bluuebunny/crossref_metadata_2025 huggingface dataset:
The treatment of aneurysmal bone cysts
Authors: van Geloven Thomas P.G. , van de Sande Michiel A.J. , van der Heijden Lizz
Published: November 2022

Purpose of review

Aneurysmal bone cysts are rare, locally aggressive bone tumors. Optimal treatment of ABCs is still matter of debate as therapies including sclerotherapy, selective arterial embolization and systemic treatment with denosumab are increasingly utilized, in addition to or instead of traditional curettage. The purpose of this review is to discuss current concepts and difficulties in diagnosing and treating primary ABCs, based on latest available literature.

Recent findings

In diagnostics, multiple new fusion partners of USP-6 have been described on next-generation sequencing specifically for primary ABCs. In a recent systematic review, failure rates of percutaneous injections and surgery were comparable. In a literature review, the use of denosumab seemed effective but resulted in multiple cases of severe hypercalcemia in children.

Accurately diagnosing primary ABC is crucial for treatment decisions. Curettage remains a valid treatment option, especially with adjuvant burring, autogenous bone grafting and phenolization. Percutaneous sclerotherapy represents a solid alternative to surgery, with polidocanol showing good results in larger studies. Systematic therapy with denosumab exhibits favorable results but should be reserved in the pediatric population for unresectable lesions, as it may result in severe hypercalcemia in children. When selecting a treatment option, localization, stability and safety should be considered.
Normothermic regional perfusion for donation after circulatory death donors
Authors: Pasrija Chetan , Tipograf Yuliya , Shah Ashish S. , Trahanas John M.
Published: November 2022

Purpose of review

This review is intended to provide an update on the logistics, technique, and outcomes associated with normothermic regional perfusion (NRP), as well as provide a discussion of the associated ethical issues.

Recent findings

There has been renewed interest in utilizing NRP to increase quality and availability of organs from donation after circulatory death (DCD) donors. Our institution has increasing experience with thoraco-abdominal NRP (TA-NRP) in controlled DCD donors (cDCD), whereas abdominal NRP (A-NRP) has been used with success in both cDCD and uncontrolled DCD (uDCD). There is increasing evidence that NRP can be conducted in a practical and cost-efficient manner, and that the organ yield may be of better quality than standard direct procurement and perfusion (DPP).

NRP is increasingly successful and will likely prove to be a superior method for cDCD recovery. However, before TA-NRP can be widely accepted the ethical debate surrounding this technique must be settled.

Video abstract

http://links.lww.com/COOT/A11
It Is Time to Focus Digital Strategy on Supporting Nurse Workflow
Authors: Virkstis Katherine , Drenkard Karen
Published: November 2022

In this column, 2 recognized healthcare leaders discuss the stresses experienced by nurses in today's workforce and offer suggestions for the use of technology in improving nurse engagement as well as the quality of patient care.
A Focus Group Study of Retirement-Age Nurses: Balancing Tension and a Love of Nursing in a Changing Healthcare Environment
Authors: Slusser Kim , Knobf M. Tish , Linsky Sarah , Kaisen Ann , Parkosewich Janet , Sterne Priscilla , Johnson Cynthia , Carley Jacqueline , Beckman Beth
Published: November 2022

OBJECTIVE

The aims of this study were to explore the experience of retirement-age nurses and identify decision-making factors and innovations to enhance retention.

BACKGROUND

A national shortage of nurses has created challenges to preserving quality patient care and level of nursing competency and managing turnover costs.

METHODS

A qualitative study using focus groups was conducted of nurses 55 years or older who were working or recently retired. Data were audiotaped and transcribed verbatim, with content analysis used to code in an iterative process until consensus was reached.

RESULTS

The tension of balancing the love of patient care within a changing healthcare system was described. Patient acuity, competing roles, and the centrality of computers were stressors and integrally related. Flexibility in work schedules and new practice models were important to retirement decision making for work-life balance and retention.

CONCLUSION

Passion for patient care dominated decisions to continue working. Innovations in practice models and scheduling offer opportunities to enhance the retention of experienced nurses.
Development and Psychometric Testing of a Leadership Competency Assessment
Authors: Ecoff Laurie , Stichler Jaynelle F.
Published: November 2022

OBJECTIVE

This article discusses the development and psychometric testing of the Nursing Leadership Competency Assessment (LCA).

BACKGROUND

Several leadership assessments are available for purchase, which are aligned with professional organizations. A competency-based leadership assessment is needed to identify the developmental needs of nurse leaders. Competent and confident nurse managers are critical to ensure positive relationships between nurse managers and clinical nurses.

METHODS

A multimethod approach was used to develop and test psychometric properties of the LCA. Items were drawn from 8 sources identifying nurse leader competencies.

RESULTS

The 76-item assessment had a Cronbach's α of 0.99. Confirmatory factor analysis supported 6 hypothesized factors (domains): leading self, people, organizations, change, innovation, and globally. Subscale reliabilities ranged from α = 0.87 to α = 0.98.

CONCLUSIONS

The LCA has demonstrated utility in assessing nurse leader competencies and guiding the development of educational opportunities in targeted content areas for specific leadership roles.
“Nasal Septal Flaps for Repair of Large or Recurrent Palatal Fistula: Report of Technique and Four Year Experience”
Authors: Fox Carly M. , McKenzie Jo-Lyn C. , Morris Helen C. , Phua Yun S. , Bade Stuart A. , Bowman James , Theile Richard J.
Published: November 2022

Large or multiply recurrent oronasal fistulas following cleft palate repair present an extremely challenging problem. Nasal septal mucoperichondrial flaps have been widely used for repair of skull base defects, however, their use in the repair of oronasal cleft palate fistulas has not previously been described. In this pilot study, we describe anterior palatal fistula repair using a nasal septal flap, and review our experience with this technique over four years. Fourteen patients with anterior palatal fistulas not amenable to repair using local palatal flaps were included for analysis. The mean size of the fistula was 12mm in maximum dimension. Flap healing with complete or near-complete closure of fistula was achieved in thirteen patients (93%). Five of these patients had a small, slit-like residual fistula that was asymptomatic. Nasal septal flaps are a new technique for repair of large or recurrent palatal fistulas. The procedure is well tolerated with minimal side effects, high success rate, and low incidence of recurrence.
A large superficial spreading melanoma with a secondary growth of fast-growing nodular melanoma: a case report from Syria
Authors: Al-Dabbagh Jacob , Al-Soufi Lina , Hasan Luna , Al-Shehabi Zuheir
Published: November 2022

Introduction:

Cutaneous melanoma (CM) is a cancer of melanocytes that has a poor prognosis and can metastasize to any organ.

Presentation of case:

Here, we report a unique case of a 59-year-old Syrian male with a nodular melanoma (NM) that grew and varied rapidly on a large superficial spreading melanoma (SSM), which was a pigmented lesion that lasted for 24 years on his trunk. The lesion developed on a part of his body that had not been exposed to the sun or any artificial sources of ultraviolet radiation. His personal and family history of melanoma and nonmelanoma skin cancer were negative. The histopathologic evaluation, along with the immunohistochemistry examination, confirmed the diagnosis.

Clinical discussion:

SSM and NM are the most common subtypes of CM.

NM has a more rapid growth rate and more aggression compared to SSM, and it tends to be more invasive, ulcerated, and fatal than SSM.

Conclusion:

Despite the advanced stage of the NM and the large size of the lesion, no metastasis or lymphadenopathy had been found during the patient’s follow-up.
Enhancing utility of interfacility triage guidelines using machine learning: Development of the Geriatric Interfacility Trauma Triage score
Authors: Garwe Tabitha , Newgard Craig D. , Stewart Kenneth , Wan Yang , Cody Patrick , Cutler James , Acharya Pawan , Albrecht Roxie M.
Published: November 2022

BACKGROUND

Undertriage of injured older adults to tertiary trauma centers (TTCs) has been demonstrated by many studies. In predominantly rural regions, a majority of trauma patients are initially transported to nontertiary trauma centers (NTCs). Current interfacility triage guidelines do not highlight the hierarchical importance of risk factors nor do they allow for individual risk prediction. We sought to develop a transfer risk score that may simplify secondary triage of injured older adults to TTCs.

METHODS

This was a retrospective prognostic study of injured adults 55 years or older initially transported to an NTC from the scene of injury. The study used data reported to the Oklahoma State Trauma Registry between 2009 and 2019. The outcome of interest was either mortality or serious injury (Injury Severity Score, ≥16) requiring an interventional procedure at the receiving facility. In developing the model, machine-learning techniques including random forests were used to reduce the number of candidate variables recorded at the initial facility.

RESULTS

Of the 5,913 injured older adults initially transported to an NTC before subsequent transfer to a TTC, 32.7% (1,696) had the outcome of interest at the TTC. The final prognostic model (area under the curve, 75.4%; 95% confidence interval, 74–76%) included the following top four predictors and weighted scores: airway intervention (10), traffic-related femur fracture (6), spinal cord injury (5), emergency department Glasgow Coma Scale score of ≤13 (5), and hemodynamic support (4). Bias-corrected and sample validation areas under the curve were 74% and 72%, respectively. A risk score of 7 yields a sensitivity of 78% and specificity of 56%.

CONCLUSION

Secondary triage of injured older adults to TTCs could be enhanced by use of a risk score. Our study is the first to develop a risk stratification tool for injured older adults requiring transfer to a higher level of care.

LEVEL OF EVIDENCE

Prognostic and Epidemiolgical; Level III.
Racial and Ethnic Disparity in Prehospital Pain Management for Trauma Patients
Authors: Bradford James M , Cardenas Tatiana , Edwards Allison , Norman Tye , Teixeira Pedro G , Trust Marc D , DuBose Joseph , Kempema James , Ali Sadia , Brown Carlos VR
Published: November 2022

Background:

Although evidence suggests that racial and ethnic minority (REM) patients receive inadequate pain management in the acute care setting, it remains unclear if these disparities also occur during the prehospital period. The aim of this study is to assess the impact of race and ethnicity on prehospital analgesic utilization by emergency medical services (EMS) in trauma patients.

Study Design:

Retrospective chart review of adult trauma patients aged 18-89 years old transported by EMS to our ACS verified Level 1 trauma center from 2014-2020. Patients who identified as Black, Asian, Native American, or Other for race and/or Hispanic or Latino or Unknown for ethnicity were considered REM. Patients who identified as White, non-Hispanic were considered White. Groups were compared in univariate and multivariate analysis. The primary outcome was prehospital analgesic administration.

Results:

2,476 patients were transported by EMS (47% White and 53% REM). White patients were older (46 vs. 38, p<0.001) and had higher rates of blunt trauma (76% vs. 60%, p<0.001). There were no differences in injury severity score (ISS) (21 vs. 20, p=0.22). Although REM patients reported higher subjective pain rating (7.2 vs. 6.6, p=0.002), they were less likely to get prehospital pain medication (24% vs. 35%, p<0.001) and that difference remained significant after controlling for baseline characteristics, transport method, pain rating, prehospital hypotension, and payor status (Adjusted OR [95% CI] 0.67 [0.47 – 0.96], p=0.03).

Conclusion:

Patients from racial and ethnic minority groups were less likely to receive prehospital pain medication after traumatic injury than White patients. Forms of conscious and unconscious bias contributing to this inequity need to be identified and addressed.
Global-local multi-field models for the stress analysis of laminated structures
Authors: Zappino Enrico , Carrera Erasmo
Published: November 2022

The present paper presents an innovative numerical model for predicting stress concentrations in composite materials in a multi-physics context. The numerical approach is based on the Carrera unified formulation, a numerical tool able to handle any kinematic model using a unified and compact notation. A general formulation for one-, two- and three-dimensional higher-order models has been presented. Equivalent single-layer and layer-wise models have been considered since they are the most effective in the analysis of composite materials. A hygro-thermo-elastic multi-physics formulation has been considered. The model has been used to investigate stress concentrations considering different configurations. Mechanical, thermal and hygroscopic loads have been considered. An innovative global-local analysis technique has been used to reduce the computational cost preserving the accuracy of the solution.

This article is part of the theme issue ‘Ageing and durability of composite materials’.
Preface to the theme issue ‘Durability and ageing of composite materials'
Authors: Gigliotti Marco , Grandidier Jean-Claude
Published: November 2022

The issue focuses on ageing and durability of composite materials for industrial applications. Ageing and durability are two fundamental topics within the context of design and optimization of materials and structures: ageing may induce degradation and leads to premature failure. Therefore, understanding the main ageing mechanisms is of paramount importance for predicting material durability. These topics are still barely studied systematically and the main related issues are debated within mechanical, chemical, and solid-state physics research communities. This issue aims to update the current research state of the art, clarifying the interplay between chemical and physical mechanisms involved in degradation processes, and providing test protocols and design rules that account for ageing and durability.

This article is part of the theme issue 'Ageing and durability of composite materials'.
Case report: a fatal case of Aspergillus felis infection in an immunocompetent host
Authors: Parkes-Smith Jill , Bauer Michelle J. , Bergh Haakon , Eidan Anthony , Forde Brian M. , Hilton John , Kidd Timothy J. , Schmidt Campbell , Stewart Adam G. , Harris Patrick N. A.
Published: November 2022

We report a fatal case of Aspergillus felis invasive rhinosinusitis with secondary cerebral abscesses in an immunocompetent host despite aggressive surgical debridement and combination antifungals. Whilst this organism is known to cause fatalities in cats, only a few cases in humans have been documented, all of which had significant immunosuppression. This is the first human death due to A. felis described in an immunocompetent host.
Structural and functional characteristics of the tripartite ABC transporter
Authors: Okada Ui , Murakami Satoshi
Published: November 2022

ATP-binding cassette (ABC) transporters are one of the largest protein superfamilies and are found in all living organisms. These transporters use the energy from ATP binding and hydrolysis to transport various substrates. In this review, we focus on the structural and functional aspects of ABC transporters, with special emphasis on type VII ABC transporters, a newly defined class possessing characteristic structures. A notable feature of type VII ABC transporters is that they assemble into tripartite complexes that span both the inner and outer membranes of Gram-negative bacteria. One of the original type VII ABC transporters, which possesses all characteristic features of this class, is the macrolide efflux transporter MacB. Recent structural analyses of MacB and homologue proteins revealed the unique mechanisms of substrate translocation by type VII ABC transporters.
Immunogenicity and safety of a 4thhomologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): a phase 2, randomized, placebo-controlled trial
Authors: Alves Katia , Plested Joyce S , Galbiati Shirley , Chau Gordon , Cloney-Clark Shane , Zhu Mingzhu , Kalkeri Raj , Patel Nita , Smith Kathy , Marcheschi Alex , Pfeiffer Susan , McFall Heather , Smith Gale , Glenn Gregory M. , Dubovsky Filip , Mallory Raburn M.
Published: November 2022

Background

The emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5µg SARS-CoV-2 rS + 50µg Matrix-M™ adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern.

Methods

A phase 2 randomized study assessed a fourth dose of NVX-CoV2373 in adults 18–84 years of age (2-dose primary series followed by third and fourth doses at 6-month intervals). Local/systemic reactogenicity was assessed the day of vaccination and for 6 days thereafter. Unsolicited adverse events (AEs) were reported. Immunogenicity was measured before, and 14 days after, fourth dose administration using anti-spike neutralization assays against the ancestral SARS-CoV-2 strain and Omicron sublineages. Antigenic cartography assessed antigenic distances between ancestral and variant strains.

Results

Among 1283 enrolled participants, 258 were randomized to receive the 2-dose primary series, of whom 104 received a third dose, and 45 received a fourth dose of NVX-CoV2373. The incidence of local/systemic reactogenicity events increased after the first three doses of NVX-CoV2373, and leveled off after dose four. Unsolicited AEs were reported in 9% of participants after dose 4 (none severe or serious). Neutralization antibody titers increased following booster doses. Antigenic cartography demonstrated reductions in antigenic distance between ancestral and variant SARS-CoV-2 strains with increased number of NVX-CoV2373 doses.

Conclusions

A fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted.

Trial registration number

NCT04368988
Network Based Identification of Holistic Drug Target for Parkinson Disease and Deep Learning assisted Drug Repurposing
Authors: Raza Ahsan , Muddassar Muhammad
Published: November 2022

Parkinson is a neurodegenerative disorder of the nervous system involved with disrupting the motor activity of the body. The current pathogenesis of the disorder is incomplete resulting in widespread use of exogenous medical treatments targeting the dopamine quantity, posing a major challenge in appropriate drug development. The plethora of high throughput techniques in the last decade has yielded a vast amount of Omics dataset with an opportunity of providing a holistic overview of the disease workings and dynamics. We integrated the Parkinson disease Omics datasets using network-based integration strategies to build Parkinson disease network. The most impactful and resilient node of the network was selected as a drug target. Deep learning based virtual screening estimator was built from physicochemical properties of different compounds having variable affinity to target binding. Virtual screening of FDA approved drugs repurposed 19 drugs with 25% of them falling under insomnia treatment; the most prevalent sleep disorder in Parkinson patients. Source Code of the project is available athttps://github.com/aysanraza/pd_repurposing_protocol
Differential effects of cobalt ionsin vitroon gill (Na+, K+)-ATPase kinetics in the blue crabCallinectes danae(Decapoda, Brachyura)
Authors: Leone Francisco A. , Fabri Leonardo M. , Costa Maria I. C. , Moraes Cintya M. , Garçon Daniela P. , McNamara John C.
Published: November 2022

To evaluate the crustacean gill (Na+, K+)-ATPase as a molecular marker for toxic contamination by heavy metals of estuarine and coastal environments, we provide a comprehensive analysis of the effects of Co2+in vitroon modulation of the K+-phosphatase activity of a gill (Na+, K+)-ATPase from the blue crabCallinectes danae. Usingp-nitrophenyl phosphate as a substrate, Co2+can act as both stimulator and inhibitor of K+-phosphatase activity. Without Mg2+, Co2+stimulates K+-phosphatase activity similarly but with a ≈4.5-fold greater affinity than with Mg2+. With Mg2+, K+-phosphatase activity is almost completely inhibited by Co2+. Substitution of Mg2+by Co2+slightly increases enzyme affinity for K+and NH4+. Independently of Mg2+, ouabain inhibition is unaffected by Co2+. Mg2+displaces bound Co2+from the Mg2+-binding site in a concentration dependent mechanism. However, at saturating Mg2+concentrations, Co2+does not displace Mg2+from its binding site even at elevated concentrations. Saturation by Co2+of the Mg2+binding site does not affectpNPP recognition by the enzyme. Given that the interactions between heavy metal ions and enzymes are particularly complex, their toxic effects at the molecular level are poorly understood. Our findings elucidate partly the mechanism of action of Co2+on a crustacean gill (Na+, K+)-ATPase.

Highlights

Without Mg2+, cobalt ions stimulate the gill (Na+, K+)-ATPase

Co2+has a 4.5-fold greater affinity for the gill (Na+, K+)-ATPase than does Mg2+

Mg2+displaces Co2+from the Mg2+-binding site in a concentration dependent manner

Ouabain inhibition with Co2+or Mg2+is identical

Saturation by Co2+of Mg2+-binding sites does not affect substrate recognition

Graphical Abstract

Graphical abstract (synopsis)

Using a crab gill (Na+, K+)-ATPase, we demonstrate that Co2+inhibits K+-phosphatase activity with Mg2+, which is stimulated without Mg2+. Mg2+displaces Co2+from the Mg2+-binding site but Co2+cannot displace Mg2+. Ouabain inhibition is unaffected by Co2+, independently of Mg2+. The molecular mechanism of Co2+toxicity is partly elucidated.
Secondary metabolites produced byColletotrichumspp. on different olive cultivars
Authors: Riolo Mario , Luz Carlos , Santilli Elena , Meca Giuseppe , Cacciola Santa Olga
Published: November 2022

This study was aimed to characterize the secondary metabolites produced by fourColletotrichumspecies,C. acutatum,C. gloeosporioides,C. godetiaeandC. karsti, bothin vitro, on potato dextrose agar (PDA) and oatmeal agar (OA), and during the infection process of fruits of four olive cultivars differing in susceptibility to anthracnose, ‘Coratina’ and ‘Ottobratica’, both susceptible, ‘Frantoio’ and ‘Leccino’, both resistant. The metabolites were extracted from axenic cultures after seven days incubation and from olives at three different times, 1, 3 and 7 days post inoculation (dpi). They were identified using the HPLC-QTOF analysis method. In total, as many as 45 diverse metabolites were identified; of these 29 were detected on infected olives and 26 in axenic cultures on agar media (OA and PDA). Only 10 metabolites were present in both fruits and axenic cultures while 19 were found exclusively on olives and 16 exclusively in axenic cultures. The 45 identified metabolites comprised fatty acid, phenolics, pyrones, sterols, terpenes and miscellaneous compounds. EachColletotrichumspecies produced a different spectrum of metabolites depending of the type of matrices. On artificially inoculated olives the severity of symptoms, the amount of fungal secondary metabolites and their number peaked 7 dpi irrespective of the cultivar susceptibility and the virulence of theColletotrichumspecies. The metabolite profiles as represented by heat maps were the result of the interaction olive cultivar xColletotrichumspecies.
Bioinformatically predicted emulsifying peptides and potato protein hydrolysate improves the oxidative stability of microencapsulated fish oil
Authors: Bjørlie Mads , Yesiltas Betül , García-Moreno Pedro J. , Espejo-Carpio F. Javier , Rahmani-Manglano Nor E. , Guadix Emilia M. , Jafarpour Ali , Hansen Egon B. , Marcatili Paolo , Overgaard Michael T. , Echers Simon Gregersen , Jacobsen Charlotte
Published: November 2022

The aim of this study was to investigate the potential of potato proteins and peptides as emulsifiers in the microencapsulation of fish oil by spray-drying. Microcapsules were produced using a potato protein extract, and fractions enriched in patatin and protease inhibitors. Furthermore, bioinformatically predicted emulsifier peptides from abundant potato proteins and a hydrolysate, obtained through targeted proteolysis of the extract, were investigated. During 28 days of storage at 25°C, peptides and hydrolysate exhibited better emulsifying properties and higher encapsulation efficiencies compared to native proteins and sodium caseinate. Significant differences (p < 0.05) were observed in the peroxide value (PV) and secondary volatile oxidation products between the microcapsules produced with peptides and native proteins. Microcapsules produced with peptides and hydrolysate showed the highest oxidative stability, not exceeding a PV of 10 meq/kg oil, and with concentrations of volatiles below the odor threshold in oil for five of the six studied compounds. These results show the emulsifying potential of potato peptides and hydrolysate for use in microencapsulation of hydrophobic bioactive ingredients such as fish oil.
Social stress induces autoimmune responses against the brain to promote stress susceptibility
Authors: Shimo Yusuke , Cathomas Flurin , Lin Hsiao-yun , Chan Kenny L , Parise Lyonna F. , Li Long , Ferrer-Pérez Carmen , Costi Sara , Murrough James W. , Russo Scott J
Published: November 2022

Clinical studies have revealed a high comorbidity between autoimmune and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes linking adaptive immune abnormalities and depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. Activation of social stress-induced antibody responses were confirmed by detecting expansion of specific T and B cell populations particularly in the cervical lymph nodes, where brain-derived antigens are preferentially delivered. IgG antibody concentrations in the brain were significantly higher in stress-susceptible mice than in unstressed mice, and positively correlated with social avoidance. IgG antibodies accumulated around the blood vessels in brain sections from stress-susceptible mice. Moreover, sera from stress-susceptible mice exhibited high reactivity against brain tissue, and brain-reactive IgG antibody levels positively correlated with depression-like behavior. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. Furthermore, high stress-resilience was observed in B cell-depleted mice, confirming a causal link between antibody-producing cells and depression-like behavior. This study provides novel mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses can therefore be devised to treat patients with MDD featuring immune abnormalities.
Generation of a hybridAppNL-G-F/NL-G-F×Thy1-GCaMP6s+/-Alzheimer disease mouse mitigates the behavioral and hippocampal encoding deficits ofAPPknock-in mutations ofAppNL-G-F/NL-G-Fmice
Authors: Inayat Samsoon , McAllister Brendan B. , Chang HaoRan , Lacoursiere Sean G. , Whishaw Ian Q. , Sutherland Robert J. , Mohajerani Majid H.
Published: November 2022

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein (App) gene exhibit stereotypical age-dependent amyloid beta (Aβ) pathology and cognitive impairment without physiologically unrealisticAppoverexpression. This study investigated the effect of familial AD-linkedAppmutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity,AppNL-G-F/NL-G-Fknock-in (APPki) mice were crossed withThy1-GCaMP6s+/-(C-TG) mice to generateAppNL-G-F/NL-G-F×Thy1-GCaMP6s+/-(A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited Aβ pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in Aβ pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect ofAPPmutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.
SARS-CoV-2 exposure in Norway rats (Rattus norvegicus) from New York City
Authors: Wang Yang , Lenoch Julianna , Kohler Dennis , DeLiberto Thomas J. , Tang Cynthia , Li Tao , Tao Yizhi Jane , Guan Minhui , Compton Susan , Zeiss Caroline , Hang Jun , Wan Xiu-Feng
Published: November 2022

Millions of Norway rats (Rattus norvegicus)inhabit New York City (NYC), presenting the potential for transmission of SARS-CoV-2 from humans to rats and other wildlife. We evaluated SARS-CoV-2 exposure among 79 rats captured from NYC during the fall of 2021. Results showed that 13 of 79 rats (16.5%) tested IgG or IgM positive, and partial genomes of SARS-CoV-2 were recovered from four rats that were qRT-PCR positive. Using a virus challenge study, we also showed that Alpha, Delta, and Omicron variants can cause robust infections in wild-type Sprague Dawley (SD) rats, including high level replications in the upper and lower respiratory tracts and induction of both innate and adaptive immune responses. Additionally, the Delta variant resulted in the highest infectivity. In summary, our results indicated that rats are susceptible to infection with Alpha, Delta, and Omicron variants, and rats in the NYC municipal sewer systems have been exposed to SARS-CoV-2. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations.

Importance

Since its emergence causing the COVID-19 pandemic, the host tropism expansion of SARS-CoV-2 raises a potential risk for reverse-zoonotic transmission of emerging variants into rodent species, including wild rat species. In this study, we presented both genetic and serological evidence for SARS-CoV-2 exposure in wild rat population from New York City, and these viruses are potentially linked to the viruses during the early stages of the pandemic. We also demonstrated that rats are susceptible to additional variants (i.e., Alpha, Delta, and Omicron) predominant in humans and that the susceptibility to different variants vary. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations.
Resting-State fMRI reveals Longitudinal Alterations in Brain Network Connectivity in a Mouse Model of Huntington’s Disease
Authors: Vasilkovska Tamara , Adhikari Mohit H. , Van Audekerke Johan , Pustina Dorian , Cachope Roger , Tang Haiying , Liu Longbin , Munoz-Sanjuan Ignacio , Van der Linden Annemie , Verhoye Marleen
Published: November 2022

Huntington’s disease is an autosomal, dominantly inherited neurodegenerative disease caused by an expansion of the CAG repeats in exon 1 of the huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result in the impairment of striatal and cortical circuits that affect the brain’s large-scale network functionality. However, the evolution of these disease-driven, large-scale connectivity alterations is still poorly understood. Here we used resting-state fMRI to investigate functional connectivity changes in a mouse model of Huntington’s disease in several relevant brain networks and how they are affected at different ages that follow a disease-like phenotypic progression. Towards this, we used the heterozygous (HET) form of the zQ175DN Huntington’s disease mouse model that recapitulates aspects of human disease pathology. Seed- and Region-based analyses were performed at different ages, on 3-, 6-, 10-, and 12-month-old HET and age-matched wild-type mice.

Our results demonstrate decreased connectivity starting at 6 months of age, most prominently in regions such as the retrosplenial and cingulate cortices, pertaining to the default mode-like network and auditory and visual cortices, part of the associative cortical network. At 12 months, we observe a shift towards decreased connectivity in regions such as the somatosensory cortices, pertaining to the lateral cortical network, and the caudate putamen, a constituent of the subcortical network. Moreover, we assessed the impact of distinct Huntington’s Disease-like pathology of the zQ175DN HET mice on age-dependent connectivity between different brain regions and networks where we demonstrate that connectivity strength follows a nonlinear, inverted U-shape pattern, a well-known phenomenon of development and normal aging. Conversely, the neuropathologically driven alteration of connectivity, especially in the default mode and associative cortical networks, showed diminished age-dependent evolution of functional connectivity.

These findings reveal that in this Huntington’s disease model, altered connectivity starts with cortical network aberrations which precede striatal connectivity changes, which appear only at a later age. Taken together, these results suggest that the age-dependent cortical network dysfunction seen in rodents could represent a relevant pathological process in Huntington’s disease progression.
Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding
Authors: Bonetti L. , Fernández-Rubio G. , Carlomagno F. , Dietz M. J. , Pantazis D. , Vuust P. , Kringelbach M. L.
Published: November 2022

Our brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we studied the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results showed feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observed backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintained the same hierarchical level, except for the final tone, where the cingulate gyrus assumed the top position within the hierarchy. The evoked responses of memorised sequences and variations engaged the same hierarchical brain network but systematically differed in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis showed that alpha and beta power was stronger for the variations, while gamma power was enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.
THE ROLE OF ALPHA- AND BETA-ADRENERGIC RECEPTORS ON COMPULSION-LIKE ALCOHOL DRINKING
Authors: Sergio Thatiane De Oliveira , Wean Sarah , Katner Simon Nicholas , Hopf Frederic W.
Published: November 2022

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), and this intake despite negative consequences can be a major clinical obstacle. With the quite limited treatment options available for AUD, there is a significant and critical unmet need for novel therapies. The noradrenergic system is an important hub for the stress response as well as maladaptive drives for alcohol, and pre-clinical (including our own) and clinical studies have shown that drugs targeting the α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking AUD has received somewhat scant investigation, and we sought to provide pre-clinical validation for possible AR utility for CLAD. Thus, we first examined whether β AR antagonist propranolol, betaxolol (β1), and ICI, 118 551 (β2) impacted compulsion-like intake and alcohol-only drinking (AOD) in male Wistar rats through systemic injections. The systemic highest dose of propranolol (10mg/kg) reduced both AOD and CLAD. 5mg/kg propranolol affected CLAD more than AOD, with no effects of 2.5mg/kg. Similar to propranolol, betaxolol also only decreased CLAD at the lower dose (2.5mg/kg). ICI 118.551 had no effects, suggesting propranolol regulates alcohol intake through β1. Also, while AR compounds might have utility for AUD, these compounds can also lead to undesirable cardiovascular system side effects; thus, any strategy incorporating lower doses of these compounds to reduce drinking could have broad utility. Importantly, here we found that a combination of ineffective doses of propranolol and prazosin administrated together did reduce both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol into two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10μg) in aINS or mPFC did not affect CLAD or AOD (although with a trend for aINS betaxolol to impact CLAD), suggesting propranolol regulation of alcohol drinking through a target other than aINS and mPFC. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.
Smart squirrels use a mortise-tenon structure to fix nuts on understory twigs
Authors: Xu Han , Xia Lian , Spence John R. , Lin Mingxian , Lu Chunyang , Li Yanpeng , Chen Jie , Luo Tushou , Li Yide , Fang Suqin
Published: November 2022

Squirrels of temperate zones commonly store nuts or seeds under leaf litter, in hollow logs or even in holes in the ground; however, in humid rainforests, it is an evolutionary challenge for squirrels to hang elliptical or oblate nuts securely on trees to minimize germination or fungal infection. Here, we report a unique behaviour used by two species of small flying squirrels (Hylopetes phayrei electilis(G. M. Allen, 1925) andHylopetes alboniger(Hodgson, 1870)) to cache nuts on Hainan Island. Squirrels intentionally carved grooves encircling ellipsoid nuts or distributed on the bottom of oblate nuts and used these grooves to fix nuts tightly between small twigs 0.1-0.6 cm in diameter and connected at angles of 25-40°. The resulting structures were similar to the mortise-tenon joint of ancient Chinese architecture. Cache sites were on small plants located 10-25 m away from the closest potentially nut-producing tree, a behaviour that likely deters discovery and consumption of the nuts by other animals. Their ability to shape individual nuts to store them more securely suggests it is a smart behavior, which is likely formed by the adaption to life in humid tropical rainforests to guarantee food supply and impacts the distribution of tree species.
Paxlovid-like nirmatrelvir/ritonavir fails to block SARS-CoV-2 transmission in ferrets
Authors: Cox Robert M , Lieber Carolin M , Wolf Josef D , Karimi Amirhossein , Lieberman Nicole A P , Sticher Zachary M , Roychoudhury Pavitra , Andrews Meghan K , Krueger Rebecca E , Natchus Michael G , Painter George R , Kolykhalov Alexander A , Greninger Alexander L , Plemper Richard K
Published: November 2022

Despite the continued spread of SARS-CoV-2 and emergence of variants of concern (VOC) that are capable of escaping preexisting immunity, therapeutic options are underutilized. In addition to preventing severe disease in high-risk patients, antivirals may contribute to interrupting transmission chains. The FDA has granted emergency use authorizations for two oral drugs, molnupiravir and paxlovid. Initial clinical trials suggested an efficacy advantage of paxlovid, giving it a standard-of-care-like status in the United States. However, recent retrospective clinical studies suggested a more comparable efficacy of both drugs in preventing complicated disease and case-fatalities in older adults. For a direct efficacy comparison under controlled conditions, we assessed potency of both drugs against SARS-CoV-2 in two relevant animal models; the Roborovski dwarf hamster model for severe COVID-19 in high-risk patients and the ferret model of upper respiratory tract disease and transmission. After infection of dwarf hamsters with VOC omicron, paxlovid and molnupiravir were efficacious in mitigating severe disease and preventing death. However, a pharmacokinetics-confirmed human equivalent dose of paxlovid did not significantly reduce shed SARS-CoV-2 titers in ferrets and failed to block virus transmission to untreated direct-contact ferrets, whereas transmission was fully suppressed in a group of animals treated with a human-equivalent dose of molnupiravir. Prophylactic administration of molnupiravir to uninfected ferrets in direct contact with infected animals blocked productive SARS-CoV-2 transmission, whereas all contacts treated with prophylactic paxlovid became infected. These data confirm retrospective reports of similar therapeutic benefit of both drugs for older adults, and reveal that treatment with molnupiravir, but not paxlovid, may be suitable to reduce the risk of SARS-CoV-2 transmission.
Subtle Structural Translation Remarkably Modulates the Super-Resolution Imaging of Self-blinking Rhodamines
Authors: Zheng Ying , Ye Zhiwei , Xiao Yi
Published: November 2022

The evolution of super-resolution imaging techniques is benefited from the ongoing competition for optimal rhodamine fluorophores. Yet, it seems blinded to select the best one among different rhodamine derivatives for specific labeling and imaging, without the knowledge on imaging impact of even the minimum structural transform. Herein, we have designed a pair of self-blinking sulforhodamines (STMR, SRhB) with the bare distinction of methyl or ethyl substituents, and engineered them with Halo protein ligands. Although the two present similar spectral properties (λab, λfl, □, etc.), they demonstrated unique single-molecule characteristics preferring to individual imaging applications. Experimentally, STMR with high emissive rates was qualified for imaging structures with rapid dynamics (endoplasmic reticulum, mitochondria), and SRhB with prolonged on-times and photostability was suited for relatively “static” nuclei and microtubules. Utilized this new knowledge, the mitochondrial morphology during apoptosis and ferroptosis was first super-resolved by STMR. Our study highlights the significance of even the smallest structural modification to the modulation of super-resolution imaging performance, and would provide insight for future fluorophore design.
Genomic clustering and sequence context of mutations in human monkeypox virus (hMPXV1) genomes
Authors: Forni Diego , Cagliani Rachele , Pozzoli Uberto , Sironi Manuela
Published: November 2022

The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted in Nigeria. Analysis of genetic differences indicated that APOBEC-mediated editing might be responsible for the unexpectedly high number of mutations observed in hMPXV1 genomes. Here, using 1624 hMPXV1 publicly available sequences, we analyzed mutations that accrued since 2017 until the emergence of the current predominant variant (B.1), as well as those that that have been accumulating during the 2022 outbreak. We found that substitutions tend to cluster and mutational hot-spots are observed.

Investigation of the sequence context of C to T changes indicated a preference for 5’-TCA/G-3’ motifs, suggesting APOBEC3F- or APOBEC3A-mediated editing. The sequence context has remained unchanged since 2017, indicating that the same mutational mechanism that is driving the accumulation of substitutions during the ongoing human-to-human transmission, was already operating before the virus left Africa. We suggest that APOBEC3A is the most likely candidate, given its expression in the skin and its known role in the editing of human papillomavirus.
Synthesis, crystal structure and biological properties of a fluorophore-labelled mixed-ligand copper(II) complex incorporating N-hydroxynaphthalene-1,8-dicarboximide
Authors: Bhat Satish Shantaram , Kawade Vitthal A. , Revankar Vidyanand K. , Kumbar Vijay , Bhat Kishore
Published: November 2022

The mixed-ligand fluorophore-labelled copper(II) complex aqua[2,4-dioxo-3-azatricyclo[7.3.1.05,13]trideca-1(12),5,7,9(13),10-pentaen-3-olato-κ2
O
2,O
3](1,10-phenanthroline-κ2
N,N′)copper(II) nitrate, [Cu(C12H6NO3)(C12H8N2)(H2O)]NO3·CH3OH or [Cu(L)(phen)(H2O)]NO3·CH3OH (where phen is 1,10-phenanthroline and HL is N-hydroxynaphthalene-1,8-dicarboximide), (1), was synthesized and structurally characterized. The structure of (1) was confirmed by single-crystal X-ray structure determination. The complex crystallized in the triclinic space group P\overline{1}. The geometry around the copper centre is distorted square pyramidal, with the apical position occupied by a water molecule. The complex is highly fluorescent in organic and aqueous solutions. It has good anticancer activity, with an IC50 value of 17 µM, which is almost five times greater than cisplatin (IC50 = 82 µM) under identical experimental conditions.
Diethyl 4,4′-[octane-1,8-diylbis(oxy)]dibenzoate
Authors: Khan Sultana Shakila , Howlader Md. Belayet Hossain , Miyatake Ryuta , Sheikh Md. Chanmiya , Zangrando Ennio
Published: November 2022

The complete molecule of the title compound, C26H34O6, is generated by a crystallographic centre of symmetry and the central octyl chain adopts an extended conformation. In the extended structure, weak C—H...π interactions link the molecules.