolpyruvate, d-mannose and shikimate show the top 3 attribution indexes to the accumulation of anthocyanin in the fruits of these genotypes across the four FDSs. The obtained results were further validated by assessing the regulatory genes expression levels and the targeted metabolism approach. Taken together, our findings provide valuable evidences on the fact that the anthocyanin biosynthesis is somehow involved in the coordination between the carbon metabolism and secondary metabolic pathway. Our report highlights as well the importance of using the feature selection approach for the predictive biomarker identification issued from the untargeted metabolomics data.
Getting Proactive with Police Proactivity: The Benefits of Computer-aided Dispatch for Directing Police Resources to Areas of Need
Authors: Henning Kris , Peterson Christian , Stewart Greg , Kahn Kimberly , Labissiere Yves , Renauer Brian , Mitchell Renèe , Sothern Sean
Published: February 2022

Sherman et al. [Sherman, L. W., Williams, S., Ariel, B., et al. (2014). ‘An Integrated Theory of Hot Spots Patrol Strategy Implementing Prevention by Scaling up and Feeding Back.’ Journal of Contemporary Criminal Justice30(2): 95–122.] argue that crime reductions associated with hot spot policing can be maximized by carefully managing the dosage of supplemental resources delivered. Fully achieving this goal in prior studies has been difficult due to resistance by officers, the use of atypical strategies for directing patrols to target locations, and insufficient attention to the measurement of treatment dosages. This has led to calls for process research examining the implementation of hot spot policing in law enforcement agencies. The current study represents one such effort. The computer-aided dispatch (CAD) system for a large US police department was pre-programmed with 16,200 supplemental community engagement patrols that were communicated to officers similar to emergency calls for service generated by the public. An interdisciplinary team comprised sworn officers, crime analysts, and academics designed and evaluated the intervention using an experimental design. The team found that the vast majority of patrols were delivered as scheduled (n = 12,965; 80.0%) and that planned dosage ratios between treatment conditions were achieved. Advantages of using CAD for proactive policing initiatives and benefits of police–academic partnerships are discussed.
Macroeconomic Attention and Announcement Risk Premia
Authors: Fisher Adlai , Martineau Charles , Sheng Jinfei
Published: February 2022

We construct macroeconomic attention indexes (MAI), which are new measures of attention to different macroeconomic risks, including unemployment and monetary policy. Individual MAI tend to increase around related announcements and following changes in related fundamentals. Further, bad news raises attention more than good news. For unemployment and FOMC, attention predicts announcement risk premiums and implied volatility changes with large economic magnitudes. Our findings support theories of endogenous attention and announcement risk premiums, while demonstrating future research directions, including that announcements can raise new concerns. Macroeconomic announcements are important not only for contents and timing but also for attention.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Gentle stroking elicits somatosensory ERP that differentiates between hairy and glabrous skin
Authors: Schirmer Annett , Lai Oscar , McGlone Francis , Cham Clare , Lau Darwin
Published: February 2022

Here we asked whether, similar to visual and auditory event-related potentials (ERPs), somatosensory ERPs reflect affect. Participants were stroked on hairy or glabrous skin at five stroking velocities (0.5, 1, 3, 10 and 20 cm/s). For stroking of hairy skin, pleasantness ratings related to velocity in an inverted u-shaped manner. ERPs showed a negativity at 400 ms following touch onset over somatosensory cortex contra-lateral to the stimulation site. This negativity, referred to as sN400, was larger for intermediate than for faster and slower velocities and positively predicted pleasantness ratings. For stroking of glabrous skin, pleasantness showed again an inverted u-shaped relation with velocity and, additionally, increased linearly with faster stroking. The sN400 revealed no quadratic effect and instead was larger for faster velocities. Its amplitude failed to significantly predict pleasantness. In sum, as was reported for other senses, a touch’s affective value modulates the somatosensory ERP. Notably, however, this ERP and associated subjective pleasantness dissociate between hairy and glabrous skin underscoring functional differences between the skin with which we typically receive touch and the skin with which we typically reach out to touch.
The development of sleep/wake disruption and cataplexy as hypocretin/orexin neurons degenerate in male vs. female Orexin/tTA; TetO-DTA Mice
Authors: Sun Yu , Tisdale Ryan , Park Sunmee , Ma Shun-Chieh , Heu Jasmine , Haire Meghan , Allocca Giancarlo , Yamanaka Akihiro , Morairty Stephen R , Kilduff Thomas S
Published: February 2022

Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. female orexin-tTA; TetO-DTA mice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, subcutaneous temperature, gross motor activity, and video recordings were conducted for 24-h at baseline and 1, 2, 4, and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Subcutaneous temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the “Delta State”, characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use.
Erk5 in Bone Marrow Mesenchymal Stem Cells Regulates Bone Homeostasis by Preventing Osteogenesis in Adulthood
Authors: Horie Tetsuhiro , Fukasawa Kazuya , Yamada Takanori , Mizuno Seiya , Iezaki Takashi , Tokumura Kazuya , Iwahashi Sayuki , Sakai Shiho , Suzuki Akane , Kubo Takuya , Osumi Ryoma , Tomizawa Akane , Ochi Hiroki , Sato Shingo , Kaneda Katsuyuki , Takahashi Satoru , Hinoi Eiichi
Published: February 2022

Extracellular signal-regulated kinase 5 (Erk5) belongs to the mitogen-activated protein kinase (MAPK) family. Previously, we demonstrated that Erk5 directly phosphorylates Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) at Thr249 (Smurf2Thr249) to activate its E3 ubiquitin ligase activity. Although we have clarified the importance of Erk5 in embryonic mesenchymal stem cells (MSCs) on skeletogenesis, its role in adult bone marrow (BM)-MSCs on bone homeostasis remains unknown. Leptin receptor-positive (LepR+) BM-MSCs represent a major source of bone in adult bone marrow and are critical regulators of postnatal bone homeostasis. Here, we identified Erk5 in BM-MSCs as an important regulator of bone homeostasis in adulthood. Bone marrow tissue was progressively osteosclerotic in mice lacking Erk5 in LepR+ BM-MSCs with age, accompanied by increased bone formation and normal bone resorption in vivo. Erk5 deficiency increased the osteogenic differentiation of BM-MSCs along with a higher expression of Runx2 and Osterix, essential transcription factors for osteogenic differentiation, without affecting their stemness in vitro. Erk5 deficiency decreased Smurf2Thr249 phosphorylation and subsequently increased Smad1/5/8-dependent signaling in BM-MSCs. The genetic introduction of the Smurf2T249E mutant (a phosphomimetic mutant) suppressed the osteosclerotic phenotype in Erk5-deficient mice. These findings suggest that the Erk5-Smurf2Thr249 axis in BM-MSCs plays a critical role in the maintenance of proper bone homeostasis by preventing excessive osteogenesis in adult bone marrow.
An Article-Based Format for Medical Specialty and Subspecialty Maintenance of Certification
Authors: Faulkner Larry R. , Juul Dorthea , Thomas Christopher R. , Anzia Joan M. , Lewis Steven L. , Schor Nina F. , Shen Linjun , Cowan Dan , Vondrak Patricia
Published: February 2022

Introduction:

This article describes an article-based alternative for maintenance of certification that the American Board of Psychiatry and Neurology developed and began pilot testing in 2019. The rationale for and components of the pilot program are presented along with data on participant performance and feedback from the first year of implementation in three primary specialties (neurology, child neurology, and psychiatry) and one subspecialty (child and adolescent psychiatry).

Methods:

Evaluation of the pilot program was guided by a widely used validity framework. Data were collected that addressed the five categories of validity evidence: content, response process, internal structure, relation to other variables, and consequences.

Results:

Enrollment ranged from 66.7% for psychiatrists to 75.3% for child neurologists. For the 2019 cohort, the pass rates ranged from 92.6% for child and adolescent psychiatry to 98.7% for neurology, and very small numbers of diplomates failed or did not complete the process. For psychiatrists, there was a modest, but significant, relationship between performance on previous and subsequent maintenance of certification examinations. Ninety percent or more agreed that: the articles were easy to access and helpful to their practices; the mini-tests were a fair assessment of their understanding of the articles; and their test-taking experience was satisfactory.

Discussion:

Most eligible diplomates participated in the article-based pilot project, and they strongly preferred this format to the traditional multiple-choice examinations. Most important, the pilot was perceived to be a meaningful and relevant learning activity that had a positive effect on patient care.
Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study
Authors: Hendriks Natasja , Koeneman Margot M. , van de Sande Anna J.M. , Penders Charlotte G.J. , Piek Jurgen M.J. , Kooreman Loes F.S. , van Kuijk Sander M.J. , Hoosemans Linde , Sep Simone J.S. , de Vos Van Steenwijk Peggy J. , van Beekhuizen Heleen J. , Slangen Brigitte F.M. , Nijman Hans W. , Kruitwagen Roy F.P.M. , Kruse Arnold-Jan
Published: February 2022

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.
Patient-Provider Communication Quality, 2002–2016
Authors: Cho Gawon , Chang Virginia W.
Published: February 2022

Background:

Effective patient-provider communication (PPC) can improve clinical outcomes and therapeutic alliance. While PPC may have improved over time due to the implementation of various policies for patient-centered care, its nationwide trend remains unclear.

Objective:

The objective of this study was to examine trends in PPC quality among US adults and whether trends vary with race-ethnicity.

Research Design:

A repeated cross-sectional study.

Participants:

We examine noninstitutionalized civilian adults who made 1 or more health care visits in the last 12 months and self-completed the mail-back questionnaire in the Medical Expenditure Panel Survey, 2002–2016.

Measures:

Outcomes include 4 top-box measures, each representing the odds of patients reporting that their providers always (vs. never, sometimes, usually) used a given communication behavior in the past 12 months regarding listening carefully, explaining things understandably, showing respect, and spending enough time. A linear mean composite score (the average of ordinal responses for the behaviors above) is also examined as an outcome. Exposures include time period and race-ethnicity.

Results:

Among 124,158 adults (181,864 observations), the quality of PPC increases monotonically between 2002 and 2016 for all outcomes. Between the first and last periods, the odds of high-quality PPC increase by 37% [95% confidence interval (CI)=32%–43%] for listen, 25% (95% CI=20%–30%) for explain, 41% (95% CI=35%–47%) for respect, and 37% (95% CI=31%–43%) for time. The composite score increases by 3.24 (95% CI=2.87–3.60) points. While increasing trends are found among all racial groups, differences exist at each period. Asians report the lowest quality throughout the study period for all outcomes, while Blacks report the highest quality. Although racial differences narrow over time, most changes are not significant.

Conclusions:

Our findings suggest that providers are increasingly likely to use patient-centered communication strategies. While racial differences have narrowed, Asians report the lowest quality throughout the study period, warranting future research.
Prognostic Implication of DNA Methylation Signature in Atypical Choroid Plexus Papilloma With Intracranial Dissemination
Authors: Yanagi Masato , Fukuoka Kohei , Mori Makiko , Arakawa Yuki , Matsushita Yuko , Hibiya Yuko , Tanami Yutaka , Ichimura Koichi , Hirato Junko , Nakazawa Atsuko , Kurihara Jun , Koh Katsuyoshi
Published: February 2022

An underestimation of pathologic diagnosis could be expected if disseminated choroid plexus tumors (CPTs) are diagnosed as lower grade tumors. Thus, molecular diagnosis using genome-wide DNA methylation profiling may be useful for clarifying the malignant potential of the tumor entity. Herein, we report a 2.7-year-old girl of pathologically atypical choroid plexus papilloma with intracranial dissemination. She was treated without radiotherapy and has been well, without recurrence for 32 months following the diagnosis. Subsequently, after a year from the diagnosis, T-stochastic neighbor embedding analysis was performed on methylation data of the case and compared with those of reference data of CPTs, revealing that the case was separated from the cluster of “Plexus tumor subclass pediatric B,” which includes a majority of choroid plexus carcinomas with the worst prognosis of these entities, and was categorized into the cluster of “Plexus tumor subclass pediatric A” consisting of choroid plexus papilloma and atypical choroid plexus papillomas diagnosed pathologically. Our case indicates the clinical significance of molecular confirmation for diagnosis among CPTs, particularly lower grade tumors with dissemination.
Introduction of Hydroxyurea Therapy to a Cohort of Sickle Cell Patients in Northern Haiti
Authors: Paul-Hanna Michele , Joseph Wesline , Mondesir Woodgina , Faustino Edward V.S. , Canarie Michael F.
Published: February 2022

Although the prevalence of sickle cell anemia is high in Haiti, treatment with hydroxyurea (HU) is uncommon. HU therapy was started at a hospital in Northern Haiti for children and young adults who had presented with complications of their disease. The patients were followed in clinic for their response to therapy and the principal outcome was hospitalization for complications. There was a 70% decrease in the rate of hospitalization in the cohort with no significant complications or deaths during the study period. Treatment with HU is a proven therapy that reduces the morbidity associated with sickle cell anemia and efforts should be made to assure access and affordability in regions with a high prevalence.
Acral Skin Rash Caused by Altered Mercaptopurine Metabolism in Maintenance Therapy for B-Cell Acute Lymphoblastic Leukemia
Authors: Newcome Jennifer , Geib Kristen B. , Thompson Patrick , Gold Stuart , Alexander Thomas B.
Published: February 2022

6-mercaptopurine is a mainstay of acute lymphoblastic leukemia treatment. It has a narrow therapeutic window, dictated by its metabolite, thioguanine and 6-methylmercaptopurine. Skin manifestations usually consist of mild facial rash or hypersensitivity exanthems. We report a child who developed a painful acral rash and mucositis while undergoing maintenance therapy for B-cell acute lymphoblastic leukemia without infectious or known drug etiology. Thiopurine metabolites were skewed toward 6-methylmercaptopurine. Two weeks after allopurinol was added and 6-mercaptopurine (6-MP) dose adjusted, the cutaneous manifestations and other constitutional symptoms resolved. We posit that the rash was because of 6-MP toxicity related to skewed metabolism, adding to the growing list of toxicity related to altered 6-MP metabolism.
Correlation of Asymmetric Dimethyl Arginine Level to Sickle Retinopathy in Children With Sickle Cell Disease
Authors: Elhawary Eslam E. , Khedr Seham F. , Nagy Hala M. , El-Bradey Mohamed H. , Elshanshory Mohamed R.
Published: February 2022

Asymmetric dimethyl arginine (ADMA) is a competitive inhibitor of nitric oxide synthetase especially in L-arginine deficiency, which is the case in sickle cell disease (SCD). we aimed to assess the level of ADMA in children with sickle retinopathy and to correlate it to the degree of retinopathy. In this cross-sectional study 40 children with SCD were included, 20 of them with sickle cell retinopathy (SCR) (group I), 20 with normal fundus examination (group II), and another 20 healthy children served as controls (group III). We measured ADMA level by ELISA and performed fundus examination. Seventeen of the 20 children included in group I had Grade I retinopathy (85%), 2 children had Grade II retinopathy (10%), and 1 child had Grade III retinopathy (5%). ADMA was significantly higher in SCD than controls (P-value <0.001), and it was even higher in patients with SCR compared those without retinopathy (P-value <0.002), and there was positive linear correlation between ADMA and the grade of retinopathy. The type of retinopathy detect in the studied patients was the nonproliferative type. In conclusion, ADMA is elevated in children with SCD, and its level is even higher in those who develop SCR.
Wastewater-based detection of two influenza outbreaks
Authors: Wolfe Marlene K. , Duong Dorothea , Bakker Kevin M. , Ammerman Michelle , Mortenson Lindsey , Hughes Bridgette , Arts Peter , Lauring Adam S. , Fitzsimmons William J , Bendall Emily , Hwang Calvin E. , Martin Emily T. , White Bradley J. , Boehm Alexandria B. , Wigginton Krista R.
Published: February 2022

Traditional influenza surveillance informs control strategies but can lag behind outbreak onset and undercount cases. Wastewater surveillance is effective for monitoring near real-time dynamics of outbreaks but has not been attempted for influenza. We quantified Influenza A virus RNA in wastewater during two active outbreaks on university campuses in different parts of the United States and during different times of year using case data from an outbreak investigation and high-quality surveillance data from student athletes. In both cases, the IAV RNA concentrations were strongly associated with reported IAV incidence rate (Kendall’s tau = 0.58 and 0.67 for University of Michigan and Stanford University, respectively). Furthermore, the RNA concentrations reflected outbreak patterns and magnitudes. For the University of Michigan outbreak, evidence from sequencing IAV RNA from wastewater indicated the same circulating strain identified in cases during the outbreak. The results demonstrate that wastewater surveillance can effectively detect influenza outbreaks and will therefore be a valuable supplement to traditional forms of influenza surveillance.

Synopsis

This study provides evidence that detection of Influenza A RNA in wastewater settled solids can be effectively used to track dynamics of influenza A outbreaks in a community.
TAMC: A deep-learning approach to predict motif-centric transcriptional factor binding activity based on ATAC-seq profile
Authors: Yang Tianqi , Henao Ricardo
Published: February 2022

Determining transcriptional factor binding sites (TFBSs) is critical for understanding the molecular mechanisms regulating gene expression in different biological conditions. Biological assays designed to directly mapping TFBSs require large sample size and intensive resources. As an alternative, ATAC-seq assay is simple to conduct and provides genomic cleavage profiles that contain rich information for imputing TFBSs indirectly. Previous footprint-based tools are inheritably limited by the accuracy of their bias correction algorithms and the efficiency of their feature extraction models. Here we introduce TAMC (Transcriptional factor binding prediction fromATAC-seq profile atMotif-predicted binding sites usingConvolutional neural networks), a deep-learning approach for predicting motif-centric TF binding activity from paired-end ATAC-seq data. TAMC does not require bias correction during signal processing. By leveraging a onedimensional convolutional neural network (1D-CNN) model, TAMC captures both footprint and non-footprint features at binding sites for each TF and outperforms existing footprinting tools in TFBS prediction particularly for ATAC-seq data with limited sequencing depth.

AUTHOR SUMMARY

Applications of deep-learning models are rapidly gaining popularity in recent biological studies because of their efficiency in analyzing non-linear patterns from feature-rich data. In this study, we developed a 1D-CNN model to predict TFBSs from ATAC-seq data. Compared to previous models using scoring functions and classical machine learning algorithms, our 1D-CNN model forgoes the need for bias correction during signal processing and significantly increases the efficiency in extracting features for TFBS prediction. In addition, the performance of our 1D-CNN model improves when the sequencing depth of training ATAC-seq data increases. Importantly, we showed that our method outperforms existing tools in TFBS prediction particularly when the sequencing depth of training ATAC-seq data is higher than the ATAC-seq data for prediction. This widened the applicability of our model to ATAC-seq data with both deep and shallow sequencing depth. Based on these results, we discussed about the potential application of our method to TFBS predication using bulk and single-cell ATAC-seq data.