bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence of globular cluster abundance anomalies in the SMC intermediate-age cluster Kron 3
Authors: Salgado C , Da Costa G S , Yong D , Salinas R , Norris J E , Mackey A D , Marino A F , Milone A P
Published: June 2022

Using spectra obtained with the VLT/FORS2 and Gemini-S/GMOS-S instruments, we have investigated carbon, nitrogen, and sodium abundances in a sample of red giant members of the Small Magellanic Cloud star cluster Kron 3. The metallicity and luminosity of the cluster are comparable to those of Galactic globular clusters but it is notably younger (age ≈ 6.5 Gyr). We have measured the strengths of the CN and CH molecular bands, finding a bimodal CN band-strength distribution and a CH/CN anticorrelation. Application of spectrum synthesis techniques reveals that the difference in the mean [N/Fe] and [C/Fe] values for the CN-strong and CN-weak stars are Δ <[N/Fe]> = 0.63 ± 0.16 dex and Δ <[C/Fe]> = −0.01 ± 0.07 dex after applying corrections for evolutionary mixing. We have also measured sodium abundances from the Na D lines finding an observed range in [Na/Fe] of ∼0.6 dex that correlates positively with the [N/Fe] values and a Δ <[Na/Fe]> = 0.12 ± 0.12 dex. While the statistical significance of the sodium abundance difference is not high, the observed correlation between the Na and N abundances supports its existence. The outcome represents the first star-by-star demonstration of correlated abundance variations involving sodium in an intermediate-age star cluster. The results add to existing photometric and spectroscopic indications of the presence of multiple populations in intermediate-age clusters with masses in excess of ∼105 M⊙. It confirms that the mechanism(s) responsible for the multiple populations in ancient globular clusters cannot solely be an early cosmological effect applying only in old clusters.
Oct4A palmitoylation modulates tumorigenicity and stemness in human glioblastoma cells
Authors: Chen Xueran , Niu Wanxiang , Fan Xiaoqing , Yang Haoran , Zhao Chenggang , Fan Junqi , Yao Xuebiao , Fang Zhiyou
Published: June 2022

Background

Glioblastoma multiforme and other solid malignancies are heterogeneous, containing subpopulations of tumor cells that exhibit stem characteristics. Oct4, also known as POU5F1, is a key transcription factor in the self-renewal, proliferation, and differentiation of stem cells. Although it has been detected in advanced gliomas, the biological function of Oct4, and transcriptional machinery maintained by the stemness of Oct4 protein-mediated glioma stem cells (GSC), has not been fully determined.

Methods

The expression of Oct4 variants was evaluated in brain cancer cell lines, and in brain tumor tissues, by quantitative real-time PCR, western blotting, and immunohistochemical analysis. The palmitoylation level of Oct4A was determined by the acyl-biotin exchange method, and the effects of palmitoylation Oct4A on GSCs were investigated by a series of in vitro (neuro-sphere formation assay, double immunofluorescence, pharmacological treatment, luciferase assay, and coimmunoprecipitation) and in vivo (xenograft model) experiments.

Results

Here, we report that all three variants of Oct4 are expressed in different types of cerebral cancer, while Oct4A is important for maintaining tumorigenicity in GSCs. Palmitoylation mediated by ZDHHC17 was indispensable for preserving Oct4A from lysosome degradation to maintain its protein stability. Oct4A palmitoylation also helped to integrate Sox4 and Oct4A in the SOX2 enhancement subregion to maintain the stem performance of GSCs. We also designed Oct4A palmitoylation competitive inhibitors, inhibiting the self-renewal ability and tumorigenicity of GSCs.

Conclusions

These findings indicate that Oct4A acts on the tumorigenic activity of glioblastoma, and Oct4A palmitoylation is a candidate therapeutic target.
Lipidomic Analysis of Arabidopsis T-DNA Insertion Lines Leads to Identification and Characterization of C-Terminal Alterations in FATTY ACID DESATURASE 6
Authors: Lusk Hannah J , Neumann Nicholas , Colter Madeline , Roth Mary R , Tamura Pamela , Yao Libin , Shiva Sunitha , Shah Jyoti , Schrick Kathrin , Durrett Timothy P , Welti Ruth
Published: June 2022

Mass-spectrometry-based screening of lipid extracts of wounded and unwounded leaves from a collection of 364 Arabidopsis thaliana T-DNA insertion lines produced lipid profiles that were scored on the number and significance of their differences from the leaf lipid profiles of wild-type plants. The analysis identified Salk_109175C, which displayed alterations in leaf chloroplast glycerolipid composition, including a decreased ratio between two monogalactosyldiacylglycerol (MGDG) molecular species, MGDG(18:3/16:3) and MGDG(18:3/18:3). Salk_109175C has a confirmed insertion in the At5g64790 locus; the insertion did not co-segregate with the recessive lipid phenotype in the F2 generation of a wild-type (Columbia-0) × Salk_109175C cross. The altered lipid compositional phenotype mapped to the At4g30950 locus, which encodes the plastidial ω-6 desaturase FATTY ACID DESATURASE 6 (FAD6). Sequencing revealed a splice-site mutation, leading to the in-frame deletion of 13 amino acids near the C-terminal end of the 448 amino acid protein. Heterologous expression in yeast showed that this deletion eliminates desaturase activity and reduces protein stability. Sequence comparison across species revealed that several amino acids within the deletion are conserved in plants and cyanobacteria. Individual point mutations in four conserved residues resulted in 77–97% reductions in desaturase activity, while a construct with all four alanine substitutions lacked activity. The data suggest that the deleted region of FAD6, which is on the C-terminal side of the four putative transmembrane segments and the histidine boxes putatively involved in catalysis, is critical for FAD6 function.
Under pressure: The extent and distribution of perceived pressure among scientists in Germany, Austria, and Switzerland
Authors: Johann David , Raabe Isabel J , Rauhut Heiko
Published: June 2022

While it has been stressed repeatedly that academics nowadays have come to face extensive pressure, the extent and distribution of pressure to publish and to secure third-party funding has not been systematically investigated on a large scale. Based on the Zurich Survey of Academics, a representative large-scale web survey among academics working at universities in Germany, Austria, and Switzerland (DACH region), which measures perceived pressure using six-point Likert scales, this article examines the extent and distribution of pressure to publish and to attract external funding. Specifically, we examine differences in perceived pressure across countries, disciplines, types of higher education institutions, sociodemographic characteristics (academic status, age, gender, relationship status, number of children), and working conditions (non-tenured/tenured, time available for research). It is shown that researchers in the DACH region feel a high level of pressure, with the pressure to publish being slightly greater than the pressure to attract external funding. The results also suggest that perceived pressure is not evenly distributed among countries and groups of academics. Specifically, the results suggest that (1) more secure and permanent (tenured) positions should be created and (2) the high-performance culture should be addressed in at least some disciplines if excessive pressure is to be alleviated. The findings also suggest that further investments should be made (3) to promote equal career opportunities for women and men and (4) to ensure that scientists have sufficient time for their research and are not too occupied with other responsibilities, such as teaching or administrative duties.
Cold White of Day: White, colour, and materiality in the twentieth-century British hospital
Authors: Bates Victoria
Published: June 2022

The built environment is central to modern history. However, scholars have paid much more attention to buildings’ architecture, appearance, and layout, than to their interior decoration, materiality and sensory qualities. There is great opportunity for historians in these latter areas of study. This article makes a case for the value of putting colour at the centre of research, as a material part of the making of modern Britain. It focuses on the uses of ‘white’, or rather surfaces and objects in many shades of white, and takes the case study of twentieth-century British hospitals to do so. It shows that whiteness stayed important in modern British hospitals as part of an expanding colour palette, rather than being replaced or relegated with the rise of the pastel-colour welfare state, particularly as a symbol of hygiene but also as a continued part of creating ‘modern’ and ‘humanistic’ hospitals. This article also suggests that historians might productively use material concepts to understand relationships between continuity and change, rather than adhering to the traditional political periodizations that dominate modern British history.
Comparative Genomics of Barley-Infecting Xanthomonas translucens Shows Overall Genetic Similarity but Globally Distributed Virulence Factor Diversity
Authors: Heiden Nathaniel , Roman-Reyna Veronica , Curland Rebecca D. , Dill-Macky Ruth , Jacobs Jonathan M.
Published: June 2022

Xanthomonas translucens pv. translucens (Xtt) is a global barley patho-gen and a concern for resistance breeding and regulation. Long-read whole genome sequences allow in-depth understanding of pathogen diversity. We have completed long-read PacBio sequencing of two Minnesotan Xtt strains and an in-depth analysis of available Xtt genomes. We found that average nucleotide identity (ANI)-based approaches organize Xtt strains different from the previous standard multilocus sequencing analysis approach. According to ANI, Xtt forms a separate clade from X. translucens pv. undulosa and consists of three main groups which are represented on multiple continents. Some virulence factors, such as 17 Type III-secreted effectors, are highly conserved and offer potential targets for the elicitation of broad resistance. However, there is a high degree of variation in virulence factors, meaning that germplasm should be screened for resistance with a diverse panel of Xtt.
A Retrospective Cohort Study of Treatment Outcomes of Adult Patients With Relapsed or Refractory Follicular Lymphoma (ReCORD-FL)
Authors: Salles Gilles , Schuster Stephen J. , Fischer Luca , Kuruvilla John , Patten Piers E. M. , von Tresckow Bastian , Smith Sonali , Jiménez-Ubieto Ana , Davis Keith L. , Nagar Saurabh , Zhang Jie , Bollu Vamsi , Jousseaume Etienne , Ramos Roberto , Wang Yucai , Link Brian K.
Published: June 2022

This study (ReCORD-FL) sought to construct a historical control cohort to augment single-arm trials in relapsed/refractory follicular lymphoma (r/r FL). A retrospective study in 10 centers across North America and Europe was conducted. Adults with grade 1–3A FL were required to be r/r after ≥2 therapy lines including an anti-CD20 and an alkylator. After first becoming r/r, patients were required to initiate ≥1 additional therapy line, which defined the study index date. Endpoints were observed from start of each therapy line (including index line) until death, last follow-up, or December 31, 2020. Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment or death (TNT-D), event-free survival (EFS), and overall survival (OS). One hundred eighty-seven patients were identified. Most patients’ (80.2%) index therapy occurred in third line (3L) (range, 3L–6L). Median follow-up from FL diagnosis was 9 years (range, 1–21 years). CR and ORR to the index therapy were 39.0% and 70.6%, respectively. Median (95% confidence interval) EFS from index was 14.6 (11.0-18.0) months; median OS from index was 10.6 years. Outcomes worsened across successive treatment lines and for patients who were double refractory (r/r to both an anti-CD20 monoclonal antibody and an alkylator) or POD24 (progressed ≤24 months after front-line anti-CD20) at index. Findings demonstrate the unmet need of FL patients with multiply relapsed, double refractory, or POD24 disease. Based on robustness of the historical data collected and comparability with a previous study (SCHOLAR-5), ReCORD-FL presents a valuable source of control data for comparative studies in r/r FL.
Visual disturbances produced after the implantation of 3 EDOF intraocular lenses vs 1 monofocal intraocular lens
Authors: Guarro Mercè , Sararols Laura , Londoño Gabriel J. , Goñi Idoia , Vázquez Meritxell , Ruiz Sergi , López Silvia
Published: June 2022

Purpose:

To compare the visual disturbances experienced by patients receiving 1 of 3 extended depth-of-focus (EDOF) intraocular lenses (IOLs) or a monofocal IOL as the control.

Setting:

OMIQ-Recerca Center. Spain.

Design:

Prospective comparative randomized double-blind study.

Methods:

22 patients were included per group. The IOLs evaluated were the AcrySof IQ Vivity (Vivity group), AT LARA 829MO (AT Lara group), or TECNIS Symfony ZXR00 (Symfony group) and the monofocal AcrySof IQ SN60WF (Monofocal group). The variables analyzed were the light distortion index (LDI), best-fit circle radius (BFCRad), and self-reported vision quality with a questionnaire (QoV). Outcomes were evaluated at the 3-month follow-up visit.

Results:

Under monocular conditions, no differences between groups were detected for the LDI and BFCRad. Under binocular conditions, significant differences in both variables were produced. The Monofocal group reported better values than Symfony (P = .025; P = .024) and AT Lara (P = .002; P = .002) groups. The Vivity group reported better values than Symfony (P = .015; P = .014) and AT Lara (P = .001; P = .001) groups. Halos were not reported by 81.8% (18) of patients in the Vivity group, 90.9% (20) of patients in the Monofocal group, 50% (11) of patients in the AT Lara group, and 59% (13) of patients in the Symfony group.

Conclusions:

The diffractive EDOF IOL models examined in this study induced similar visual disturbances, which were worse than those produced by the nondiffractive extended-range IOL and the monofocal IOL. The nondiffractive lens and the monofocal lens did not show differences.
Acute-onset postoperative endophthalmitis after cataract surgery performed by resident and attending physicians at a university teaching hospital
Authors: Kunkler Anne L. , Sengillo Jesse D. , Al-Khersan Hasenin , Fan Kenneth C. , Laura Diana M. , Miller Darlene , Donaldson Kendall E. , Yoo Sonia H. , Yannuzzi Nicolas A. , Sridhar Jayanth , Gedde Steven J. , Smiddy William E. , Flynn Harry W.
Published: June 2022

Purpose:

To evaluate acute-onset postoperative endophthalmitis following cataract surgery and to compare rates between resident and attending physician-performed cohorts.

Setting:

Bascom Palmer Eye Institute, Miami, Florida.

Design:

Retrospective chart review.

Methods:

Records of patients diagnosed with endophthalmitis within 6 weeks of surgery performed by attending and resident physicians between January 1, 2015, and December 31, 2020, were reviewed. Total cataract volume was obtained from institutional records, and resident case totals were obtained from case logs. Endophthalmitis cases were obtained from billing records and confirmed with chart review.

Results:

There were 22 cases of endophthalmitis among 32 505 cases (0.068%). Endophthalmitis occurred in 6 of 6447 (0.093%) resident cases and 16 of 26 058 (0.061%) attending cases (P = .55). The most common bacterial isolates were coagulase-negative Staphylococcus (8/22, 36.3%) and Streptococcus species (3/22, 13.6%), with negative cultures in 10 (10/22, 45.5%). Initial treatment with vitreous tap and injection of intravitreal antibiotics was performed in 21 eyes (21/22, 95.4%) and vitrectomy with intravitreal antibiotic injection in one (1/22, 4.5%). Vitrectomy was performed secondarily in 9 patients (9/22, 40.9%). Corrected distance visual acuity (CDVA) at last follow-up was ≥20/40 in 13 eyes (13/22, 59%) and ≤hand motions in 3 eyes (3/22, 13.6%). CDVA (logMAR mean ± SD) was 1.22 ± 1.16 in resident and 0.49 ± 0.79 in attending cases (P = .11).

Conclusions:

In the current study, acute-onset postoperative endophthalmitis developed infrequently following cataract surgery. The rates and visual outcomes of endophthalmitis were similar in resident and attending cases.
Dermoscopic Assessment of Lymphangioma Circumscriptum Treated With Topical Sirolimus Ointment: A Case Report
Authors: Ankad Balachandra Suryakant , Smitha Sankappanavara Veeranna , Nagur Sushila
Published: June 2022

Introduction:

Lymphangioma circumscriptum (LC) is characterized by malformation of superficial lymphatics. Dermoscopy reveals brownish-yellow lacunae and white septa. In scrotal LC, gray and red areas are also noted. Treatment of LC is challenging because of its high recurrence.

We herein report a case of scrotal LC that was successfully treated with topical sirolimus with dermoscopic assessment of the therapeutic response.

Case presentation:

A male patient presented with fluid-filled lesions on the scrotum after partial penectomy. Examination revealed multiple skin-colored vesicles containing serous fluid on either side of the scrotum. Dermoscopy showed brownish-yellow lacunae with white septa as specific patterns. A diagnosis of secondary LC was made based on the clinical and dermoscopic features, and the patient was treated with 0.1% topical sirolimus ointment.

Discussion:

Management of LC includes close follow-up. Sirolimus, by inhibiting cellular proliferation and angiogenesis, helps in the regression of vesicular lesions of LC. Furthermore, dermoscopy supports an accurate evaluation of the therapeutic response.

Conclusion:

Sirolimus is a promising topical agent in the treatment of LC. Dermoscopy comes handy in the evaluation of treatment response. Any residual lesions could be noted and treated accordingly.
Photoprotection Knowledge and Photoprotective Behavior of University Students: A Cross-sectional Study in Indonesia
Authors: Roren Regina Stefani , Mario Christopher Paulus , Novia Jayadi Nana
Published: June 2022

Objective:

Awareness regarding the negative effects of ultraviolet radiation are commonly neglected in Asian countries. This study sought to evaluate the ultraviolet radiation knowledge and photoprotective behaviors of university students in Indonesia.

Methods:

This observational cross-sectional was conducted at Pelita Harapan University, Indonesia.

Results:

A total of 89 (45.4%) medical students and 107 (54.6%) nonmedical students participated in this study. Their mean age was 21.03 ± 2.03 years, and 46.4% of them had Fitzpatrick type III skin. Medical students as well as older students exhibited a higher level of knowledge regarding photoprotection (P ≤ 0.05). Factors related to good photoprotective behaviors were sex, older age, and average expenditure on skincare. Further analysis revealed that a high level of knowledge regarding photoprotection was related to acceptable photoprotective behaviors (P = 0.01; odds ratio = 1.97; 95% confidence interval = 1.13–3.54).

Conclusions:

Knowledge regarding sun-related damage and practice of photoprotective behaviors were low among the participants. The results indicate that formal education and academic subjects should incorporate the topic of sun-related damage and promote the practice of photoprotective behaviors early on to increase awareness among populations.
Management of hypertension in advanced kidney disease
Authors: Georgianos Panagiotis I. , Agarwal Rajiv
Published: June 2022

Purpose of review

The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).

Recent findings

In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11–12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7–10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension.

Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.
Physical Activity After Transient Ischemic Attack or Mild Stroke Is Business as Usual
Authors: Sammut Maria , Haracz Kirsti , Shakespeare David , English Coralie , Crowfoot Gary , Fini Natalie , Nilsson Michael , Janssen Heidi
Published: June 2022

Background and Purpose:

Regular, sustained moderate-to-vigorous physical activity (MVPA) is a recommended strategy to reduce the risk of recurrent stroke for people who have had transient ischemic attack (TIA) or mild stroke. This study aimed to explore attitudes toward, and experience of engaging in physical activity by adults following a TIA or mild stroke.

Methods:

Constructivist grounded theory methodology informed data collection and analysis. Interviews from 33 adults with TIA or mild stroke (mean age 65 [SD 10] years, 48% female, 40% TIA) were collected.

Results:

Business as usual characterized physical activity engagement post-TIA or mild stroke. Most participants returned to prestroke habits, as either regular exerciser or nonexerciser, with only a small number making changes. Influencing factors for physical activity participation included information, challenges, strategies, and support. Business as usual was associated with a perceived lack of information to suggest a need to change behaviors. Nonexercisers and those who decreased physical activity emphasized challenges to physical activity, while regular exercisers and those who increased physical activity focused on strategies and support that enabled participation despite challenges.

Discussion and Conclusion:

Information about the necessity to engage in recommended physical activity levels requires tailoring to the needs of the people with TIA or mild stroke. Helpful information in combination with support and strategies may guide how to navigate factors preventing engagement and might influence the low level of physical activity prevalent in this population.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A376).
Pediatric Return Visits to the Emergency Department
Authors: Ramgopal Sriram , Varma Selina , Victor Timothy W. , McCarthy Danielle M. , Rising Kristin L.
Published: June 2022

Objective

Although 72-hour return visits are a frequently reported metric for pediatric patients discharged from the emergency department (ED), the basis for this metric is not established. Our objective was to statistically derive a cutoff time point for the characterization of pediatric return visits.

Methods

We performed a retrospective cohort study using data of patients discharged from any of 44 pediatric EDs. We selected the first encounter per patient from January 1 to December 31, 2019, as the index encounter and included the first return visit within 30 days. We constructed a cumulative hazard curve to characterize the timing of return visits and constructed a multivariable adaptive regression spline model to identify a hinge point in return visit presentations. We identified the association between admission for early return visits and admission for late return visits using generalized linear mixed modeling.

Results

Of 1,986,778 index ED discharges, 193,605 (9.7%) ED return visits were included. A double-exponential decay model demonstrated superior fit compared with a single exponential model (P < 0.0001). Multivariable adaptive regression spline modeling identified a hinge at 7 days. When comparing proportions of return visits leading to hospitalization between early (23.8%) and late (15.1%) return visits, early visits (≤7 days) had higher adjusted odds of hospital admission (adjusted odds ratio, 1.73; 95% confidence interval, 1.69–1.77) relative to late return visits (>7 days). Findings were similar in sensitivity analyses within age subgroups, Census region, and in which the diagnosis (using the Diagnosis and Grouping System) was the same between the index and return visit. Among return visits that occurred within 7 days of the index visit, 46.3% had the same diagnosis grouping in both visits.

Conclusions

An empirically derived 7-day cutoff may be more appropriate for characterization of pediatric return visits to the ED. Encounters after this period had lower adjusted odds of admission.
Long-Term Follow-Up into Adulthood of Pediatric-Onset Primary Sclerosing Cholangitis and Autoimmune Sclerosing Cholangitis
Authors: Hercun Julian , Willems Philippe , Bilodeau Marc , Vincent Catherine , Alvarez Fernando
Published: June 2022

Objectives:

Studies on pediatric patients with primary sclerosing cholangitis (PSC) have been limited by short follow-up and inconsistent classification of pediatric patients with autoimmune hepatitis-sclerosing cholangitis overlap (AIC). We conducted a retrospective study of patients diagnosed with AIC or PSC during childhood with extension of follow-up into adulthood.

Methods:

We reviewed records of patients followed for PSC or AIC between 1998 and 2019 at a pediatric referral center. Features at diagnosis, biochemical and liver-related outcomes (cholangitis, liver transplant, and cirrhosis) were compared.

Results:

Forty patients (27 PSC, 13 AIC) were followed for 92 months on average (standard deviation 79 months) with extension into adulthood in 52.5%; 70% had associated inflammatory bowel disease (IBD). The proportion of patients with significant fibrosis and abnormal baseline liver tests (serum bilirubin and transaminase levels) were similar in both groups. One year postdiagnosis, 55% (15/27) of PSC patients had normal liver tests versus only 15% (2/13) in the AIC group (P = 0.02). During follow-up, more liver-related events occurred in the AIC group (69% versus 27%, hazard ratio [HR] = 3.7 [95% confidence interval (CI): 1.4–10] P = 0.01). Baseline elevated serum bilirubin levels (HR = 5.3 [95% CI: 1.7–16.9] P = 0.005) and elevated transaminase levels at 1 year (HR = 9.09 [95% CI: 1.18–66.7) P = 0.03) were predictive of liver-related events, while having IBD was not (HR = 0.48 (95% CI: 0.15–1.5) P = 0.22).

Conclusions:

Pediatric patients with AIC and PSC presented at a similar fibrosis stage, however, with a more severe hepatitis in AIC. In this cohort, AIC was associated with more liver-related events, primarily driven by a higher rate of cirrhosis compared with PSC; transplant rates were similar.
Switching from tenofovir alafenamide to tenofovir disoproxil fumarate improves lipid profile and protects from weight gain
Authors: Kauppinen Kai Juhani , Aho Inka , Sutinen Jussi
Published: June 2022

Background:

Switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) increases low-density lipoprotein cholesterol (LDL-C) and body weight. Metabolic effects of the opposite TAF-to-TDF switch are unknown.

Objectives:

To investigate the effect of TAF-to-TDF switch on plasma lipids, body weight, and atherosclerotic cardiovascular disease (ASCVD) risk score.

Design:

A retrospective chart review.

Methods:

One hundred and forty-six patients with TAF-to-TDF switch (Switch group) were compared with 146 patients matched for sex, age, and third antiretroviral agent class who continued unchanged TAF-containing regimen (Control group). Data were collected at approximately 1 year (follow-up FU-1) and 2 years (follow-up FU-2) after baseline values.

Results:

In Switch group at FU-1, total cholesterol (TC) and LDL-C decreased 12.1% and 12.4% (P < 0.001 in both), respectively. High-density lipoprotein cholesterol (HDL-C) also decreased 8.2% (P < 0.001) in Switch group, but TC/HDL-C ratio did not change. No statistically significant changes were observed in Control group in any lipid values. TC remained similarly decreased through FU-2 in Switch group, but LDL-C increased from FU-1 to FU-2 in both groups. ASCVD risk score decreased from 6.3% at baseline to 6.0% at FU-2 (P = 0.012) in Switch group but increased from 8.4 to 9.1% (P = 0.162) in Control group. Body weight increased from 83.4 kg at baseline to 84.9 kg at FU-2 (P = 0.025) in Control group but remained stable in Switch group (83.1−83.7 kg, P = 0.978).

Conclusions:

TAF-to-TDF switch improved plasma lipid profile and ASCVD risk score, as well as prevented weight gain, when compared with ongoing TAF-based antiretroviral therapy.
A retrospective real-world observational pilot analysis of Waya: a self-monitoring fitness app in Germany
Authors: Balakrishnan Preetha , Owen Elizabeth , Eberl Markus , Friedrich Benjamin , Etter Tobias
Published: June 2022

Background

The increasing prevalence of lifestyle-driven metabolic disorders poses a heavy burden on the healthcare system. Several low-cost, easily accessible, and effective weight loss interventions are being developed to improve this situation. Waya is one such German digital application that guides users to reach their desired weight in a healthy manner, by monitoring their eating habits and physical activity levels. In this retrospective real-world observational pilot study, we aimed to identify if the use of Waya helps in reducing weight as intended and the underlying factors associated with it.

Methods

Data from healthy overweight or obese participants who provided their weight information and answered the short form of the Weight Efficacy Lifestyle Questionnaire and the International Physical Activity Questionnaire activity questionnaires once before the completion of the first module (baseline) were compared with data provided after the beginning of the last module. Age and sex-based distribution were studied and the correlation between nutrition, physical activity, and weight was analyzed.

Results

Waya participants showed an improvement in nutritional behavior, physical activity levels, and weight reduction compared with baseline. These changes were independent of age and sex. Weight loss mainly correlated with improvements in nutritional behavior but not physical activity.

Conclusion

The results from our pilot study showed that Waya is beneficial in bringing about short-term weight loss mainly through behavioral changes in nutrition. Although physical activity levels improved, its influence on weight loss was not apparent.
An Automated Method for the Assessment of Memory and Learning in Larval Zebrafish
Authors: Widder Mark , Carbaugh Chance , van der Schalie William , Li Yuanzhang , Martin Monica , Pybus Brandon , Lee Patricia , Lanteri Charlotte
Published: June 2022

Zebrafish have shown value in translational research for many human diseases, including neuropsychiatric disorders and cognitive dysfunction, with low cost and rapid testing facilitating drug screening and discovery. However, some endpoints, such as associative learning and long-term memory, have relied historically on manual data tracking that slows data acquisition and increases costs. We automated an associative learning/long-term memory test developed by Hinz et al.1 using a Noldus DanioVision system and EthoVision software to enhance assay throughput and utility for monitoring learning and memory behavior through automated tracking of location and movement of individual fish.
Reduced emergent character of neural dynamics in patients with a disrupted connectome
Authors: Luppi Andrea I. , Mediano Pedro A.M. , Rosas Fernando E. , Allanson Judith , Pickard John D. , Williams Guy B. , Craig Michael M. , Finoia Paola , Peattie Alexander R.D. , Coppola Peter , Menon David K. , Bor Daniel , Stamatakis Emmanuel A.
Published: June 2022

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as “Integrated Information Decomposition,” which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems — including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients’ structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be due to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.
Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms
Authors: Verkhivker Gennady , Agajanian Steve , Kassab Ryan , Krishnan Keerthi
Published: June 2022

In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-Cov-2 Spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify local and global effects of mutations in the complexes, identify structural stability centers, characterize binding energy hotspots and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific structural stability signatures of the spike complexes that can dictate the pattern of mutational escape. By employing an integrated analysis of conformational dynamics and binding energetics, we found that the potent antibodies that efficiently neutralize Omicron spike variant can form the dominant binding energy hotpots with the conserved stability centers in which mutations may be restricted by the requirements of the folding stability and binding to the host receptor. The results show that protein stability and binding energetics of the SARS-CoV-2 spike complexes with the panel of cross-reactive ultrapotent antibodies are tolerant to the constellation of Omicron mutations. A network-based perturbation approach for mutational profiling of allosteric residues potentials revealed how antibody binding can modulate allosteric interactions and identified allosteric control points that can form vulnerable sites for mutational escape. This study suggested a mechanism in which the pattern of specific escape mutants for ultrapotent antibodies may not be solely determined by the binding interaction changes but are driven by a complex balance and tradeoffs between different local and global factors including the impact of mutations on structural stability, binding strength, long-range interactions and fidelity of allosteric signaling.
Host genetics maps to behaviour and brain structure in mice
Authors: Asbury Sarah , Lai Jonathan K.Y. , Rilett Kelly C. , Haqqee Zeeshan , Darwin Benjamin C. , Ellegood Jacob , Lerch Jason P. , Foster Jane A.
Published: June 2022

Gene-environment interactions in the postnatal period have a long-term impact on neurodevelopment. To effectively model neurodevelopment in the mouse, we incorporated several validated behavioural tests to develop a behavioural pipeline that measures translationally relevant milestones of development in mice. The behavioral phenotype of 1060 wild type and genetically-modified mice was examined in parallel with structural brain imaging. The influence of genetics, sex, and early life stress on behaviour and neuroanatomy was determined using traditional statistical and machine learning methods. The results demonstrated that neuroanatomical diversity was primarily associated with genotype whereas behavioural phenotypic diversity was observed to be more susceptible to gene-environment interactions.
A MICROFLUIDIC DEVICE FOR LONG-TERM MAINTENANCE OF ORGANOTYPIC LIVER CULTURES
Authors: de Hoyos Vega José M. , Hong Hye Jin , Loutherback Kevin , Stybayeva Gulnaz , Revzin Alexander
Published: June 2022

Liver cultures may be used for modeling disease progression, testing therapies and predicting drug induced liver injury. The complexity of the liver cultures has evolved over the years from monocultures of hepatocytes to co-cultures with non-parenchymal cells and finally to precision cut liver slices. The latter culture format retains biomolecular and cellular complexity of the native liver and therefore holds considerable promise for in vitro testing. However, liver slices remain functional for ~72 h in vitro and hold only limited utility for some of the disease modeling and therapy testing applications that require longer culture times. This paper describes a microfluidic device for longer-term maintenance of functional organotypic liver cultures. Our microfluidic culture system was designed to enable direct injection of liver tissue into a culture chamber through a valve-enabled side port. Liver tissue was embedded in collagen and remained functional for up to 31 days as highlighted by continued production of albumin. These organotypic cultures also produced bile and urea and expressed several enzymes involved in metabolism of xenobiotics. In contrast, matched liver tissue embedded in collagen and cultured in the same media in a 96-well plate lost its phenotype and function on the timescale of 3 to 5 days. The microfluidic organotypic liver cultures described here represent a significant advance in liver cultivation and may be used in the future for modeling liver diseases or for individualized selection of liver-directed therapies.
A Multi-omics Study on the Oncogenic Roles and Clinical Significance of Dynactin Family Gene (DCTN1-6) Expression in Liver Hepatocellular Carcinoma
Authors: Ullah Md. Asad , Tabassum Tahani , Rashid Afrah , Islam Nafisa Nawal , Park Moon Nyeo , Moin Abu Tayab , Kim Bonglee
Published: June 2022

In this study, we employed a comprehensive database mining approach to examine the possible oncogenic roles and clinical relevance of Dynactin family genes (DCTN1-6) in Liver Hepatocellular Carcinoma (LIHC). All the DCTNs were observed to be differentially expressed in LIHC tissues compared to the adjacent normal liver tissues. Most of the DCTNs were discovered to be aberrantly methylated (less methylated) and contain multiple somatic mutations (alteration frequency: 0.2-2.5%) in LIHC tissues. Overexpression of DCTNs was mostly associated with poor overall and relapse-free survival of LIHC patients. Alongside, all the DCTN genes were reported to be overexpressed across different demographic and clinical conditions, i.e., age, cancer stage, tumor grades, and metastatic stages of LIHC patients. DCTN expression was also associated with the infiltration levels of different immune cells, i.e., B cell, T cell, and macrophages in LIHC microenvironment. The co-expressed genes of DCTNs in the LIHC tissues were previously found to be involved in oncogenic processes in different cancer types and control crucial biological processes, i.e., nucleotide metabolism, RNA degradation, and chromosome organization. Later, the expression pattern of DCTNs was validated in two independent microarray datasets (i.e., GSE17856, GSE98383), which also supported our initial findings. All these findings suggest that DCTNs and their transcriptional and translational products are potential prognostic and therapeutic targets for LIHC diagnosis and treatment. This study will help further the development of DCTN-based diagnostic and therapeutic measures for LIHC and translate them into clinical implications.
Autophagy initiation triggers p150Glued-AP-2β interaction on the lysosomes to facilitate their transport
Authors: Tempes Aleksandra , Bogusz Karolina , Brzozowska Agnieszka , Weslawski Jan , Macias Matylda , Tkaczyk Oliver , Lew Aleksandra , Calka-Kresa Malgorzata , Bernas Tytus , Szczepankiewicz Andrzej A. , Orzoł Katarzyna , Mlostek Magdalena , Kumari Shiwani , Bakun Magdalena , Rubel Tymon , Malik Anna R. , Jaworski Jacek
Published: June 2022

The endocytic adaptor protein 2 (AP-2) complex binds dynactin as part of its noncanonical function, which is necessary for dynein-driven autophagosome transport along microtubules in neuronal axons. The absence of this AP-2-dependent transport causes neuronal morphology simplification and neurodegeneration. The mechanisms that lead to formation of the AP-2–dynactin complex have not been studied to date. However, the inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) enhances the transport of newly formed autophagosomes by influencing the biogenesis and protein interactions of Rab-interacting lysosomal protein (RILP), another dynein cargo adaptor. We tested effects of mTORC1 inhibition on interactions between the AP-2 and dynactin complexes, with a focus on their two essential subunits, AP-2β and p150Glued. We found that the mTORC1 inhibitor rapamycin enhanced p150Glued–AP-2β complex formation in both neurons and non-neuronal cells. Additional analysis revealed that the p150Glued–AP-2β interaction was indirect and required integrity of the dynactin complex. In non-neuronal cells rapamycin-driven enhancement of the p150Glued–AP-2β interaction also required the presence of cytoplasmic linker protein 170 (CLIP-170), the activation of autophagy, and an undisturbed endolysosomal system. The rapamycin-dependent p150Glued–AP-2β interaction occurred on lysosomal-associated membrane protein 1 (Lamp-1)-positive organelles but without the need for autolysosome formation. Rapamycin treatment also increased the acidification and number of acidic organelles and increased speed of the long-distance retrograde movement of Lamp-1-positive organelles. Altogether, our results indicate that autophagy regulates the p150Glued–AP-2β interaction, possibly to coordinate sufficient motor-adaptor complex availability for effective lysosome transport.
Design, development, and preliminary assessment of a novel peripheral intravenous catheter aimed at reducing early failure rates
Authors: Doyle Barry J. , Kelsey Lachlan J. , Shelverton Caroline , Abbate Gabriella , Ainola Carmen , Sato Noriko , Livingstone Samantha , Bouquet Mahe , Passmore Margaret R , Wilson Emily S. , Colombo Sebastiano , Sato Kei , Liu Keibun , Heinsar Silver , Wildi Karin , Carr Peter J. , Suen Jacky , Fraser John , Li Bassi Gianluigi , Keogh Samantha
Published: June 2022

Background

Peripheral intravenous catheters (PIVCs) are the most commonly used invasive medical device, yet despite best efforts by end-users, PIVCs experience unacceptably high early failure rates. We aimed to design a new PIVC that reduces the early failure rate of in-dwelling PIVCs and we conducted preliminary tests to assess its efficacy and safety in a large animal model of intravenous access.

Methods

We used computer-aided design and simulation to create a PIVC with a ramped tip geometry, which directs the infused fluid away from the vein wall; we called the design the FloRamp™. We created FloRamp prototypes (test device) and tested them against a market-leading device (BD Insyte™; control device) in a highly-controlled setting with five insertion sites per device in four pigs. We measured resistance to infusion and visual infusion phlebitis (VIP) every six hours and terminated the experiment at 48 hours. Veins were harvested for histology and seven pathological markers were assessed.

Results

Computer simulations showed that the optimum FloRamp tip reduced maximum endothelial shear stress by 60%, from 12.7Pa to 5.1Pa, compared to a typical PIVC tip, and improved the infusion dynamics of saline in the blood stream. In the animal study, we found that 2/5 of the control devices were occluded after 24 hours, whereas all test devices remained patent and functional. The FloRamp created less resistance to infusion (0.73±0.81 vs 0.47±0.50, p=0.06) and lower VIP scores (0.60±0.93 vs 0.31±0.70, p=0.09) that the control device, although neither findings were significantly different. Histopathology revealed that 5/7 of the assessed markers were lower in veins with the FloRamp.

Conclusions

As PIVCs are used in almost every hospitalized patient, there is an urgent need to reduce failure rates. Herein we report preliminary assessment of a novel PIVC design, which could be advantageous in clinical settings through decreased device occlusion.
SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D
Authors: Lee Madeline J. , Leong Michelle W. , Rustagi Arjun , Beck Aimee , Zeng Leiping , Holmes Susan , Qi Lei S. , Blish Catherine A.
Published: June 2022

Natural killer (NK) cells are cytotoxic effector cells that target and lyse virally-infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogated the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. We found that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells. We demonstrate that this escape is driven by downregulation of ligands for the activating receptor NKG2D (“NKG2D-L”). Indeed, early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed. Finally, we found that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work reveals that SARS-CoV-2 evades NK cell cytotoxicity and describes a mechanism by which this occurs.

Graphical abstract