bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-588 acts as an oncogene in ovarian cancer and increases the radioresistance of ovarian cancer cells
Authors: Su Xiaojuan , Wang Binbin , Zhang Bo , Pan Shiwen
Published: May 2023

The therapeutic outcomes of ovarian cancer (OVCA) patients are majorly limited by the development of acquired chemo/radioresistance and the lack of targeted therapies. Accumulating studies demonstrate that microRNAs are involved in tumorigenesis and radioresistance. This study aims to illustrate the role of miR-588 in the radioresistance of OVCA cells. The levels of miR-588 and mRNAs were detected by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). OVCA cell viability, proliferative, migratory and invasive capacities were evaluated by the cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay and transwell assay, respectively. The luciferase activities of plasmids containing wild -type and mutant serine/arginine-rich splicing factor 6 (SRSF6) 3'-untranslated region in miR-588 silenced OVCA cells were detected by a luciferase reporter assay. We found that miR-588 was overexpressed in OVCA tissues and cells. Knockdown of miR-588 exerted an inhibitory effect on the proliferation, migration and invasion and strengthened the radiosensitivity of OVCA cells, whereas overexpression of miR-588 increased the radioresistance of OVCA cells. SRSF6 was verified to be targeted by miR-588 in OVCA cells. In addition, the expression level of miR-588 was negatively correlated with that of SRSF6 in OVCA clinical samples. Rescue assays indicated that SRSF6 knockdown reversed the effect of miR-588 inhibition of OVCA cells under radiation. Overall, miR-588 acts as an oncogene in OVCA and increases the radioresistance of OVCA cells by targeting SRSF6.
Non-parametric inference about mean functionals of non-ignorable non-response data without identifying the joint distribution
Authors: Li Wei , Miao Wang , Tchetgen Tchetgen Eric
Published: May 2023

We consider identification and inference about mean functionals of observed covariates and an outcome variable subject to non-ignorable missingness. By leveraging a shadow variable, we establish a necessary and sufficient condition for identification of the mean functional even if the full data distribution is not identified. We further characterize a necessary condition for n-estimability of the mean functional. This condition naturally strengthens the identifying condition, and it requires the existence of a function as a solution to a representer equation that connects the shadow variable to the mean functional. Solutions to the representer equation may not be unique, which presents substantial challenges for non-parametric estimation, and standard theories for non-parametric sieve estimators are not applicable here. We construct a consistent estimator of the solution set and then adapt the theory of extremum estimators to find from the estimated set a consistent estimator of an appropriately chosen solution. The estimator is asymptotically normal, locally efficient and attains the semi-parametric efficiency bound under certain regularity conditions. We illustrate the proposed approach via simulations and a real data application on home pricing.
The phenomenon of autonomous endosperm in sexual and apomictic plants
Authors: Rojek Joanna , Ohad Nir
Published: May 2023

Endosperm is a key nutritive tissue that supports the developing embryo or seedling, and serves as a major nutritional source for human and livestock feed. In sexually-reproducing flowering plants, it generally develops after fertilization. However, autonomous endosperm (AE) formation (i.e. independent of fertilization) is also possible. Recent findings of AE loci/ genes and aberrant imprinting in native apomicts, together with a successful initiation of parthenogenesis in rice and lettuce, have enhanced our understanding of the mechanisms bridging sexual and apomictic seed formation. However, the mechanisms driving AE development are not well understood. This review presents novel aspects related to AE development in sexual and asexual plants underlying stress conditions as the primary trigger for AE. Both application of hormones to unfertilized ovules and mutations that impair epigenetic regulation lead to AE development in sexual Arabidopsis thaliana, which may point to a common pathway for both phenomena. Apomictic-like AE development under experimental conditions can take place due to auxin-dependent gene expression and/or DNA methylation.
Acclimation strategies of the green alga Chlorella vulgaris to different light regimes revealed by physiological and comparative proteomic analyses
Authors: Cecchin Michela , Simicevic Jovan , Chaput Louise , Hernandez Gil Manuel , Girolomoni Laura , Cazzaniga Stefano , Remacle Claire , Hoeng Julia , Ivanov Nikolai V , Titz Bjoern , Ballottari Matteo
Published: May 2023

Acclimation to different light regimes is at the basis of survival for photosynthetic organisms, regardless of their evolutionary origin. Previous research efforts largely focused on acclimation events occurring at the level of the photosynthetic apparatus and often highlighted species-specific mechanisms. Here, we investigated the consequences of acclimation to different irradiances in Chlorella vulgaris, a green alga that is one of the most promising species for industrial application, focusing on both photosynthetic and mitochondrial activities. Moreover, proteomic analysis of cells acclimated to high light (HL) or low light (LL) allowed identification of the main targets of acclimation in terms of differentially expressed proteins. The results obtained demonstrate photosynthetic adaptation to HL versus LL that was only partially consistent with previous findings in Chlamydomonas reinhardtii, a model organism for green algae, but in many cases similar to vascular plant acclimation events. Increased mitochondrial respiration measured in HL-acclimated cells mainly relied on alternative oxidative pathway dissipating the excessive reducing power produced due to enhanced carbon flow. Finally, proteins involved in cell metabolism, intracellular transport, gene expression, and signaling—including a heliorhodopsin homolog—were identified as strongly differentially expressed in HL versus LL, suggesting their key roles in acclimation to different light regimes.
Obscured AGN enhancement in galaxy pairs at cosmic noon: evidence from a probabilistic treatment of photometric redshifts
Authors: Dougherty Sean L , Harrison C M , Kocevski Dale D , Rosario D J
Published: May 2023

Observations of the nearby universe reveal an increasing fraction of active galactic nuclei (AGNs) with decreasing projected separation for close galaxy pairs, relative to control galaxies. This implies galaxy interactions play a role in enhancing AGN activity. However, the picture at higher redshift is less established, partly due to limited spectroscopic redshifts. We combine spectroscopic surveys with photometric redshift probability distribution functions for galaxies in the CANDELS and COSMOS surveys, to produce the largest ever sample of galaxy pairs used in an AGN fraction calculation for cosmic noon (0.5 < z < 3). We present a new technique for assessing galaxy pair probability (based on line-of-sight velocities ±1000 km s−1) from photometric redshift posterior convolutions and use these to produce weighted AGN fractions. Over projected separations 5–100 kpc, we find no evidence for enhancement, relative to isolated control galaxies, of X-ray (LX > 1042 erg s−1) or infrared-selected AGN in major (mass ratios up to 4:1) or minor (4:1 to 10:1) galaxy pairs. However, defining the most obscured AGN as those detected in the infrared but not in X-rays, we observe a trend of increasing obscured AGN enhancement at decreasing separations. The peak enhancement, relative to isolated controls, is a factor of 2.08 ± 0.61 for separations <25 kpc. Our simulations with mock data, indicates this could be a lower limit of the true enhancement. If confirmed with improved infrared imaging (e.g. with JWST) and redshifts (e.g. with forthcoming multi-object spectrograph surveys), this would suggest that galaxy interactions play a role in enhancing the most obscured black hole growth at cosmic noon.
The phase structure of cosmic ray driven outflows in stream fed disc galaxies
Authors: Peschken N , Hanasz M , Naab T , Wóltański D , Gawryszczak A
Published: May 2023

Feeding with gas in streams is well established to be an important galaxy growth mechanism. Using an idealized set-up of an isolated galaxy, we study the impact of stream feeding (with 107 M⊙ Myr−1 rate) on the star formation and outflows of disc galaxies with ∼1011 M⊙ baryonic mass. The magnetohydrodynamical simulations are carried out with the piernik code and include star formation, feedback from supernova, and cosmic ray advection and diffusion, on a uniform grid with 195 pc spatial resolution. We find that the introduction of a cold gas stream accreted by the disc enhances galactic star formation. Lower angular momentum streams result in more compact discs, higher star formation rates and stronger outflows. In agreement with previous studies, models including cosmic rays launch stronger outflows travelling much further into the galactic halo. Cosmic ray supported outflows are also cooler than supernova only driven outflows. With cosmic rays, the star formation is suppressed and the thermal pressure is reduced. We find evidence for two distinct outflow phases. The warm outflows have high angular momentum and stay close to the galactic disc, while the hot outflow phase has low angular momentum and escapes from the centre deep into the halo. Cosmic rays can therefore have a strong impact on galaxy evolution by removing low angular momentum, possibly metal enriched gas from the disc and injecting it into the circumgalactic medium.
A geometric probe of cosmology – II. Gravitational lensing time delays and quasar reverberation mapping revisited
Authors: Ng Angela L H
Published: May 2023

The time delay between images of strongly gravitationally lensed quasars is an established cosmological probe. Its limitations, however, include uncertainties in the assumed mass distribution of the lens. We re-examine the methodology of a prior work presenting a geometric probe of cosmology independent of the lensing potential, which considers differential time delays over images originating from spatially separated photometric signals within a strongly lensed quasar. We give an analytic description of the effect of differential lensing on the emission line spectral flux for axisymmetric broad line region geometries, with the inclined ring or disc, spherical shell, and double cone as examples. The proposed method is unable to recover cosmological information as the observed time delay and inferred line-of-sight velocity do not uniquely map to the three-dimensional position within the source.
Dynamics of Gene Loss following Ancient Whole-Genome Duplication in the CrypticParameciumComplex
Authors: Gout Jean-Francois , Hao Yue , Johri Parul , Arnaiz Olivier , Doak Thomas G , Bhullar Simran , Couloux Arnaud , Guérin Fréderic , Malinsky Sophie , Potekhin Alexey , Sawka Natalia , Sperling Linda , Labadie Karine , Meyer Eric , Duharcourt Sandra , Lynch Michael
Published: May 2023

Whole-genome duplications (WGDs) have shaped the gene repertoire of many eukaryotic lineages. The redundancy created by WGDs typically results in a phase of massive gene loss. However, some WGD–derived paralogs are maintained over long evolutionary periods, and the relative contributions of different selective pressures to their maintenance are still debated. Previous studies have revealed a history of three successive WGDs in the lineage of the ciliate Paramecium tetraurelia and two of its sister species from the Paramecium aurelia complex. Here, we report the genome sequence and analysis of 10 additional P. aurelia species and 1 additional out group, revealing aspects of post-WGD evolution in 13 species sharing a common ancestral WGD. Contrary to the morphological radiation of vertebrates that putatively followed two WGD events, members of the cryptic P. aurelia complex have remained morphologically indistinguishable after hundreds of millions of years. Biases in gene retention compatible with dosage constraints appear to play a major role opposing post-WGD gene loss across all 13 species. In addition, post-WGD gene loss has been slower in Paramecium than in other species having experienced genome duplication, suggesting that the selective pressures against post-WGD gene loss are especially strong in Paramecium. A near complete lack of recent single-gene duplications in Paramecium provides additional evidence for strong selective pressures against gene dosage changes. This exceptional data set of 13 species sharing an ancestral WGD and 2 closely related out group species will be a useful resource for future studies on Paramecium as a major model organism in the evolutionary cell biology.
Pancreatic Enzyme Replacement and Nutritional Support With n﻿ab-Paclitaxel-based First-Line Chemotherapy Regimens in Metastatic Pancreatic Cancer
Authors: Giordano Guido , Cincione Raffaele Ivan , Losavio Francesca , Senia Tiziano , Aquilini Mummolo Arianna , Pacilli Mario , Lizzi Vincenzo , Bruno Giuseppina , Piscazzi Annamaria , Conteduca Vincenza , Landriscina Matteo
Published: May 2023

Background

At diagnosis, more than 80% of patients with pancreatic cancer (PC) suffer from significant weight loss due to malnutrition which is a major concern for patient management, and this may negatively impact treatment outcomes and patient prognosis.

Patients and Methods

We performed an observational, retrospective study on patients with metastatic PC (mPC) undergoing first-line chemotherapy with nab-Paclitaxel containing schedules and receiving or not receiving nutritional support (NS) and pancreatic enzyme replacement therapy (PERT) to investigate their relevance in this setting.

Results

We observed that PERT and ancillary dietary interventions are related to longer overall survival (OS; median: 16.5 vs. 7.5 months, P < .001) and have a significant, independent, prognostic impact for better outcomes (P = .013), independently from the therapeutic regimen. Furthermore, PERT and NS prevented weight loss during chemotherapy and obtained an improvement of nutritional parameters such as phase angle and free-fat mass index, after 3 months of anticancer treatment. Consistently, the positive impact on OS correlated also with the prevention of Karnofsky performance status deterioration and a lower incidence of maldigestion-related symptoms.

Conclusions

Our data suggest that an early and well-conducted NS in patients with mPC may impact on survival and preserve performance status, thus improving quality of life.
Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience
Authors: Altan Mehmet , Soto Felipe , Zhong Linda L , Akhmedzhanov Fechukwu O , Wilson Nathaniel R , Zarifa Abdulrazzak , Albittar Aya A , Yang Vincent , Lewis Jeff , Rinsurongkawong Waree , Jack Lee J , Rinsurongkawong Vadeerat , Zhang Jianjun , Gibbons Don L , Vaporciyan Ara A , Jennings Kristofer , Khawaja Fareed , Faiz Saadia A , Shannon Vickie R , Shroff Girish , Godoy Myrna C B , Daver Naval G , Gandhi Saumil , Mendoza Tito R , Naing Aung , Daniel-MacDougall Carrie , Heymach John V , Sheshadri Ajay
Published: May 2023

Introduction

Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially.

Methods

We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models.

Results

We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0).

Conclusion

Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.
New results on the two low-mass-ratio overcontact binaries V1309 Herculis and AS Coronae Borealis
Authors: Matekov Azizbek , Meng Fangbin , Qian Shengbang , Asfandiyarov Ildar , Li Linjia , Ehgamberdiev Shuhrat , Zhu Liying
Published: May 2023

We present new multi-color light curves of V1309 Her and AS CrB, which were observed by the 60 cm telescope located at the Maidanak Astronomical Observatory. Combined with the Large-Sky-Area Multi-Object Fiber Spectroscopic Telescope atmospheric parameters, we analyzed our BVRCIC light curves for both systems by employing the Wilson–Devinney program. Our results show that both systems are low-mass-ratio overcontact binaries (V1309 Her: q = 0.213, AS CrB: q = 0.16). AS CrB has a high fill-out factor, while that of V1309 Her is moderate. By adding our new times of minimum light, we found the periodic oscillations in their O − C curves, which could be explained by the light travel-time effect of the third bodies. The third lights detected during the light curve analysis support the existence of the third bodies in V1309 Her and AS CrB. Third bodies usually play an important role for the origin and evolution of the central pair by removing their angular momentum. With the angular momentum loss, a moderate-fill-out overcontact binary like V1309 Her will evolve to a deep one like AS CrB. AS CrB lies at the late evolutionary stage of contact binaries. A long-term period increase at a rate of dP/dt = 5.22(± 0.28) × 10−7 d yr−1 was detected in our O − C diagram analysis. When its orbital angular momentum is less than three times the total spin angular momentum, a system may finally evolve into a rapid-rotating single star.
Resilience in patients with complex regional pain syndrome 1—a cross-sectional analysis of patients participating in a cross-sectional cohort study
Authors: Wertli Maria Monika , Aegler Barbara , McCabe Candida S , Grieve Sharon , Llewellyn Alison , Schneider Stephanie , Bachmann Lucas M , Brunner Florian
Published: May 2023

Objective

To assess the degree of resilience in patients with complex regional pain syndrome (CRPS) 1, to explore the relationship between resilience and patient-related outcome measurements and to describe a pattern of clinical manifestations associated with low resilience.

Methods

This study presents a cross-sectional analysis of baseline information collected from patients enrolled in a single center study between February 2019 and June 2021. Participants were recruited from the outpatient clinic of the Department of Physical Medicine & Rheumatology of the Balgrist University Hospital, Zurich, Switzerland. We used linear regression analysis to explore association of resilience with patient reported outcomes at baseline. Furthermore, we explored the impact of significant variables on the low degree resilience using logistic regression analysis.

Results

Seventy-one patients (females 90.1%, mean age 51.2 ± 12.9 years) were enrolled. There was no association between CRPS severity and the level of resilience. Quality of Life was positively correlated with resilience, as was pain self-efficacy. Pain catastrophizing was inversely correlated with the level of resilience. We observed a significant inverse association between anxiety, depression and fatigue and the level of resilience. The proportion of patients with a low resilience increased with higher level of anxiety, depression and fatigue on the PROMIS-29, without reaching statistical significance.

Conclusion

Resilience seems to be an independent factor in CRPS 1 and is associated with relevant parameters of the condition. Therefore, caretakers may screen the current resilience status of CRPS 1 patients to offer a supplementary treatment approach. Whether specific resilience training modifies CRPS 1 course, requires further investigations.
3D-printed GelMA/CaSiO3 composite hydrogel scaffold for vascularized adipose tissue restoration
Authors: Zhang Jupei , Zeng Zhen , Chen Yanxin , Deng Li , Zhang Yanxin , Que Yumei , Jiao Yiren , Chang Jiang , Dong Zhihong , Yang Chen
Published: May 2023

The increased number of mastectomies, combined with rising patient expectations for cosmetic and psychosocial outcomes, has necessitated the use of adipose tissue restoration techniques. However, the therapeutic effect of current clinical strategies is not satisfying due to the high demand of personalized customization and the timely vascularization in the process of adipose regeneration. Here, a composite hydrogel scaffold was prepared by three-dimensional (3D) printing technology, applying gelatin methacrylate anhydride (GelMA) as printing ink and calcium silicate (CS) bioceramic as an active ingredient for breast adipose tissue regeneration. The in vitro experiments showed that the composite hydrogel scaffolds could not only be customized with controllable architectures, but also significantly stimulated both 3T3-L1 preadipocytes and human umbilical vein endothelial cells in multiple cell behaviors, including cell adhesion, proliferation, migration and differentiation. Moreover, the composite scaffold promoted vascularized adipose tissue restoration under the skin of nude mice in vivo. These findings suggest that 3D-printed GelMA/CS composite scaffolds might be a good candidate for adipose tissue engineering.
Shocked by Bank Funding Shocks: Evidence from Consumer Credit Cards
Authors: Chava Sudheer , Ganduri Rohan , Paradkar Nikhil , Zeng Linghang
Published: May 2023

Using the near universe of U.S. consumer credit cards, we show that banks transmit their wholesale funding shocks to consumers by reducing their credit card limits. Credit-constrained consumers who are unable to hedge against the transmitted shock by accessing other credit cards experience a stronger and more persistent reduction in aggregate credit card limits at the consumer level. Consequently, these credit-constrained consumers reduce their aggregate credit card borrowing. Our results document a credit card lending channel for the transmission of adverse bank shocks and show who bears the costs of fragile bank funding structures.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Quantitative measurement of motor activity during sleep in isolated REM sleep behavior disorder patients using actigraphy before and after treatment with clonazepam
Authors: Park Kyoungeun , Shin Yong Woo , Hwang Sungeun , Jeong El , Kim Tae-Joon , Jun Jin-Sun , Shin Jung-Won , Byun Jung-Ick , Sunwoo Jun-Sang , Kim Han-Joon , Schenck Carlos H , Jung Ki-Young
Published: May 2023

Study Objectives

We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD).

Methods

The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures.

Results

Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered “much or very much improved” on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman’s rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements).

Conclusions

Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.
PFKFB2 Inhibits Ferroptosis in Myocardial Ischemia/Reperfusion Injury Through Adenosine Monophosphate–Activated Protein Kinase Activation
Authors: Fu Caihua , Yu Shengbo , Liu Zhiquan , Wang Jiayu , Liu Ping , Su Guohai
Published: May 2023

Six-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) is a key regulator of glycolytic enzyme. This study identified whether PFKFB2 can regulate myocardial ferroptosis in ischemia/reperfusion (I/R) injury. Mice myocardial (I/R) injury and H9c2 cells oxygen-glucose deprivation/reperfusion (OGD/R) models were established. PFKFB2 expression was enhanced in I/R mice and OGD/R H9c2 cells. Overexpression of PFKFB2 improves heart function in I/R mice. Overexpression of PFKFB2 inhibits I/R and OGD/R-induced ferroptosis in mice and H9c2 cells. Mechanistically, overexpression of PFKFB2 activates the adenosine monophosphate–activated protein kinase (AMPK). AMPK inhibitor compound C reverses effect of PFKFB2 overexpression in reducing ferroptosis under OGD/R treatment. In conclusion, PFKFB2 protects hearts against I/R-induced ferroptosis through activation of the AMPK signaling pathway.
Double-Docking Technique for Femtosecond Laser-Assisted Deep Anterior Lamellar Keratoplasty: A Retrospective Consecutive Case Series Study of Advanced Keratoconus
Authors: Gabison Eric E. , Gree Eva , Azar Georges , Cochereau Isabelle , Guindolet Damien
Published: May 2023

Purpose:

The aim of this study was to report the clinical outcomes and prognosis of femtosecond laser (FSL)-assisted double-docking deep anterior lamellar keratoplasty (DD-DALK) for advanced keratoconus (AK).

Methods:

Records of consecutive patients with keratoconus who underwent FSL-assisted DALK (DD-DALK) were reviewed.

Results:

We analyzed 37 eyes from 37 patients who underwent DD-DALK. Sixty-eight percent of eyes had a successful big-bubble formation and 27% had a manual dissection to achieve the DALK deep dissection. Stromal scarring was associated with not achieving a big bubble. Intraoperative conversion to penetrating keratoplasty was conducted in 2 cases (5%). The best-corrected visual acuity improved from a median (± interquartile range) of 1.55 ±0.25 logMAR preoperatively to 0.2 ±0.2 logMAR (P < 0.0001). The median postoperative spherical equivalent was −5.75 ±2.75 D with a median astigmatism of −3.5 ±1.3 D. BCVA, SE, and astigmatism were not statistically different between patients who underwent DD-DALK and patients who underwent manual DALK. Stromal scarring was associated with big-bubble (BB) formation failure (P = 0.003). All patients with failed BB requiring manual dissection had anterior stromal scarring.

Conclusions:

DD-DALK is safe and reproducible. The success rate of BB formation is hampered by stromal scarring.
IDO Regulates Macrophage Functions by Inhibiting the CCL2/CCR2 Signaling Pathway in Fungal Keratitis
Authors: Yu Feifei , Jiang Wei , Zhang Li , Jiang Nan
Published: May 2023

Purpose:

The aim of this study was to investigate the effects of indoleamine 2,3-dioxygenase (IDO) on macrophage polarization, phagocytosis, and killing through regulation of the CCL2/CCR2 signaling pathway in Aspergillus fumigatus keratitis.

Methods:

In vivo and in vitro experiments were conducted in mice and mouse peritoneal macrophages after infection with A. fumigatus. Clinical scoring, reverse transcription–polymerase chain reaction, and immunofluorescence staining were used to evaluate the fungal keratitis lesions, macrophage-related cytokines, and macrophage recruitment. The expression of CCL2 and CCR2 was detected by reverse transcription–polymerase chain reaction and western blot after pretreatment with or without an IDO inhibitor (1-MT). After pretreatment with 1-MT, a CCR2 antagonist, a CCL2 neutralizing antibody, an IDO agonist (IFNG), and recombinant CCL2 protein (CCL2), the flow cytometry and colony-forming unit counts were used to detect the polarization, phagocytosis, and killing function.

Results:

Compared with the control group, the infected eyes showed increased clinical scores, macrophage-related cytokine expression, and macrophage recruitment. 1-MT pretreatment increased the expression of CCL2 and CCR2 and the proportion of CD206+/CD86+ macrophages; macrophages polarized toward the M2 type, with enhanced killing function. CCR2 antagonists and CCL2 neutralizing antibodies reversed the effects of 1-MT. Compared with the infected group, IFNG pretreatment decreased the proportion of CD206+/CD86+ macrophages, and macrophages polarized toward the M1 type, with decreased phagocytosis and impaired killing function. CCL2 reversed the effect of IFNG.

Conclusions:

IDO can promote the polarization of macrophages to the M1 type by blocking the CCL2/CCR2 signaling pathway, inhibiting the phagocytosis and killing function of macrophages, and mediating the protective immune role of A. fumigatus.
Long-Term Risk of Steroid-Induced Ocular Hypertension/Glaucoma With Topical Prednisolone Acetate 1% After Descemet Stripping Endothelial Keratoplasty
Authors: Price Marianne O. , Price David A. , Price Francis W.
Published: May 2023

Purpose:

The aim of this study was to assess the long-term risk of steroid-induced ocular hypertension and the need for glaucoma treatment with long-term use of topical prednisolone acetate 1% in patients without preexisting glaucoma.

Methods:

We retrospectively reviewed the charts of 211 patients without previous glaucoma, who underwent Descemet stripping endothelial keratoplasty (DSEK) and used topical prednisolone acetate long-term to prevent graft rejection. Dosing was 4 times daily for 4 months and tapered to once daily. The main outcomes were ocular hypertension (defined as intraocular pressure ≥24 mm Hg, or increase of ≥10 mm Hg over baseline) and initiation of glaucoma treatment.

Results:

The median patient age was 70 years (range: 34–94 years). The indications for DSEK were Fuchs dystrophy (88%), pseudophakic corneal edema (7%), failed DSEK (3%), and failed penetrating keratoplasty (2%). The median follow-up period was 7 years (range, 1–17 years). At 1, 5, and 10 years, the cumulative risks of steroid-induced ocular hypertension were 29%, 41%, and 49%, respectively, and the risks of requiring glaucoma treatment were 11%, 17%, and 25%, respectively. Among 35 eyes treated for glaucoma, 28 (80%) were managed medically and 7 (20%) had filtration surgery.

Conclusions:

Long-term use of potent topical corticosteroids, such as prednisolone acetate 1%, entails substantial risk of developing steroid-induced ocular hypertension, so frequent monitoring of intraocular pressure is required. With corneal transplantation, the risk can be mitigated by using techniques with a low inherent risk of rejection, such as Descemet membrane endothelial keratoplasty, whenever possible, to allow earlier reduction of steroid potency.
Moderate-Intensity Continuous Training Versus Moderate-Intensity Interval Training
Authors: Sánchez-Polo Andrés , De-Llano Elisa , Gómez-Conesa Antonia
Published: May 2023

Background

Excess weight and obesity are related to cardiometabolic diseases and limit physical activity. Until now, the effects of moderate-intensity continuous training (MICT) compared with moderate-intensity interval training (MIIT) in Spanish obese adults have not been analyzed.

Objective

This study aimed to investigate the effect of MICT and MIIT together with a 1300-to-1400 caloric restrictive diet on cardiovascular disease risk factors in overweight and obese patients.

Methods

The MICT and MIIT groups trained during 4 sessions a week for 12 weeks while performing the diet. The MICT group trained for 32 minutes per session in a cycloergometer, initially at 60% maximal oxygen uptake during the first month and increasing by 10% every 4 weeks. The MIIT group performed 4 × 4 intervals (at 60% maximal oxygen uptake and active rest at 60% maximal oxygen uptake minus 20 W), with a 10% increase every 4 weeks. The control group neither trained nor followed the restrictive diet.

Results

One hundred fifty-nine obese adults participated in the study. The control group did not present any significant changes during the study. The MICT group significantly improved in all the variables (P < .05) except for high-density lipoproteins. The MIIT group improved in all the variables (P < .05) except for high-density lipoproteins and triglycerides. The MIIT group lost weight in less time than the MICT group.

Conclusions

Overweight and obese adults of both the MICT and MIIT groups decreased their risk for cardiovascular disease, although the MIIT group lost weight in a shorter amount of time.
Development and Evaluation of a Digital HIV Risk Assessment Tool Incorporated Within an App-Based Self-Testing Program
Authors: Leung Soo Cindy , Bhatnagar Sahir , Bartlett Susan J. , Esmail Aliasgar , Dheda Keertan , Pant Pai Nitika
Published: May 2023

Background:

Low-risk perception is an important barrier to the utilization of HIV services. In this context, offering an online platform for people to assess their risk of HIV and inform their decision to test can be impactful in increasing testing uptake. Using secondary data from the HIVSmart! quasirandomized trial, we aimed to identify predictors of HIV, develop a risk staging model for South African township populations, and validate it in combination with the HIVSmart! digital self-testing program.

Setting:

Townships in Cape Town, South Africa.

Methods:

Using Bayesian predictive projection, we identified predictors of HIV and constructed a risk assessment model that we validated in external data.

Results:

Our analyses included 3095 participants from the HIVSmart! trial. We identified a model of 5 predictors (being unmarried, HIV testing history, having had sex with a partner living with HIV, dwelling situation, and education) that performed best during external validation (area under the receiver operating characteristic curve, 89% credible intervals: 0.71, 0.68 to 0.72). The sensitivity of our HIV risk staging model was 91.0% (89.1% to 92.7%) and the specificity was 13.2% (8.5% to 19.8%) but increased when combined with a digital HIV self-testing program, the specificity was 91.6% (95.9% to 96.4%) and sensitivity remained similar at 90.9% (89.1% to 92.6%).

Conclusions:

This is the first validated digital HIV risk assessment tool developed for South African township populations and the first study to evaluate the added value of a risk assessment tool with an app-based HIV self-testing program. Study findings are relevant for application of digital programs to improve utilization of HIV testing services.
Fibroblast Growth Factor 23 is a strong independent marker of worse cardiovascular outcomes after an acute coronary syndrome
Authors: Kallmeyer Andrea , Pello Ana , Cánovas Ester , Aceña Álvaro , González-Casaus María Luisa , Tarín Nieves , Cristóbal Carmen , Gutiérrez-Landaluce Carlos , Huelmos Ana , Rodríguez-Valer Aida , González-Lorenzo Óscar , Alonso Joaquín , López-Bescós Lorenzo , Egido Jesús , Mahillo Ignacio , Lorenzo Óscar , Tuñón José
Published: May 2023

Background and aims

This study aimed to assess the role of plasmatic fibroblast growth factor 23 (FGF23) as a prognostic marker after an acute coronary syndrome (ACS).

Methods

This prospective and multicentric study included 1,190 patients with ACS. FGF23 plasma levels and other components of mineral metabolism (calcidiol, parathormone [PTH], klotho, and phosphate), lipids, troponin, high-sensitivity C-reactive protein, N-terminal-pro-brain natriuretic peptide and estimated glomerular filtration rate (eGFR) were measured at discharge. The primary outcome was a combination of acute ischemic events, heart failure (HF) and death. Secondary outcomes were the separate components of the primary outcome.

Results

Median follow-up was 5.44 (3.03-7.46) years. 294 patients developed the primary outcome. Patients with FGF23 levels below the median were predominantly males, younger, and with lower load of cardiovascular risk factors. Calcidiol and PTH levels were lower among them. Multivariable analysis showed that FGF23 (HR 1.18 [1.08-1.29], p<0.001), calcidiol (HR 0.86 [0.74-1.00], p=0.046), previous CAD or cerebrovascular accidents, and hypertension were independent predictors of the primary outcome. The predictive power of FGF23 was homogeneous across different subgroups of population. FGF23 resulted an independent predictor of HF (HR 1.38 [1.22-1.57], p<0.001), and death (HR 1.21 [1.07-1.37], p=0.002), but not of acute ischemic events. According to renal function, FGF-23 was an independent predictor for the primary outcome in patients with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73m2.

Conclusions

FGF23 is a strong, independent predictor of HF and death among patients with ACS. This effect is homogeneous across different subgroups of population and not limited to patients with chronic kidney disease (CKD).
A Tape Spring Steerable Needle Capable of Sharp Turns
Authors: Abdoun Omar T. , Yim Mark
Published: May 2023

Objective

To make steerable needles more effective, researchers have been trying to minimize turning radius, develop mechanics-based models, and simplify control. This paper introduces a novel cable-driven steerable needle that has a 3mm turning radius based on tape spring mechanics, which sets a new minimum turn radius in stiffness-matched tissue models. Methods: We characterize the turn radius and the forces that affect control and performance and create predictive models to estimate required insertion forces and maximum insertion depth. Finally, we demonstrate the performance of a task outside the capabilities of a conventional needle. Results: Minimal force is required to maintain bends, allowing surrounding tissue to fix them in place, and minimal energy is required to propagate bends, allowing the device to navigate easily through various tissue phantoms. The turn radius of the device is independent of surrounding tissue stiffness, making for simple and precise control. We show that all aspects of performance depend on minimizing the tip cutting force. Under ultrasound guidance, we successfully navigate into and then follow a deep blood vessel model at a steep angle of approach. Conclusion: This design allows the system to accurately control the direction of the device while maintaining a smaller turn radius than other steerable needles, providing the potential to broaden access to challenging targets in patients.
Reduced frequency of clonal hematopoiesis in Parkinson’s disease
Authors: Sun Shixiang , Sproviero Daisy , Payán-Gómez César , Huang Zhenqiu , Hoeijmakers Jan H.J. , Maslov Alexander Y. , Mastroberardino Pier G. , Vijg Jan
Published: May 2023

To test if clonal hematopoiesis of indeterminate potential (CHIP) is associated with the incidence of Parkinson’s Disease (PD), we analyzed blood whole exome sequencing data from 181 healthy controls and 391 PD subjects in the Parkinson’s Progression Markers Initiative. We observed an age-related increase of CHIP carriers in the healthy controls. Surprisingly, the percentage of CHIP carriers was significantly lower in PD patients than in age-matched controls.
Evolutionary graph theory on rugged fitness landscapes
Authors: Kuo Yang Ping , Carja Oana
Published: May 2023

Spatially-resolved datasets are revolutionizing knowledge in molecular biology, yet are under-utilized for questions in evolutionary biology. To gain insight from these large-scale datasets of spatial organization, we need mathematical representations and modeling techniques that can both capture their complexity, but also allow for mathematical tractability. Specifically, it is hard to link previous deme-based or lattice-based models with datasets exhibiting complex patterns of spatial organization and the role of heterogeneous population structure in shaping evolutionary dynamics is still poorly understood. Evolutionary graph theory utilizes the mathematical representation of networks as a proxy for population structure and has started to reshape our understanding of how spatial structure can direct evolutionary dynamics. However, previous results are derived for the case of a single mutation appearing in the population. Complex traits arise from interactions among multiple genes and these interaction can result in rugged fitness landscapes, where evolutionary dynamics can vastly differ from the dynamics of stepwise fixation. Here, we develop a unifying theory of how heterogenous population structure shapes evolutionary dynamics on rugged fitness landscapes. We show that even a simple extension to a two- mutational landscape can exhibit evolutionary dynamics not observed in deme-based models and that cannot be predicted using previous single-mutation results. We also show how to link these models to spatially-resolved datasets and build the networks of the stem cell niches of the bone marrow. We show that these cellular spatial architectures reduce the probability of neoplasm initiation across biologically relevant mutation rate and fitness distributions.
Association between Prevalent Flagellated Bacteria in Gut Microbiota and Cardiovascular Benefits in Humans
Authors: Yiu Jensen H. C. , Cai Jieling , Cheung Samson W. M. , Chin Karie Tsz-Ching , Chan Chi Fai , Ma Edward S.C. , Sharma Rakesh , Dorweiler Bernhard , Woo Connie W.
Published: May 2023

Background

Increasing evidence has shown associations between gut microbiota and cardiovascular risks. However, whether sex influences the cardiovascular outcome of gut microbiota remains elusive.

Methods

The gut microbiota metagenomic data from two previous population-based cohorts and the proteomics data from human liver samples were analyzed.

Results

Through a sex-based analysis of 500 Functional Genomics Project (500FG) cohort, we found that the capacity of producing flagellin inEubacterium rectale, Roseburia IntestinalisandRoseburia inulinivoranspartially explained the levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 in female participants. By comparing the bacterial species showing positive correlations with HDL-C and the flagellin species found in human liver samples, we found thatE. rectaleandR. inulinivoransappeared to be the major prevalent flagellated species in gut microbiota contributed to the host’s HDL-C level. The analysis of the Chinese-based cohort in which the male participants had relatively higher abundance of these two bacteria, the abovementioned positive correlation was also observed.

Conclusions

The flagellin-producing function ofE. rectaleandR. inulinivoransin the gut microbiota partially explained the HDL-C level in the host, and there is a sex-specific difference in the sensitivity of this beneficial interaction. Our findings suggest a potential interaction between commensal bacteria and the host that yields a cardiovascular benefit.

Clinical Perspective

What is new?

The flagellin-producing capacity of certain species in gut microbiota is positively associated with the HDL-C and ApoA1 levels in human.

By comparing the flagellated bacteria in the gut and flagellin species in the liver,Eubacterium rectaleandRoseburia inulinivoransare shown to be the most prevalent species contributing to such cardiovascular benefits.

The sensitivity of such beneficial interaction with the gut flagellated bacteria is different between male and female.

What are the clinical implications? (maximum 100 words, formatted as 2-3 bullets)

Beside the role in metabolic inflammation, gut microbiota can be beneficial against cardiovascular risk by modulating HDL-C level through certain flagellated species.

The interaction between flagellated bacteria in the gut and the host provide a different insight in exploring potential therapeutic targets to increase HDL-C level.
BAG6 is a novel player in controlling nonalcoholic steatohepatitis: result from a comprehensivein-silicostudy
Authors: Sarmah Dipanka Tanu , Paul Abhijit , Berry Umang , Surjit Milan , Bairagi Nandadulal , Chatterjee Samrat
Published: May 2023

Nonalcoholic steatohepatitis, or NASH, is a multifactorial disease characterized by hepatic lipid accumulation, inflammation, cell death, and fibrosis, and an efficacious pharmaceutical intervention for this is yet to be discovered. The present study aims to identify potential targets capable of reversing the disease-specific molecular alterations and elucidate their possible action mechanism. Our study uses combinations of different methods, such as genome-scale metabolic modelling, directional protein-protein interaction network, connectivity map, and network controllability, to identify potential targets in NASH. Our approach yielded three promising targets, BAG6, CASP3, and CYCS, and captured their effects on inflammation, fibrosis, steatosis, and apoptosis. The association of CASP3 and CYCS with NASH are already reported in the literature. So BAG6 was selected as a novel target. In the Huh-7 cell-line, its ablation reduced fatty acid accumulation and decreased levels of NASH-signature transcripts, supporting our hypothesis on BAG6 as a potential NASH target.
RFP-Cyanine Dye Probe Pair forIn vivoNeurovascular Multiphoton Imaging
Authors: Xia Fei , Sinefeld David , Chang Zong , Gong Xiaojing , Sun Qinchao
Published: May 2023

In vivoimaging of the neurovascular network is considered to be one of the most powerful approaches for understanding brain functionality. Nevertheless, simultaneously imaging the neuron network and blood vessels in deeper brain layers in a non-invasive manner remains to be a major challenge due to the lack of appropriate labeling fluorescence probe pairs. Herein, we proposed a 2P and 3P fluorescence probe pair for neurovascular imaging. Specifically, the red fluorescence protein (RFP) with an absorption maximum around 550 nm is used as a 3P excited probe to label neurons, and a cyanine derivative dye Q820 has a NIR absorption maximum of 825 nm as a 2P excited probe to label the vasculature, enabling single wavelength excitation at 1650 nm for neurovascular imaging. In particular, the two-photon cross section of Q820 was found to be about 2-fold higher than that of indocyanine green (ICG), a commonly used red two-photon fluorescence labeling agent, at the same excitation wavelength. Benefited from the long wavelength advantage in reducing scattering in both 2 and 3-photon excitation of the fluorescence pairs, we demonstrated in vivo neurovascular imaging in intact mouse brains through white matter and deep into the hippocampus in somatosensory cortex.