bluuebunny/crossref_metadata_2025 huggingface dataset:
Taxing the wealthy: the choice between wealth and capital income taxation
Authors: Bastani Spencer , Waldenström Daniel
Published: August 2023

This paper analyses the relative merits of wealth and capital income taxes as instruments for taxing the rich. The main rationale for a wealth tax is to address the incompleteness of the tax code in taxing unrealized capital gains, which can be enormous and concentrated among the wealthy. However, by taxing presumed rather than actual returns, a wealth tax fails to address inequality among taxpayers with the same wealth but different capital incomes. In addition, wealth taxation creates liquidity problems that may adversely affect growth firms and start-ups, which is why wealth taxes typically provide exemptions and deductions for certain business assets. Our empirical analysis, based on Swedish register data, describes the wealth composition of the wealthiest and assesses the distributional incidence of different combinations of wealth and capital income taxation.
The messy boundary between pass-through and corporate taxation
Authors: Kopczuk Wojciech
Published: August 2023

Businesses may be subject to either individual income taxes or entity-level taxes. Policy choices surrounding the boundary between these taxes can and do vary between countries and over time. I discuss the need for and implications of the existence of this boundary for behaviour, economic measurement, and policy.
Statewide Trends in Buprenorphine Prescribing in Rural and Nonrural Vermont: Analysis of Population-based Patient Pharmacy Claims
Authors: Nowak Sarah A. , Harder Valerie S. , Villanti Andrea C. , Heil Sarah H. , Sigmon Stacey C.
Published: August 2023

Importance

Opioid-related mortality rates have risen dramatically over the past decade, and office-based opioid treatment using buprenorphine offers hope for combatting this trend. Vermont's policymakers, health care systems, and treatment providers have worked to expand access to treatment throughout the rural state.

Objective

The objective of the current study was to characterize the trends in the number of buprenorphine prescribers and the number of patients per prescriber in Vermont over the past decade (2010–2020).

Methods

We used Vermont's all-payer claims database to identify patients with buprenorphine claims between 2010 and 2020 and their prescribers. We conducted analyses of trends in the number of prescribers treating different numbers of patients, the number of patients treated by prescribers in those categories, and the number of rural (vs nonrural) patients filling buprenorphine prescriptions. We used Z tests to determine if there were statistical differences between trends.

Results

The number of buprenorphine prescribers treating 10+ patients grew more rapidly than other prescriber groups (P < 0.001). Nearly half of Vermont patients in 2020 were treated by 33 high-volume prescribers who treated 100 or more patients with buprenorphine. The number of patients filling buprenorphine prescriptions in Vermont increased by 98% between 2010 and 2020, with greater increases seen among rural than nonrural residents (107% vs 72%; P = 0.008).

Conclusions and Relevance

Since 2010, Vermont has increased utilization of its office-based opioid treatment capacity, particularly in rural counties.
Risk Factors for Perinatal Transmission of Hepatitis C Virus
Authors: Prasad Mona , Saade George R. , Clifton Rebecca G. , Sandoval Grecio J. , Hughes Brenna L. , Reddy Uma M. , Bartholomew Anna , Salazar Ashley , Chien Edward K. , Tita Alan T. N. , Thorp John M. , Metz Torri D. , Wapner Ronald J. , Sabharwal Vishakha , Simhan Hyagriv N. , Swamy Geeta K. , Heyborne Kent D. , Sibai Baha M. , Grobman William A. , El-Sayed Yasser Y. , Casey Brian M. , Parry Samuel , Rathore Mobeen , Diaz-Velasco Rodrigo , Puga Ana M. , Wiznia Andrew , Kovacs Andrea , Garry David J. , Macones George A. ,   for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network*
Published: August 2023

OBJECTIVE:

To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for perinatal transmission.

METHODS:

This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody–positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2–6 months (HCV RNA testing) and at 18–24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point.

RESULTS:

A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0–8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2–11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio [aOR] 8.22, 95% CI 3.16–21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32–8.03). A viremic threshold for perinatal transmission could not be established.

CONCLUSION:

Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.
Toward a Listening Training Paradigm: Evaluation in Normal-Hearing Young and Middle-Aged Adults
Authors: Van Wilderode Mira , Van Humbeeck Nathan , Krampe Ralf T. , van Wieringen Astrid
Published: August 2023

Objectives:

Adults’ most common complaint relates to understanding speech in noisy environments. Hearing aids can compensate for sensory loss but do not restore hearing to normal. Listening training has the potential to partially remediate these problems. In this study, we propose and evaluate a Flemish version of a listening training paradigm, which involves the use of cognitive control as well as auditory perception. The paradigm entails a discrimination task where participants are cued to attend to one of two concurrent talkers with target speakers randomly varying between a female and a male voice. We evaluate learning effects, different scenarios, and masking types.

Design:

In total, 70 young and 54 middle-aged adults participated in this study. Each adult performed one or more conditions. Participants’ hearing was screened before participation, all middle-aged adults passed a cognitive screening task.

Results:

Analyses indicated learning effects across scenarios that were similar in terms of speech intelligibility. Our results indicated better speech intelligibility when the female speaker was the target, but speech intelligibility did not differ when the target was the male speaker. An unintelligible masker noise results in worse speech intelligibility than a competing talker masker. Our results suggest that listeners could use an intensity cue to identify and/or select the target speaker when presented at a lower signal to noise ratio (SNR). Error analysis suggested higher cognitive control demands when the target and masker were presented at similar levels (i.e., around 0 dB SNR). The addition of independent trials with the intensity of target and masker reversed improved speech intelligibility. Inhibitory control, but not task switching, was reliably correlated with listening performance.

Conclusions:

The proposed paradigm turned out to be feasible and practicable, demonstrating its potential for training speech intelligibility in noise. We believe that this training paradigm can generate real-life benefits including for persons with hearing loss. This latter application awaits future evaluation.
The Effectiveness of a Yoga Program on Psychological and Cardiovascular Outcomes of Undergraduate Nursing Students
Authors: Andrabi Mudasir , Mumba Mercy , Mathews Jeremiah , Rattan Jesse , Scheiner Andrea
Published: August 2023

Psychological problems among nursing students are well documented. Unfortunately, only a minority of these populations seek help related to their psychological distress. Yoga exercises improve individuals' psychological distress and cardiovascular outcomes. Therefore, we conducted this study to test the feasibility and preliminary efficacy of our health promotion theme-based yoga program to reduce the participants' stress levels and anxiety symptoms and improve their blood pressure and heart rate. This study has a pre/posttest quasi-experimental design. A convenience sampling method was used to recruit the participants who were 18 years or older and could speak and read English. Individuals with any contraindication to participate in yoga or receiving any medications for their mental health or cardiovascular health were excluded from the study. The Perceived Stress Scale and the Depression Anxiety Stress Scale-21 were used to measure the participants' stress levels and anxiety symptoms, respectively. Their blood pressure and heart rate were measured by using a standard blood pressure measuring machine. Participants received 50 minutes of weekly yoga sessions in groups and also performed individual yoga sessions 3 times a week for 8 weeks. Descriptive statistics were used to answer our research questions. Our recruitment rate of 47% (n = 19) was lower than our anticipated rate of 80%; however, we had a retention rate of 90%. There was a reduction in participants' stress levels and anxiety symptoms from the preintervention phase to the postintervention phase. A larger study and a randomized controlled trial are warranted to draw conclusions.
Ophthalmic manifestations of tuberculosis
Authors: Bates Brandon , Crowell Eric L.
Published: August 2023

Purpose of review

To evaluate the epidemiology, microbiology, and pathology of Mycobacterium Tuberculosis (MTB). Utilizing these basic science concepts, the reader will discover how MTB can cause disease in any part of ophthalmic system. This article will aid clinicians in establishing the difficult diagnosis and management strategies for ophthalmic tuberculosis (OTB).

Recent findings

Recently, expert panels have reached a consensus on naming conventions and treatment strategies for the variety of ocular tuberculosis (TB). This consensus helps individual clinicians decide when to recommend full anti-TB treatment.

Globally, TB is nearly ubiquitous in the human population. It is most recognized for its pulmonary disease, but pathology of nearly every structure of the ophthalmic system has been identified. This heterogeneity makes establishing a diagnosis difficult, but recent improvements in expert panel naming consensus and nucleic acid amplification tests are improving diagnostic abilities. Clinicians are now feeling more confident with prescribing anti-TB regimens, but ongoing questions regarding the use of oral steroids and risk of medication-induced ocular toxicity remain.
Intraoperative phacoemulsification tip fracture
Authors: Kumar Ameeta , Toia Diana-Maria , Khan Sharmina
Published: August 2023

Introduction:

Intraoperative instrument fractures pose a serious risk during cataract surgery through the retention of metallic foreign bodies and subsequent injury to intraocular structures.

Patient and Clinical Findings:

An 83-year-old woman underwent phacoemulsification and insertion of an intraocular lens, during which an intraoperative phacoemulsification tip fracture was encountered during quadrant removal.

Diagnosis, Intervention, and Outcome:

A thorough examination of the operative field revealed the broken tip fragment in the drape bag, with no intraocular fragments. The surgery was completed with a replacement phacoemulsification probe without issues, and the patient made an uneventful recovery.

Conclusions:

Early diagnosis and management after instrument breakage are necessary to prevent the retention of metallic foreign bodies.
Revisiting the Cephalic Index: The Origin, Purpose, and Current Applicability—A Narrative Review
Authors: Fish Deanna , Hinton Christina , Barrios Amy
Published: August 2023

Introduction

Cephalometry is the measurement and study of the proportions of the head and face, and infant skull deformities have been the subject of many clinical studies over the last 30 years. Clinical protocols to document change are especially critical during periods of growth and development, but reference values and norms are lacking for infants, especially in the first year after birth.

Discussion

Key publications were reviewed by the authors to provide a narrative review of the 1) origin of the cephalic index (CI), 2) adaptations of the measure over time, 3) anatomical landmarks and alignments used, 4) clinical tools, 5) necessary considerations for different ethnic, sex, and cultural influences, 6) value and limitations of CI measurements, and 7) appropriate use of the CI in the documentation of infant skull deformities. The CI calculation has remained constant since the 1840s, although the cranial shape classifications have changed many times over the years.

Conclusions

Used in isolation, the two-dimensional (2D) and linear nature of the CI fails to describe the magnitude of the three-dimensional (3D) head deformity. However, the CI can and should be used in conjunction with other 2D and 3D measurements to provide a more detailed description and understanding of the entire cranial deformity. For today's cranial clinicians and allied health care professionals, the commonly referenced CI chart fails to reflect 1) the natural skull changes noted with supine sleeping infants, and 2) the cultural diversity of the infant population currently treated. Although the CI provides information about one of the most obvious features of the dysmorphology, clinicians must also document and report other distinct features such as frontal flattening or bossing, parietal shape or involvement, sloping, displacement, and/or posterior asymmetry.

Clinical Relevance

The CI should be used in conjunction with other 2D and 3D anthropometric measurements to provide a more detailed assessment of the entire cranial deformity. The CI results should be discussed with the medical team along with a complete review of other 2D and 3D measurements to determine the best course of action for orthotic treatment or nontreatment of the head shape.
Acute pancreatitis in children: risk factors, management, and outcomes
Authors: Mehta Megha S.
Published: August 2023

Purpose of review

Pediatric acute pancreatitis is an infrequent but potentially serious condition in children. Most have mild cases with spontaneous resolution, but up to one-third of patients can have moderate or severe disease or progress to recurrent or chronic pancreatitis.

Recent findings

Significant advances have been made in the field of pediatric pancreatology with a recognition that pediatric acute pancreatitis can vary significantly from adult disease with different risk factors and outcomes. There is better understanding of appropriate management for pediatric pancreatitis as well as growing literature in complications of pancreatitis.

The most common risk factors for pediatric acute pancreatitis include biliary disease, drug/toxin and idiopathic. Management involves adequate fluid resuscitation, early enteral nutrition and appropriate pain control. Systemic and local complications, including SIRS, necrosis and fluid collections, can occur in up to one-third of patients and care is largely supportive with a careful step-up approach to fluid collections and necrosis.
Project to Publication—A Writing Mentorship Program
Authors: Harne-Britner Sarah , Leaver Cynthia A.
Published: August 2023

Purpose/Aims

Evidence is required to inform effective interventions promoting publication among clinical nurses. This study examined the effect of a mentored writing program on clinical nurse perceptions of writerly self-efficacy and publication.

Design

A mixed-methods, pretest-posttest study design with an education intervention was implemented. The Revised for Nursing Practice - Postsecondary Writerly Self-efficacy Scale (RNP-PSWSES) measured perception of writerly self-efficacy before and after intervention. Manuscripts submitted for publication were counted.

Methods

The purposive, convenience sample included registered nurses with completed research, evidence-based practice, or quality improvement projects. Subjects participated in a 3-month structured mentored writing program and completed the RNP-PSWSES survey before and after program completion. A Wilcoxon signed rank test was performed to determine the significance of difference between the pretest and posttest, and the number of published manuscripts was reported.

Results

The RNP-PSWSES items identified pretest-posttest Cronbach's α (.728, .818). Posttest RNP-PSWSES scores were statistically significantly higher than pretest scores (z = −1.96, P = .050) with a large effect size of r = 0.69. Two manuscripts were accepted for publication, and 1 manuscript was withdrawn after the third request for revisions.

Conclusions

In this study, mentored writing workshops improve nurses' perceptions of writing ability and increase publications. Generalization of findings is limited by small sample size. Clinical nurse specialists are critical to champion writing and publication.
Credentialed and Privileged Clinical Nurse Specialists
Authors: Iseler Jackeline , Long Taylor , Barach Melissa , McClelland Molly L. , Saunders Mitzi M.
Published: August 2023

Purpose/Objectives

The purpose of this article is to illustrate, using exemplars, the practice of clinical nurse specialists (CNSs) in Michigan who are credentialed and privileged as providers by hospital/healthcare agencies to practice in acute inpatient and ambulatory settings.

Description

The CNS provides expert specialty direct patient care to improve patient outcomes. They hold a graduate degree as a CNS, are professionally certified as a CNS in a specialty practice population, and are licensed or otherwise recognized to practice as an advanced practice nurse by the state nursing practice regulatory agency.

Outcome

The exemplars illustrate CNS practice as an independent provider within a health system.

Conclusion

Hospital-based credentialing and privileging facilitates CNS practice within the full scope of practice authority that consists of education, certification, and licensure and is a valuable contribution to cost-effective, high-quality clinical care for specialty populations.
Decreasing the Frequency of Nursing Assessment for Medically Stable Hospitalized Patients
Authors: Nelson Jessica L. , Chambers Stephanie P. , Brakke Holly E. , Hus Jessica H.
Published: August 2023

Purpose/Objectives

During the COVID-19 pandemic, a large Midwest tertiary care medical center had prolonged hospitalizations due to strained staffing and few options for post–acute care recovery. Patients deemed medically ready for discharge were receiving the same care interventions as all other hospitalized medical-surgical patients. The study objective was to appropriately match care assessment frequency for these patients with their individual needs by reducing the frequency of routine nursing assessments.

Description of the Project/Program

This quality improvement initiative reduced the frequency of nursing assessments, including routine monitoring of vital signs, to once daily for medically stable patients whose discharge was delayed.

Outcome

During the 4-week pilot, 40 hospitalized patients were enrolled; 960 assessments were eliminated, and nurses were able to reallocate approximately 500 hours to other nursing tasks. No adverse outcomes were observed among patients who received once-daily assessment.

Conclusion

By decreasing nursing assessment frequency for hospitalized patients with discharge delays, nurses appropriately matched care interventions with the patient's needs.
Medical management of cystic echinococcosis
Authors: Chiodini Peter L.
Published: August 2023

Purpose of review

Cystic echinococcosis is a neglected zoonosis for which humans are dead end hosts. It is not only widely distributed in sheep rearing areas of low-income and middle-income countries but also has a significant presence in wealthy countries, for example, in Europe. It results in considerable morbidity, and its current management is far from optimal. Medical management is with a benzimidazole, with the addition of praziquantel under some circumstances.

Recent findings

Interest in mebendazole as an anticancer drug has stimulated research into new drug formulations to improve bioavailability and possibly reduce inter-individual variability in in-vivo drug levels, which may help its activity against cystic echinococcosis. Further evidence to support administration of albendazole with a fatty meal has been provided. GlaxoSmithKilne (GSK) has agreed to extend its albendazole donation programme to include echinococcosis. The search for new drugs has focussed on natural products, such as essential oils and on repurposing of existing drugs licensed for human use against other conditions.

The medical treatment of cystic echinococcosis remains sorely neglected, with no new drugs for almost 40 years. We need a better understanding of how to use the drugs we do have, whilst seeking new ones. Drug repurposing may be the best pathway.
Cystic echinococcosis of the bone
Authors: Monge-Maillo Begoña , Lopez-Velez Rogelio
Published: August 2023

Purpose of review

Cystic echinococcosis (CE) has a wide world distribution causing important morbidity. Osseous involvement is present in less than 4% of the CE cases. Its diagnosis and therapeutic management is full of challenges and low grade of evidence.

Recent findings

The study summarizes literature evidence on the management of osseous CE with particular emphasis on new data regarding diagnosis and treatment.

Clinical presentation of osseous CE depends on the skeletal area affected. Diagnosis is mostly based on radiological findings and serology. Recent advances with qPCR on osseous tissue samples seem to be a good option for diagnosis confirmation. Complete resection of the cystic lesion is the only curative option, but it is usually not possible performing palliative surgery and prolonged albendazole intake in most cases. Radiotherapy could be an option, but experience to date is only based on clinical cases.
The Role of Nursing Staff Regarding Goal Setting and Achieving in Geriatric Rehabilitation: A Focus Group Study
Authors: Vaalburg Anne Marie , Wattel Elizabeth M. , Boersma Petra , Hertogh Cees M. P. M. , Gobbens Robbert J. J.
Published: August 2023

Purpose

The aim of this study was to explore and clarify the role of nursing staff in geriatric rehabilitation on supporting patients in goal setting and achieving, through reflecting on rehabilitation interventions.

Design

A descriptive qualitative study was conducted.

Methods

We conducted four online focus group interviews with 23 members of the nursing staff working in geriatric rehabilitation. They reflected on six interventions, preclassified into three types: setting goals in the admission phase, increasing patient participation in order to personalize the rehabilitation trajectory, and supporting patients in working on short-term goals. Data were analyzed using thematic content analysis.

Results

Setting goals in the admission phase is primarily the task of the multidisciplinary team rather than the nursing staff. Interventions to increase patient participation align with the coordinating role of nursing staff in the rehabilitation team. Working on short-term goals is of great value to patients.

Clinical Relevance to the Practice of Rehabilitation Nursing

The connection between the patient’s personal goals and professional treatment aimed at functional recovery can be enhanced by strengthening the position of nursing staff working in geriatric rehabilitation.

Conclusion

Members of nursing staff in geriatric rehabilitation see themselves playing a coordinating role in the multidisciplinary team, supporting the patient in goal work. Interventions aimed at advancing patient participation and providing support for short-term goals reinforce this role.
Posterior Nasal Septal Abscess Detected During Evaluation of Cavernous Sinus Thrombosis
Authors: Kim Tae Hoon , Bae Seong Yoon
Published: August 2023

Septic cavernous sinus thrombosis (CST) is a rare, life-threatening condition that commonly originates from sinusitis. Posterior nasal septal abscess (NSA) is an extremely rare cause of septic CST because it is a very rare condition by itself. Here we report a rare case involving an elderly woman with septic CST associated with a posterior NSA that was successfully treated without any sequelae. Incision and drainage of the posterior NSA were performed under local anesthesia, and the nasal packing was removed 2 days postoperatively. Pus from the abscess was sent for culture and sensitivity analyses, which revealed Enterococcus faecium. She was treated with intravenous (IV) third-generation cephalosporin (2 g twice daily) and IV vancomycin (0.75 g twice daily) for 4 weeks. IV low–molecular-weight heparin was administered at a dose of 40 mg twice daily for 4 days, followed by warfarin (3 mg once a day) for 21 days. The patient was discharged without any sequelae after 4 weeks. At the 2-month follow-up, she did not complain of any further symptoms. The findings from this case suggest that clinicians should maintain a high index of suspicion and provide prompt treatment to prevent mortality and morbidity associated with septic CST.
Partial Release of Pyriform Ligament to Prevent Deformities on Keystone Area
Authors: Öztürk Güncel
Published: August 2023

The dorsal hump deformity is common among Western countries based on the nasal structure of Caucasians. Dorsal preservation techniques which leads keeping the keystone area intact can bring positive outcomes such as obtaining aesthetic dorsal lines and better functional results. The positions of soft tissue in the face are supported with a combination of static and dynamic ansatomy. The static support is maintained by ligaments and their associations. Among the ligaments, the pyriform ligament takes a particular role in terms of supporting the alar base, lower lateral cartilages, and nasal tip. In the present research, it was aimed to investigate the beneficial effects of releasing pyriform ligament partially in patients who received dorsal preservation rhinoplasty. The data of the patients who had dorsal rhinoplasty operations for hump deformity were screened retrospectively. A total of 139 patients were included according to inclusion and exclusion criteria and their records were assessed (112 females and 27 males). Twelve months after surgery, the median Rhinoplasty Outcome Evaluation score increased from 52.5 to 91.5 points (P<0.001). Patient satisfaction was excellent in 86.95% of the included cases according to the Rhinoplasty Outcome Evaluation score. The present study shows a new, suitable, and easy approach for releasing the pyriform ligaments partially and as well as also were left intact. It is suggested that manipulation of the pyriform ligament during push-down and let-down procedures seems to be essential for obtaining a better nasal tip as well as narrowing the nose base and getting better functional outcomes.
An update on Becker muscular dystrophy
Authors: Straub Volker , Guglieri Michela
Published: August 2023

Purpose of review

The purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular dystrophy (BMD).

Recent findings

As several treatment concepts have claimed to convert patients with Duchenne muscular dystrophy (DMD) into a BMD phenotype, BMD itself has moved into the focus of clinical research. Natural history studies have helped to better characterize patients with BMD and the disease is now a target for interventional trials. In parallel, there have been advances in diagnostics and in the development of preclinical models.

Despite increased collaborative efforts to improve trial readiness amongst patients with BMD, there is still a lack of long-term natural history data, and the broad spectrum of disease severity remains a challenge for well designed clinical trials.
Genetic Association ofSLC47A1Gene Variant (17:19571562C >T) and Bioinformatics Analyses of MATE1 Protein in Chronic Kidney Disease Patients of Pakistani Origin
Authors: Hussain Mehnaz Ghulam , Saif Rashid , Younus Amna , Zahid Mehmoona , Jabeen Sadia , Younas Hooria
Published: August 2023

Chronic Kidney Disease (CKD) is a serious human threat worldwide which is associated with a number of environmental, clinical and genetic factors that affect serum creatinine (SCr) and glomerular filtration rate (eGFR). One of the best biochemical and genetic markers to study renal functioning isSLC47A1which encodes MATE1 protein and can be a promising target to study its genetic causes, subject protein is a cationic transporter involved in the regulation of creatinine and urea levels in the blood which may cause toxicity and renal disorders. Hence, the current study focused to interrogate the putative association ofSLC47A1gene variant (17:19571562C>T) in 75 individuals (cases=50, controls=25) of Pakistani origin using ARMS-PCR genotyping, out of which 10 were found heterozygous, 57 homozygous wild-type and 08 homozygous mutants. PLINK data analysis toolset was used which manifested that sampled population complies the Hardy-Weinberg Equilibrium by χ2(2,N= 75) =,p= 4.756 × 10-005, similarly the Chi-square statisticsp= 0.03274 along with odds-ratio of 3.244 showing a significant genotypic association with the subject phenotype indicating that mutant allele is almost 3-times more prevalent in cases vs control cohorts with an alternative allele frequency of 0.22 and 0.08 in CKD patients and healthy controls respectively. Besides, few of the bioinformatics tools i.e., ProtParam, PsiPred, PDB-RCSB, Motif Scan, CTU-TMHMM-2.0, ScanProsite, PRmePRed, GPS PAIL2.0, NetOGlyc4.0, NetPhos3, SIFT, Polyphen-2 and STRING were also used for the prediction of different parameters of both the wild-type and mutant MATE1 proteins such as physiochemical properties, secondary structure prediction, 3-D structure, protein conserved domains, transmembrane structures, posttranslational modifications, SNP prediction/amino acid substitution, pathogenicity and protein-protein interaction networks. Current preliminary genotyping provided an insight into the association of the aforementioned genetic variant with CKD to estimate the genetic risks along with prediction of its functional effects in the system biology context which may be considered for developing new targeted drugs along with genetic counselling initiatives to evade this peril in the population.
PARG inhibition induces nuclear aggregation of PARylated PARP1
Authors: Paradkar Sateja , Purcell Julia , Cui Annie , Friedman Sam , Sundaram Ranjini , Jensen Ryan , Bindra Ranjit
Published: August 2023

PARG inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers, however, their precise mechanism of action is still unclear. Here we report that PARG inhibition causes increased nuclear PARylated PARP1 that limits PARP1 chromatin binding in response to DNA damage. This PARylated PARP1 accumulates as aggregates at sites distinct from the site of DNA damage, leading to the mis-localization of PARP1. Additionally, these aggregates are formed through PAR chains as abrogating PARP1 catalytic activity prevents their formation. Finally, these PARP1 nuclear aggregates persist long-term and are associated with cleaved cytoplasmic PARP1, a cell death hallmark, which ultimately leads to a non-apoptotic form of cell death. Overall, our data uncovers a novel mechanism of PARG inhibitor cytotoxicity, which will inform ongoing clinical studies.
MidRISH: Unbiased harmonization of rotationally invariant harmonics of the diffusion signal
Authors: Newlin Nancy R. , Kim Michael E. , Kanakaraj Praitayini , Yao Tianyuan , Hohman Timothy , Pechman Kimberly R. , Beason-Held Lori L. , Resnick Susan M. , Archer Derek , Jefferson Angela , Landman Bennett A. , Moyer Daniel
Published: August 2023

Objective

Data harmonization is necessary for removing confounding effects in multi-site diffusion image analysis. One such harmonization method, LinearRISH, scales rotationally invariant spherical harmonic (RISH) features from one site (“target”) to the second (“reference”) to reduce confounding scanner effects. However, reference and target site designations are not arbitrary and resultant diffusion metrics (fractional anisotropy, mean diffusivity) are biased by this choice. In this work we propose MidRISH: rather than scaling reference RISH features to target RISH features, we project both sites to a mid-space.

Methods

We validate MidRISH with the following experiments: harmonizing scanner differences from 37 matched patients free of cognitive impairment, and harmonizing acquisition and study differences on 117 matched patients free of cognitive impairment.

Conclusion

MidRISH reduces bias of reference selection while preserving harmonization efficacy of LinearRISH.

Significance

Users should be cautious when performing LinearRISH harmonization. To select a reference site is to choose diffusion metric effect-size. Our proposed method eliminates the bias-inducing site selection step.
Water migration through enzyme tunnels is sensitive to choice of explicit water model
Authors: Thirunavukarasu Aravind Selvaram , Szleper Katarzyna , Tanriver Gamze , Mitusinska Karolina , Gora Artur , Brezovsky Jan
Published: August 2023

Understanding the utilization of tunnels and water transport within enzymes is crucial for the catalytic function of enzymes, as water molecules can stabilize bound substrates and help with unbinding processes of products and inhibitors. Since the choice of water models for molecular dynamics simulations was shown to determine the accuracy of various calculated properties of the bulk solvent and solvated proteins, we have investigated if and to what extent the water transport through the enzyme tunnels depends on the selection of the water model. Here, we have focused on simulating enzymes with various well-defined tunnel geometries. In a systematic investigation using haloalkane dehalogenase as a model system, we focused on the well-established TIP3P, OPC, and TIP4P-Ew water models to explore their impact on using tunnels for water molecules transport. The TIP3P water model showed significantly faster migration, resulting in the transport of approximately 2.5 times more water molecules in comparison to OPC and 2.0 times greater than the TIP4P-Ew. The increase in migration of TIP3P water molecules was mainly due to faster transit times, and in the case of narrower tunnels, greater concurrent transport was evident as well. We have observed similar behavior in two different enzymes with buried active sites and different tunnel network topologies, indicating that our findings are likely not restricted to a particular enzyme family. Our study emphasizes the critical importance of water models in comprehending the use of enzyme tunnels for small molecule transport. Given the significant role of water availability in various stages of the catalytic cycle and solvation of substrates, products, and drugs, choosing an appropriate water model might be crucial for accurate simulations of complex enzymatic reactions, rational enzyme design, and predicting drug residence times.
PROTAC-mediated Degradation of HIV-1 Nef Efficiently Restores Cell-surface CD4 and MHC-I Expression and Blocks HIV-1 Replication
Authors: Emert-Sedlak Lori A. , Tice Colin M. , Shi Haibin , Alvarado John J. , Shu Sherry T. , Reitz Allen B. , Smithgall Thomas E.
Published: August 2023

The HIV-1 Nef accessory factor is critical to the viral life cyclein vivowhere it promotes immune escape of HIV-infected cells and viral persistence. While these features identify Nef as an attractive antiretroviral drug target, Nef lacks enzymatic activity and an active site, complicating development of occupancy-based drugs. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on a previously reported hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the Cereblon E3 ubiquitin ligase, resulting in ubiquitylation of Nef and proteolytic degradation. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation of Nef is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cellsin vivo.
Apparent RNA bridging between PRC2 and chromatin is an artefact of non-specific chromatin precipitation upon RNA degradation
Authors: Hickman Alex Hall , Jenner Richard G.
Published: August 2023

Polycomb repressive complex 2 (PRC2) modifies chromatin to maintain repression of genes specific for other cell lineages and is essential for development. In vitro, RNA inhibits PRC2 catalytic activity and interaction with nucleosomes but the effect of RNA on PRC2 in cells has been unclear, with studies concluding that RNA either antagonises or promotes the association of PRC2 with chromatin. The addition of RNase A to chromatin immunoprecipitation reactions has been reported to reduce detection of PRC2 target sites, suggesting the existence of an RNA bridge that connects PRC2 to chromatin. Here, we show that this apparent loss of PRC2 chromatin association after RNase A treatment is due to non-specific chromatin precipitation. RNA degradation causes chromatin to precipitate out of solution, thereby reducing the enrichment of specific DNA sequences in chromatin immunoprecipitation reactions. Maintaining chromatin solubility by the addition of poly-L-glutamic acid (PGA) rescues detection of PRC2 chromatin association upon RNA degradation. These findings undermine support for the model that RNA bridges PRC2 and chromatin in cells.
Pure wild forest reindeer (Rangifer tarandus fennicus) or hybrids? A whole-genome sequencing approach to solve the taxonomical status
Authors: Weldenegodguad Melak , Niemi Milla , Mykrä-Pohja Sakari , Pokharel Kisun , Hamama Tuula-Marjatta , Paasivaara Antti , Kantanen Juha
Published: August 2023

In Finland, the geographic distribution of semi-domestic reindeer (Rangifer tarandus tarandus) and wild forest reindeer (Rangifer tarandus fennicus) partly overlap in the vicinity of the southern border of the reindeer herding area. Hybridisation of these two subspecies is one of the major threats for the wild forest reindeer population, and the implemented conservation program targets preventing the crossbreeding of these reindeer. In this paper, we resequenced genomes of fourRangifer tarandusindividuals with unknown taxonomical status and investigated their ancestries by comparing the genomic data with the existing resequenced data of the Finnish semi-domestic reindeer and Finnish wild forest reindeer. The genetic relationship investigations suggest that the four individuals were pure forest reindeer animals. Our study provides critical knowledge for practical conservation actions of wild forest reindeer in the reintroduction project, for which it is essential to recognise each individual’s origin. In the future, it will also offer novel insights into the spread of native wild forest reindeer to new geographic regions in Finland. For subsequent studies, additional resequenced genomic data ofRangiferindividuals will be needed to develop an ancestry information marker panel of single nucleotide polymorphisms for rapid and cost-effective identification of hybrid individuals of semi-domestic reindeer and wild forest reindeer.
Shocker - a molecular dynamics protocol and tool for accelerating and analyzing the effects of osmotic shocks
Authors: van Tilburg Marco P. A. , Marrink Siewert J. , König Melanie , Grünewald Fabian
Published: August 2023

The process of osmosis, a fundamental phenomenon in life, drives water through a semi-permeable membrane in response to a solute concentration gradient across this membrane. In vitro, osmotic shocks are often used to drive shape changes in lipid vesicles, for instance, to study fission events in the context of artificial cells. While experimental techniques provide a macroscopic picture of large-scale membrane remodeling processes, molecular dynamics (MD) simulations are a powerful tool to study membrane deformations at the molecular level. However, simulating an osmotic shock is a time-consuming process due to the slow water diffusion across the membrane, making it practically impossible to examine its effects in classic MD simulations. In this paper, we present Shocker, a Python-based MD tool for simulating the effects of an osmotic shock by selecting and relocating water particles across a membrane over the course of several pumping cycles. Although this method is primarily aimed at efficiently simulating volume changes of vesicles it can handle membrane tubes and double bilayer systems as well. Additionally, Shocker is force field independent and compatible with both coarse-grained and all-atom systems. We demonstrate that our tool is applicable to simulate both hypertonic and hypotonic osmotic shocks for a range of vesicular and bilamellar setups, including complex multi-component systems containing membrane proteins or crowded internal solutions.
Automated, high-throughput quantification of EGFP-expressing neutrophils in zebrafish by machine learning and a highly-parallelized microscope
Authors: Efromson John , Ferrero Giuliano , Bègue Aurélien , Doman Thomas Jedidiah Jenks , Dugo Clay , Barker Andi , Saliu Veton , Reamey Paul , Kim Kanghyun , Harfouche Mark , Yoder Jeffrey A.
Published: August 2023

Normal development of the immune system is essential for overall health and disease resistance. Bony fish, such as the zebrafish (Danio rerio), possess all the major immune cell lineages as mammals and can be employed to model human host response to immune challenge. Zebrafish neutrophils, for example, are present in the transparent larvae as early as 48 hours post fertilization and have been examined in numerous infection and immunotoxicology reports. One significant advantage of the zebrafish model is the ability to affordably generate high numbers of individual larvae that can be arrayed in multi-well plates for high throughput genetic and chemical exposure screens. However, traditional workflows for imaging individual larvae have been limited to low-throughput studies using traditional microscopes and manual analyses. Using a newly developed, parallelized microscope, the Multi-Camera Array Microscope (MCAM™), we have optimized a rapid, high-resolution algorithmic method to count fluorescently labeled cells in zebrafish larvaein vivo. Using transgenic zebrafish larvae, in which neutrophils express EGFP, we captured 18 gigapixels of images across a full 96-well plate, in 75 seconds, and processed the resulting datastream, counting individual fluorescent neutrophils in all individual larvae in 5 minutes. This automation is facilitated by a machine learning segmentation algorithm that defines the most in-focus view of each larva in each well after which pixel intensity thresholding and blob detection are employed to locate and count fluorescent cells. We validated this method by comparing algorithmic neutrophil counts to manual counts in larvae subjected to changes in neutrophil numbers, demonstrating the utility of this approach for high-throughput genetic and chemical screens where a change in neutrophil number is an endpoint metric. Using the MCAM™ we have been able to, within minutes, acquire both enough data to create an automated algorithm and execute a biological experiment with statistical significance. Finally, we present this open-source software package which allows the user to train and evaluate a custom machine learning segmentation model and use it to localize zebrafish and analyze cell counts within the segmented region of interest. This software can be modified as needed for studies involving other zebrafish cell lineages using different transgenic reporter lines and can also be adapted for studies using other amenable model species.
Molecular evolution and adaptation of SARS-CoV-2 omicron XBB sub-lineage Spike protein under African selection pressure
Authors: Kambarami Milton S , Godwins Ngorima , Moyo Praise K , Lucy Mabaya , Tawanda Mushiri , Justen Manasa
Published: August 2023

The SARS-CoV-2 Omicron variant of concern (VOC) has multiple mutations in the spike (S) protein, which mediates viral infection and immunity. We analysed a sub-lineage of Omicron, designated XBB, that showed structural and functional changes in the S protein in response to the African selection pressures. We used molecular modelling to compare the S protein structures of Omicron and XBB and found that XBB had a reduced receptor-binding domain (RBD) due to the loss of some β-sheets, which may increase its affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. We also used Fast Unconstrained Bayesian AppRoximation (FUBAR) and Recombination Detection Program 4 (RDP 4) to perform selection and recombination analysis of the S protein sequences of Omicron and XBB and detected signals of positive selection and recombination in the N-terminal domain (NTD) of the S1 subunit, which contains antibody-binding epitopes, and the RBD, which is involved in viral entry. Our results reveal the structural and functional adaptation of the Omicron XBB variant in Africa and its potential implications for viral pathogenesis and immunity.
GSK3α/β restrains IFNγ-inducible costimulatory molecule expression in alveolar macrophages, limiting CD4+T cell activation
Authors: Ankley Laurisa M. , Conner Kayla N. , Vielma Taryn E. , Thapa Mahima , Olive Andrew J
Published: August 2023

Macrophages play a crucial role in eliminating respiratory pathogens. Both pulmonary resident alveolar macrophages (AMs) and recruited macrophages contribute to detecting, responding to, and resolving infections in the lungs. Despite their distinct functions, it remains unclear how these macrophage subsets regulate their responses to infection, including how activation by the cytokine IFNγ is regulated. This shortcoming prevents the development of therapeutics that effectively target distinct lung macrophage populations without exacerbating inflammation. We aimed to better understand the transcriptional regulation of resting and IFNγ-activated cells using a newex vivomodel of AMs from mice, fetal liver-derived alveolar-like macrophages (FLAMs), and immortalized bone marrow-derived macrophages (iBMDMs). Our findings reveal that IFNγ robustly activates both macrophage types; however, the profile of activated IFNγ-stimulated genes varies greatly between these cell types. Notably, FLAMs show limited expression of costimulatory markers essential for T cell activation upon stimulation with only IFNγ. To understand cell type-specific differences, we examined how the inhibition of the regulatory kinases GSK3α/β alters the IFNγ response. GSK3α/β controlled distinct IFNγ responses, and in AM-like cells, we found GSK3α/β restrained the induction of type I IFN and TNF, thus preventing the robust expression of costimulatory molecules and limiting CD4+T cell activation. Together, these data suggest that the capacity of AMs to respond to IFNγ is restricted in a GSK3α/β-dependent manner and that IFNγ responses differ across distinct macrophage populations. These findings lay the groundwork to identify new therapeutic targets that activate protective pulmonary responses without driving deleterious inflammation.