bluuebunny/crossref_metadata_2025 huggingface dataset:
Ratio Analysis 1: Profitability, Efficiency And Performance
Authors: Scott Peter
Published: October 2023

This chapter discusses ratio analysis, the most commonly used technique to evaluate and assess a firm's profitability, efficiency, performance, liquidity, and long-term financial stability. It shows the importance and advantages of ratios, as well as how ratios interact with the interpretation of financial statements. Calculations of the various ratios such as the profitability ratio, efficiency ratio, and performance ratio are illustrated. To tie it all up, the chapter shows how to compare an entity's financial and operational performance with that of other companies in the same industry.
Capital Investment Appraisal
Authors: Scott Peter
Published: October 2023

This chapter focuses on capital investment appraisal, which is essential when considering investments in new projects or in new assets. The chapter explores why businesses undertake capital investment appraisal when making long-term investment decisions. The chapter also presents the four main capital investment appraisal techniques and how they work. Importantly, the chapter illustrates the application of these capital investment appraisal techniques to capital investment decisions.
Dynamic modeling of stem water content during the dormant period in walnut trees
Authors: Charrier Guillaume , Améglio Thierry
Published: October 2023

Water content (WC) is a key variable in plant physiology even during the winter period. To simulate stem WC during the dormant season, a series of experiments were carried out on walnut trees under controlled conditions. In the field, WC was significantly correlated with soil temperature at 50 cm depth (R2 = 0.526). In the greenhouse, WC remained low as long as soil temperature was kept cold (<+5 °C) and increased after the soil temperature was warmed to +15 °C regardless of the date. Stem dehydration rate was significantly influenced by the WC and evaporative demand. A parsimonious model with functions describing the main experimental results was calibrated and validated with field data from 13 independent winter dynamics in Juglans regia L. orchards. Three functions of water uptake were tested, and these gave equivalent accuracies (root-mean-square error (RMSE) = 0.127–8; predictive root-mean-square error = 0.116). However, only a sigmoid function describing the relationship between the root water uptake and soil temperature gave values in agreement with the experimental results. Finally, the simulated WC provided a similar accuracy in predicting frost hardiness compared with the measured WC (RMSE ca 3 °C) and was excellent in spring (RMSE ca 2 °C). This model may be a relevant tool for predicting the risk of spring frost in walnut trees. Its genericity should be tested in other fruit and forest tree species.
Residential Treatment Exclusively for Tobacco Use Disorder: A Narrative Review
Authors: Spoelstra Symen Kornelis , van de Graaf Robert C. , Dijkstra Arie
Published: October 2023

Introduction

Tobacco use disorder is a major public health issue, and novel smoking cessation approaches are urgently needed. Residential treatment programs have been suggested as a potentially effective treatment for tobacco use disorder. However, there is limited literature on residential treatment programs for patients who are exclusively dependent on nicotine.

Aim

The aim of this study is to review the literature on residential treatment programs for patients admitted exclusively for tobacco use disorder.

Methods

A literature search was conducted in PubMed with the aim of identifying relevant articles on residential treatment exclusively for tobacco use disorder from inception until February 2023. References in retrieved articles were screened for additional relevant articles.

Results

Fourteen studies on residential treatment programs for tobacco use disorder were identified. The duration of the residential cessation programs ranged from 3 days to 3 weeks. Individualized or group cognitive behavioral therapy and tailored pharmacotherapy were the key components of the programs. Eligibility criteria for the programs included moderate to severe tobacco use disorder as measured by Fagerström or Diagnostic and Statistical Manual of Mental Disorders (DSM), consistent relapses, smoking-related comorbidities (eg, cardiovascular or pulmonary diseases), and daily use of (smokeless) tobacco. The 6- and 12-month 7-day point prevalence rate ranged from 58% to 26%, whereas the 6- and 12-month continuous abstinence rate ranged from 52% to 29%.

Conclusions

Based on the literature we reviewed, residential smoking cessation programs targeted exclusively at individuals with tobacco use disorder have shown effectiveness, particularly for those who are highly dependent on tobacco and have a history of relapse. However, more research is needed to further explore the effectiveness of these programs and to determine the optimal program components and duration.
Artificial Intelligence in the Prevention and Detection of Cardiovascular Disease
Authors: Whiteson Harris Z. , Frishman William H.
Published: October 2023

For more than 60 years, artificial intelligence (AI) has served as a mainstay in augmenting and assisting the lives of individuals across a wide array of interests and professional fields. Functioning to create deep computer simulations, analyze data, solve problems, and synthesize human behavior/emotion, AI has recently become a topic of popular interest in many fields of medicine. Despite decades of usage, modern AI—and its newer branch of machine learning (ML)—have yet to find a fully established and regulated niche in medicine. Understanding the clinical implications that AI and ML might be able to play in cardiovascular medicine, studies have sought to understand and compare how this technology compares with human rationality and diagnostics. Utilizing AI and ML in an array of cardiovascular medical techniques, analyses, and predictive measurements seems to have produced accurate results while also saving healthcare providers time and enabling them to expand their reach to further populations. Although current research and literature might hypothesize AI’s potential clinical applications, it is nearly impossible to fully understand the breadth and scope that this new technology can play in the future. In this article, we attempt to analyze a few of the potential applications of AI and ML for the detection, prevention, and treatment of cardiovascular disease. Additionally, we discuss how AI might make cardiovascular care more equitable and highlight a few precautions for utilizing this technology.
Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches
Authors: Newman Mark S. , Saltiel Doreen , Smeaton Jaclyn , Stanczyk Frank Z.
Published: October 2023

Objective

The aim of this study was to evaluate the amount of estrogen exposure associated with the use of compounded transdermal estradiol (E2) creams and compare it with estrogen exposure associated with the use of Food and Drug Administration (FDA)-approved transdermal E2 patches and gels.

Methods

This was a retrospective cohort study that used clinical laboratory data collected from January 1, 2016, to December 31, 2019. Participants were first divided into three groups: postmenopausal women on no menopausal hormone therapy (n = 8,720); postmenopausal women using either a transdermal E2 patch, gel, or cream (n = 1,062); and premenopausal women on no hormonal therapy (n = 16,308). The postmenopausal menopausal hormone therapy group was further subdivided by formulation (patch [n = 777], gel [n = 132], or cream [n = 153]) and dose range (low, mid, or high). The Jonckheere-Terpstra trend test was used to determine if there was a dose-dependent trend in urinary E2 with increasing dose of compounded E2 cream (dose categories for E2 cream subanalysis, <0.5 mg [n = 49], ≥0.5-≤1.0 mg [n = 50], ≥1.0-≤1.5 mg [n = 58], and >1.5-≤3.0 mg [n = 46]). Urinary E2 and other characteristics were compared across formulations (within each dose range) using Kruskal-Wallis one-way analysis of variance.

Results

A dose-dependent, ordered trend existed for urinary E2 with increasing doses of compounded E2 cream (urinary E2 medians [ng/mg-Cr], 0.80 for <0.5 mg, 0.73 for ≥0.5-≤1.0 mg, 1.39 for ≥1.0-≤1.5 mg, and 1.74 for >1.5-≤3.0 mg; Jonckheere-Terpstra trend test, P < 0.001). Significant differences in urinary E2 concentrations were observed in all three dose ranges (Kruskal-Wallis one-way analysis of variance, P = 0.013 for low dose, P < 0.001 for mid dose, P = 0.009 for high dose). Comparison of E2 concentrations of compounded creams to E2 concentrations obtained with similar doses of FDA-approved patches and gels showed that the creams had significantly lower values than the patches and gels.

Conclusions

Estrogen exposure from compounded transdermal E2 creams increases in a dose-dependent manner; however, the amount of estrogen exposure associated with compounded creams is significantly lower than estrogen exposure associated with FDA-approved transdermal E2 patches and gels. Clinicians should be aware of the direction and magnitude of these potential differences in estrogen exposure when encountering women who have either previously used or are currently using compounded E2 creams.
'Tis but a scratch: a critical review of the Women's Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer
Authors: Bluming Avrum Z. , Hodis Howard N. , Langer Robert D.
Published: October 2023

Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased breast cancer risk and did not improve quality of life. More recently, Women's Health Initiative (WHI) publications acknowledge HT as the most effective treatment for managing menopausal vasomotor symptoms and report that CEE alone reduces the risk of breast cancer by 23% while reducing breast cancer death by 40%. Their sole remaining concern is a small increase in breast cancer incidence with CEE and medroxyprogesterone acetate (1 per 1,000 women per year) but with no increased risk of breast cancer mortality. This article closely examines evidence that calls even this claim of breast cancer risk into serious question, including the WHI's reporting of nonsignificant results as if they were meaningful, a misinterpretation of its own data, and the misleading assertion that the WHI's findings have reduced the incidence of breast cancer in the United States. A generation of women has been deprived of HT largely as a result of this widely publicized misinterpretation of the data. This article attempts to rectify this misunderstanding, with the goal of helping patients and physicians make informed joint decisions about the use of HT.
Visual performance and photic disturbances with diffractive and nondiffractive EDOF intraocular lenses using mini-monovision: randomized trial
Authors: Fernandes Marcelo Caram , Nunomura Carlos Yuji , Messias André
Published: October 2023

Purpose:

To compare visual performance and photic visual disturbances of patients implanted with 2 different extended depth-of-focus (EDOF) intraocular lenses (IOLs) using mini-monovision.

Setting:

Ambulatory surgical center at the University of São Paulo in Ribeirão Preto, Brazil.

Design:

Prospective, examiner-masked, randomized clinical trial.

Methods:

Patients were assigned to either a bilateral Symfony (SYM) or Vivity (VIV) IOL group, with 1 eye targeted for myopia (−0.75 diopter [D]). Defocus curve, contrast sensitivity (Pelli-Robson), Patient-Reported Spectacle Independence Questionnaire, and Quality of Vision questionnaire were recorded at 3 months postoperatively.

Results:

A total of 126 patients finished the follow-up: group SYM: n = 60 and group VIV: n = 66. Regarding near visual acuity, 80% of patients in the SYM group and 84% of patients in the VIV group achieved J2 or better on the near-planned eye (P = .3840). No significant differences were found between groups for distance visual acuity, defocus profiles, PRISC, contrast sensitivity, or reading speed (P > .05). Notably, significant between-group differences were observed for bothersome visual disturbances (P = .0235), with 45% of patients in the SYM group with a score of 0 for bothersome disturbances compared with 66% in the VIV group.

Conclusions:

Mini-monovision using these EDOF IOLs was well-tolerated in the patient cohort. No significant differences were found for visual performance tests between the VIV and SYM groups. However, the data suggest that Vivity IOL is associated with a lower probability of bothersome visual disturbances compared with Symfony IOL.
Limitations of constant optimization with disclosed intraocular lens power formulae
Authors: Langenbucher Achim , Hoffmann Peter , Cayless Alan , Wendelstein Jascha , Szentmáry Nóra
Published: October 2023

Purpose:

To investigate the effect of formula constants on predicted refraction and limitations of constant optimization for classical and modern intraocular lens (IOL) power calculation formulae.

Setting:

Tertiary care center.

Design:

Retrospective single-center consecutive case series.

Methods:

This analysis is based on a dataset of 888 eyes before and after cataract surgery with IOL implantation (Hoya Vivinex). Spherical equivalent refraction predSEQ was predicted using IOLMaster 700 data, IOL power, and formula constants from IOLCon (https://iolcon.org). The formula prediction error (PE) was derived as predSEQ minus achieved spherical equivalent refraction for the SRKT, Hoffer Q, Holladay, Haigis, and Castrop formulae. The gradient of predSEQ (gradSEQ) as a measure for the effect of the constants on refraction was calculated and used for constant optimization.

Results:

Using initial formula constants, the mean PE was −0.1782 ± 0.4450, −0.1814 ± 0.4159, −0.1702 ± 0.4207, −0.1211 ± 0.3740, and −0.1912 ± 0.3449 diopters (D) for the SRKT, Hoffer Q, Holladay, Haigis, and Castrop formulas, respectively. gradSEQ for all formula constants (except gradSEQ for the Castrop R) decay with axial length because of interaction with the effective lens position (ELP). Constant optimization for a zero mean PE (SD: 0.4410, 0.4307, 0.4272, 0.3742, 0.3436 D) results in a change in the PE trend over axial length in all formulae where the constant acts directly on the ELP.

Conclusions:

With IOL power calculation formulae where the constant(s) act directly on the ELP, a change in constant(s) always changes the trend of the PE according to gradSEQ. Formulae where at least 1 constant does not act on the ELP have more flexibility to zero the mean or median PE without coupling with a PE trend error over axial length.
Portuguese consensus on the prevention and treatment of nausea and vomiting induced by cancer treatments
Authors: Vieira Cláudia , Bergantim Rui , Madureira Elsa , Barroso Juan C.M. , Labareda Miguel , Parreira Sara T. , Castro Ana , Macedo Ana , Custódio Sandra
Published: October 2023

Chemotherapy-induced nausea and vomiting (CINV) and radiotherapy-induced nausea and vomiting (RINV) strongly affect the quality of life of patients with cancer. Inadequate antiemetic control leads to the decline of patients' quality of life, increases rescue interventions, and may even compromise adherence to cancer treatment. Although there are international recommendations for controlling CINV and RINV, these recommendations focus mainly on pharmacological management, with scarce information on additional measures that patients may adopt. Moreover, the prophylaxis and management of CINV/RINV are not always applied. Thus, we identified the need to systematize the strategies for preventing and managing CINV/RINV and the associated risk factors to implement and promote effective prophylactic antiemetic regimens therapy in patients with cancer. This review sought to create a set of practical recommendations for managing and controlling CINV/RINV, according to the current international recommendations for antiemetic therapy and the main risk factors. Conclusively, we intended to produce a patient-centered guidance document for health care professionals focused on the awareness, monitoring, and treatment of CINV/RINV.
Role of gut microbiota in cardiovascular diseases – a comprehensive review
Authors: Rashid Safia , Sado Abdulmaleek Idanesimhe , Afzal Muhammad Sohaib , Ahmed Amna , Almaalouli Bsher , Waheed Tallha , Abid Rabia , Majumder Koushik , Kumar Vikash , Tejwaney Usha , Kumar Sarwan
Published: October 2023

The connection between cardiovascular illnesses and the gut microbiota has drawn more and more attention in recent years. According to research, there are intricate relationships between dietary elements, gut bacteria, and their metabolites that affect cardiovascular health. In this study, the role of gut microbiota in cardiovascular disorders is examined, with an emphasis on the cardiac consequences brought on by changes in gut microbiota. This essay discusses the gut-heart axis in depth and in detail. It talks about clinical research looking at how soy consumption, probiotic supplements, and dietary changes affected gut microbiota and cardiovascular risk variables. Our goal is to clarify the possible pathways that connect gut microbiota to cardiovascular health and the implications for upcoming treatment approaches. The authors examine the composition, roles, and effects of the gut microbiota on cardiovascular health, including their contributions to hypertension, atherosclerosis, lipid metabolism, and heart failure. Endotoxemia, inflammation, immunological dysfunction, and host lipid metabolism are some of the potential processes investigated for how the gut microbiota affects cardiac outcomes. The research emphasizes the need for larger interventional studies and personalized medicine strategies to completely understand the complexity of the gut-heart axis and its implications for the management of cardiovascular disease. The development of novel treatment strategies and cutting-edge diagnostic technologies in cardiovascular medicine may be facilitated by a better understanding of this axis.
Anterior dislocation of the shoulder associated with a diaphyseal fracture of the ipsilateral humerus: a case report
Authors: Diop Badara , Mendy Ountyess , Tene Nde Armel F. , Dione Alioune B. , Diop Malick , Diouf Pape A. , Sow Mayoro , Sarr Ndiame , Faye Ibrahima , Ndoye Abdou Y. , Konate Ibrahima
Published: October 2023

Background:

Anterior dislocation of the shoulder associated with a diaphyseal fracture of the ipsilateral humerus is a rare and controversial occurrence, with very few cases reported in the literature.

Case presentation:

We present a case of a 39-year-old right-handed driver who presented with an anterior dislocation of the shoulder associated with a diaphyseal fracture of the ipsilateral humerus following a road traffic accident. The lateral approach to the fracture allowed us to use two forceps to gain a good grip on the proximal fragment and perform the maneuver to reduce the dislocation. The fracture was reduced and fixed with a molded Lecestre-type plate.

Conclusion:

In this case, we employed the approach of initially reducing the shoulder dislocation with forceps, followed by osteosynthesis of the humeral fracture. The functional results were excellent after 6 months.
Yokenella regensburgei urinary tract infection in an immunocompetent patient: a case report
Authors: V Annie Sheeba , Suji Thangamani , Jayanth Selvin Theodore , Sahni Rani Diana
Published: October 2023

Yokenella regensburgei

, belonging to the order

Enterobacterales

, is a rare and emerging human pathogen reported to cause both superficial and invasive infections. The 13 case reports in the literature worldwide highlight blood, bone and wound infections. To our knowledge this is the first case description of

Y. regensburgei

causing a urinary tract infection in a 69-year-old immunocompetent patient which was isolated in two separate specimens and identified using matrix-assisted laser desorption ionization time-of-flight MS. It was found to be susceptible to most antimicrobials but resistant to penicillin, amoxicillin-clavulanate, cefoxitin and colistin. Inducible chromosomal ampC resistance was demonstrated on disc approximation testing, and blaYOC-1 class C beta-lactamase, beta lactamase superfamily and MBL fold metallo-hydrolase genes were found on whole genome sequencing.
A fatal case of necrotizing fasciitis by Aeromonas jandaei
Authors: Anil Anjali , Kumar Mani Bhushan , Chauhan Sachin , Ray Pallab , Dahiya Divya , Angrup Archana
Published: October 2023

Introduction : Necrotizing soft tissue infections are associated with an extremely fulminating course, owing to their rapid destruction of tissue planes underlying the skin. Aeromonas associated monomicrobial NSTIs are usually associated with exposure to fresh water, via trauma, trivial abrasions or even reptile bites, particularly among agricultural workers and fish handlers. Albeit uncommon in incidence, urgent medical and surgical intervention is required once diagnosis is reached.
Case report : A 40-year-old male patient, known case of alcoholic liver disease, presented to the emergency department with pain and diffuse swelling of bilateral lower limbs, which quickly progressed to form blackish discolouration and blebs. Blood for preliminary haematological and biochemical investigations, as well as fluid draining from blebs were sent for microbiological investigation. The gram stain revealed occasional neutrophils and gram-negative bacilli, pure growth in aerobic culture was identified as Aeromonasjandaei by Matrix-assisted laser desorption/ionization Time of Flight Mass Spectrometry (MALDI-TOF MS). Patient was started on empirical antimicrobials, though lesions continued to progress and he ultimately succumbed within 12 hours of his hospital stay.
Conclusion : As appropriate antimicrobial therapy and early surgical intervention are required for management of the same, occupational exposure and the fulminant course should raise suspicion of likelihood of Aeromonas associated infections.
Radioimmunotherapy as a pathogen-agnostic treatment method for opportunistic fungal infections
Authors: Carvalho Jorge L.C. , Malo Mackenzie E. , Allen Kevin J.H. , Frank Connor , Xiao Zhiwen , Jiao Rubin , Dadachova Ekaterina
Published: October 2023

Invasive fungal infections (IFI) such as mucormycosis are causing devastating morbidity and mortality in immunocompromised patients as anti-fungal agents do not work in the setting of suppressed immune system. COVID-19 pandemic has created a novel landscape for IFI in post-pandemic patients, which results from severe immune suppression caused by COVID-19 infection, comorbidities (diabetes, obesity) and immunosuppressive treatments such as steroids. The antigen-antibody interaction has been employed in radioimmunotherapy (RIT) to deliver lethal doses of ionizing radiation emitted by radionuclides to targeted cells and has demonstrated efficacy in several cancers. One of the advantages of RIT is its independence of immune status of a host which is crucial for immunosuppressed post-COVID-19 patients. In present work we targeted with RIT fungal pan-antigens 1,3-beta-glucan and melanin pigment, which are present in the majority of pathogenic fungi, thus making such targeting pathogen-agnostic. We demonstrated in experimental murine mucormycosis in immunocompetent and immunocompromised mice that 177Lutetium-labeled antibodies to these two antigens effectively decreased the fungal burden in major organs including the brain. These results are encouraging because they show the effectiveness of pathogen-agnostic RIT in significantly decreasing fungal burden in vivo, while they can be also potentially applied to treat the broad range of invasive fungal infections which express pan-antigens 1,3-beta-glucan or melanin.
Dimension Reduction by Spatial Components Analysis Improves Pattern Detection in Multivariate Spatial Data
Authors: Kleinenkuhnen Niklas , Köhler David , Baar Till , Nikopoulou Chrysa , Kondylis Vangelis , Schmid Matthias , Tessarz Peter , Tresch Achim
Published: October 2023

We introduce a multivariate statistical approach for pattern recognition in spatial transcriptomics data. Our algorithm (SPACO) constructs a low-dimensional projection of the data maximising Moran’s I, which mitigates non-spatial variation and outperforms PCA for pre-processing. Our method also provides a calibrated, powerful test of spatial gene expression that excels in robustness and specificity.
Ant identity determines the fungi richness and composition of a myrmecochorous seed
Authors: Fernandes Tiago V. , Fernandes Otavio L. , Gomes Inácio J. M. T. , Solar Ricardo R. C. , Campos Ricardo I.
Published: October 2023

Myrmecochory - seed dispersal by ants - is a mutualistic interaction in which ants attracted by seed appendices take them away from the parental plant location, where seeds usually have better development odds. Not all ant species benefit plants, and the mechanisms of those divergent outcomes are still unclear, especially from the perspective of microbial third parties. Here, we explore the effects of seed manipulation on fungi communities promoted by two ant species with contrasting effects on seed germination and antimicrobial cleaning strategies. We hypothesize that: i) fungi richness is higher in seeds manipulated byAcromyrmex subterraneus(species that negatively affect seed germination), followed by unmanipulated seeds and seeds manipulated byAtta sexdens(ant species that increase seed germination) and ii) seeds manipulated byA. sexdens, Ac. subterraneusand unmanipulated seeds present dissimilar fungi compositions. We identified fungal morphotypes in three groups of seeds: i) manipulated byA. sexdens; ii) manipulated byAc. subterraneus; iii) unmanipulated. Seeds manipulated byAc. subterraneusexhibited higher fungal richness than those manipulated byA. sexdensand unmanipulated seeds, indicating that the ant species known to impair germination increases the fungal load on seeds. Additionally, we found thatA. sexdensants were unable to reduce fungal richness compared to unmanipulated seeds. Furthermore, fungal composition differed among all three treatments. Our results underscore the significance of ant species identity in shaping the fungal communities associated with myrmecochorous seeds. Given the potential influence of microbial infection on seed fate, we suggest considering manipulation strategies when evaluating the overall quality of an ant as a seed disperser.
Resilience-driven neural synchrony during naturalistic movie watching
Authors: Ye Shuer , Batz Leona Rahel , Jain Avneesh , Salami Alireza , Ziaei Maryam
Published: October 2023

Psychological resilience protects individuals against the negative consequences of exposure to adversity. Despite increasing attention given to resilience for its role in maintaining mental health, a clear conceptualization of resilience remains elusive, and the intricacies of its neural correlates are poorly understood. Here, we recorded brain activity in healthy young adults using a 7T MRI scanner while they naturally watched movies. Stronger and more extensive resilience-driven neural synchrony, as estimated by inter-subject correlation, was observed in a wider set of brain regions in response to the negative movie compared to the neutral movie. Moreover, we found that high-resilience individuals had similar neural activities to their peers, while low-resilience individuals showed more variable neural activities. Intolerance of uncertainty (IU), a personality trait that shapes biased perception and cognition, damped the resilience-driven brain synchrony in regions related to attention, indicating IU may compromise resilience by affecting attentional functions. We propose that similarity of neural responses among resilient individuals highlights adaptive emotional processing. Conversely, the variability in neural responses indicates vulnerability to adverse psychological outcomes. These insights shed light on the mechanisms of resilience, highlighting that it operates as a system encompassing multiple neuropsychological processes crucial for adapting to external stimuli.
Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease
Authors: Lo Chih Hung , Zeng Jialiu , Loi Gavin Wen Zhao , Saipuljumri Eka Norfaishanty , O’Connor Lance M. , Indajang Jonathan , Reynolds Richard , Barron Anna M.
Published: October 2023

Background

Tumor necrosis factor (TNF) receptor 1 (TNFR1) signaling mediates neuronal necroptosis in Alzheimer’s disease (AD). Interaction of TNFR1 signaling axis with autolysosomal pathway and the accumulation of necrosome molecules in impaired lysosomes have been shown to lead to necroptotic neuronal death. This has been attributed to the terminal failure of the autophagic process, primarily due to lysosomal degradation dysfunction. Being the final and determining step of the autolysosomal pathway, lysosomes with sufficient acidification as maintained by functional vacuolar (H+)-ATPase (V-ATPase) are required to achieve complete autophagic degradation of toxic cellular components. Here, we aim to investigate the role of defective lysosomal acidification in mediating TNFR1 induced neuronal necroptosis in AD.

Methods

Neuropathological analysis of human post-mortem AD brains was performed to examine the correlation between TNFR1 induced neuronal necroptosis and autolysosomal dysfunction. Specifically, we probed for the level of V-ATPase subunits in AD brains to determine the extent of lysosomal acidification and function. Cell-based assays were conducted to understand the effect of TNFR1 activation in driving lysosomal acidification defect, autophagic impairment, mitochondrial dysfunction, and neuronal death in SH-SY5Y neuroblastoma cells. Furthermore, we applied lysosome-acidifying nanoparticles (AcNPs) to determine whether restoration of lysosomal acidification can rescue neuronal necroptosis in both TNF-treated SH-SY5Y cells and APPNL-G-Fknock-in mouse model of AD.

Results

We revealed that TNFR1 activated neuronal necroptosis correlates with autolysosomal dysfunction as characterized by downregulation of V-ATPase subunits and accumulation of autophagy receptor p62 in human AD brains. In cell culture, we showed for the first time that lysosomal acidification is only impaired in cells treated with TNF and not with other cytokines, contributing to inhibition of autophagic degradation in SH-SY5Y cells. We also illustrated that there is defective mitochondrial turnover, together with reduced mitochondrial functions and elevated reactive oxygen species, leading to neuronal death in SH-SY5Y cells. Importantly, we demonstrated that AcNPs restore lysosomal acidification, autophagic activity, and mitochondrial function, as well as rescue neuronal necroptosis in both TNF-treated SH-SY5Y cells and APPNL-G-Fmice.

Conclusions

Defective lysosomal acidification plays a key role in TNFR1 mediated neuronal necroptosis. This opens avenues for new therapeutic strategies to target lysosomal acidification dysfunction in AD.
Culture system for longitudinal monitoring of bone remodelingex vivo
Authors: Cramer E.E.A. , Hermsen K.C.J. , Kock L.M. , Ito K. , Hofmann S.
Published: October 2023

To quantify and visualize both bone formation and resorption within osteochondral explants culturedex vivois challenging with the current analysis techniques. An approach that enables monitoring of bone remodeling dynamics is longitudinal micro-computed tomography (µCT), a non-destructive technique that relies on repeated µCT scanning and subsequent registration of consecutive scans. In this study, a two-compartment culture system suitable for osteochondral explants that allowed for µCT scanning duringex vivoculture was established. Explants were scanned repeatedly in a fixed orientation, which allowed assessment of bone remodeling due to adequate image registration. Using this method, bone formation was found to be restricted to the outer surfaces when cultured statically. To demonstrate that the culture system could capture differences in bone remodeling, explants were cultured statically and under dynamic compression as loading promotes osteogenesis. No quantitative differences between static and dynamic culture were revealed. Still, only in dynamic conditions, bone formation was visualized on trabecular surfaces located within the inner cores, suggesting enhanced bone formation towards the center of the explants upon mechanical loading. Taken together, theex vivoculture system in combination with longitudinal µCT scanning and subsequent registration of images demonstrated potential for evaluating bone remodeling within explants.
Molecular Time Capsules Enable Transcriptomic Recording in Living Cells
Authors: Parker Mirae , Rubien Jack , McCormick Dylan , Li Gene-Wei
Published: October 2023

Live-cell transcriptomic recording can help reveal hidden cellular states that precede phenotypic transformation. Here we demonstrate the use of protein-based encapsulation for preserving samples of cytoplasmic RNAs inside living cells. These molecular time capsules (MTCs) can be induced to create time-stamped transcriptome snapshots, preserve RNAs after cellular transitions, and enable retrospective investigations of gene expression programs that drive distinct developmental trajectories. MTCs also open the possibility to uncover transcriptomes in difficult-to-reach conditions.
Quantifiable TCR repertoire changes in pre-diagnostic blood specimens among high-grade ovarian cancer patients
Authors: Yu Xuexin , Ye Jianfeng , Hathaway Cassandra A. , Tworoger Shelley , Lea Jayanthi , Li Bo
Published: October 2023

High grade serous ovarian cancer (HGOC) is a major cause of death in women. Early detection of HGOC usually leads to a cure, yet it remains a clinical challenge with over 90% HGOCs diagnosed at advanced stages. This is mainly because conventional biomarkers are not sensitive to detect the microscopic yet metastatic early HGOC lesions. In this study, we sequenced the blood T cell receptor (TCR) repertoires of 466 ovarian cancer patients and controls, and systematically investigated the immune repertoire signatures in HGOCs. We observed quantifiable changes of selected TCRs in HGOCs that are reproducible in multiple independent cohorts. Importantly, these changes are stronger during stage I. Using pre-diagnostic patient blood samples from the Nurses’ Health Study, we confirmed that HGOC signals can be detected in the blood TCR repertoire up to 4 years proceeding conventional diagnosis. Our findings may provide the basis of an immune-based HGOC early detection criterion.

Statement of significance

We made an unprecedented discovery that a strong and quantifiable change in the blood TCR repertoire occurs 4 to 2 years before high grade ovarian cancers could be diagnosed with conventional clinical tests. This finding might be useful to develop novel screening biomarkers to detect early-stage ovarian cancers.
On metallic luster and iridescence in animal coloration
Authors: Nordén Klara K. , Steiner Raphael S. , Stephenson Anna B. , Stoddard Mary Caswell
Published: October 2023

Some structural colors in nature are frequently described as metallic. For example, hummingbird plumage, jewel beetles andMorphobutterflies have this attribute. While much attention has been paid to describing the often-shifting hues of these structural colors, there has been little interest in explaining why they appear metallic. In this paper, we argue that the metallic luster (the metallic appearance or sheen) of some structural colors arises in part from a combination of two factors: a colored specular reflection and a very low diffuse reflection. Reflections with these characteristics are found in metals and are distinct from other material reflections in nature. We propose that metallic luster can be classified based on these two reflectance properties (colored specular reflection and low diffuse reflection). We also suggest that some of the ambiguity surrounding the term “iridescent structural color” can be traced to the frequent confounding of metallic luster with a common definition of iridescence: a shift of peak spectral wavelength (often referred to as hue) with viewing angle. We show using optical models and cross-polarization imaging of bird plumage that two types of structural colors that are often classified as “iridescent” and “non-iridescent” both display iridescence—but only one type has metallic luster. By considering metallic luster and iridescence separately, we simultaneously clarify terminology in structural colors and open up many new lines of inquiry regarding the perception of metallic luster in animals.
Dynamic trait distribution as a source for shifts in interaction strength and population density
Authors: Jackson Zachary , Xue BingKan
Published: October 2023

Intraspecific trait variation has been increasingly recognized as an important factor in determining species interaction and diversity. Eco-evolutionary models have studied the distribution of trait values within a population that changes over the generations as a result of selection and heritability. Non-heritable traits that can change within the lifetime, such as behavior, can cause trait-mediated indirect effects, often studied by modeling the dynamics of a homogeneous trait. Complementary to these two approaches, we study the distribution of traits within a population and its dynamics on short timescales due to ecological processes. We consider several mechanisms by which the trait distribution can shift dynamically: phenotypic plasticity within each individual, differential growth among individuals, and preferential consumption by the predator. Through a simple predator-prey model that explicitly tracks the trait distribution within the prey, we illustrate some unusual consequences of trait shifts, including the healthy herd effect and the emergent promotion of the prey by the predator. We analyze the cause of these phenomena by identifying the density and trait effects from the predator. Our results show that intraspecific trait variation and the dynamics of its distribution can lead to the modification of species interactions and result in outcomes that are otherwise unexpected.
Genome-wide analysis of transcription-coupled repair reveals novel transcription events inCaenorhabditis elegans
Authors: Kose Cansu , Lindsey-Boltz Laura A. , Sancar Aziz , Jiang Yuchao
Published: October 2023

Bulky DNA adducts such as those induced by ultraviolet light are removed from the genomes of multicellular organisms by nucleotide excision repair, which occurs through two distinct mechanisms, global repair, requiring the DNA damage recognition-factor XPC (xeroderma pigmentosum complementation group C), and transcription-coupled repair (TCR), which does not. TCR is initiated when elongating RNA polymerase II encounters DNA damage, and thus analysis of genome-wide excision repair in XPC-mutants only repairing by TCR provides a unique opportunity to map transcription events missed by methods dependent on capturing RNA transcription products and thus limited by their stability and/or modifications (5’-capping or 3’- polyadenylation). Here, we have performed the eXcision Repair-sequencing (XR-seq) in the model organismCaenorhabditis elegansto generate genome-wide repair maps from a wild-type strain with normal excision repair, a strain lacking TCR (csb-1), or one that only repairs by TCR (xpc- 1). Analysis of the intersections between thexpc-1XR-seq repair maps with RNA-mapping datasets (RNA-seq, long- and short-capped RNA-seq) reveal previously unrecognized sites of transcription and further enhance our understanding of the genome of this important model organism.
Assessing rapid adaptation through epigenetic inheritance: a new experimental approach
Authors: Chávez Alexandra , Huber Meret
Published: October 2023

Epigenetic inheritance is hypothesized to mediate rapid adaptation to stresses via two fundamentally different routes: first, through spontaneous epimutations that arise in a largely stochastic manner in the presence or absence of stress; if these spontaneous epimutations are heritable and beneficial, they may be selected upon (“stochastic route”); and second, through environment-induced epialleles that arise uniformly among individuals; if heritable, these epialleles may lead to stress adaptation even in the absence of selection (“deterministic route”). Testing and teasing apart these two routes is challenging, largely because a suitable experimental approach is lacking.

Here, we propose an experimental approach that allows to simultaneously assess the contribution of the stochastic and deterministic route. The essence of the approach is to manipulate the efficacy of selection through the population size and thereby to test whether selection is required for adaptation (stochastic route). To this end, genetically uniform populations are grown under different environments across multiple generations (“pre-treatment”) at two different population sizes: in large populations, in which selection is effective; and in small populations, in which drift overcomes the effect of selection. If the deterministic route contributes to adaptation, variation in fitness, phenotypes or epigenetic marks will arise between the small populations of the different pre-treatments. If the stochastic route contributes to adaptation, variation will arise between the small and large population within each pre-treatment. As a proof-of-principle, we tested whether small and large monoclonal populations of the aquatic duckweedSpirodela polyrhizamay adapt to copper excess outdoors.

After five to seven generations of pre-treatment and a subsequent multi-generational growth under control conditions, large populations outperformed small populations under copper excess. Furthermore, small populations pre-treated with copper excess tended to have higher fitness under copper excess than small populations pre-treated under control conditions. These data suggest that both the stochastic and deterministic route may alter plant fitness under recurring stress.

The proposed approach will allow to experimentally evaluate whether species may adapt to stresses through either stochastic and deterministic epigenetic changes, which is fundamental to understand whether and how epigenetic inheritance may lead to rapid stress adaptation.
Metabolic bypass rescues aberrant S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons
Authors: Andreyev Alexander Y. , Yang Hongmei , Doulias Paschalis-Thomas , Dolatabadi Nima , Zhang Xu , Luevanos Melissa , Blanco Mayra , Baal Christine , Putra Ivan , Nakamura Tomohiro , Ischiropoulos Harry , Tannenbaum Steven R. , Lipton Stuart A.
Published: October 2023

In Alzheimer’s disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), we found evidence for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block we found aberrant protein S-nitrosylation of αKGDH subunits that are known to inhibit enzyme function. This aberrant S-nitrosylation was documented not only in AD-hiN but also in postmortem human AD brains vs. controls, as assessed by two separate unbiased mass spectrometry platforms using bothSNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate (downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. Our findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.
Long chain monomethyl branched-chain fatty acid levels in human milk vary with gestational weight gain
Authors: O’Sullivan Aifric , Brady Emer , Lafferty Lucy , O’Shea Fiona , O’Regan Zoe , Meurs Noah , Baldini Michelle , Gengatharan Jivani , Metallo Christian M. , Wallace Martina
Published: October 2023

Breastfeeding is an important determinant of infant health and there is immense interest in understanding its metabolite composition so that key beneficial components can be identified. The aim of this research was to measure the fatty acid composition of human milk in an Irish cohort where we examined changes depending on lactation stage and gestational weight gain trajectory. Utilising a chromatography approach optimal for isomer separation, we identified 44 individual fatty acid species via GCMS and showed that monomethyl branched-chain fatty acids(mmBCFA’s), C15:0 and C16:1 are lower in women with excess gestational weight gain versus low gestational weight gain. To further explore the potential contribution of the activity of endogenous metabolic pathways to levels of these fatty acids in milk, we administered D2O to C57BL/6J dams fed a purified lard based high fat diet (HFD) or low-fat diet during gestation and quantified the total andde novosynthesized levels of fatty acids in their milk. We found thatde novosynthesis over three days can account for between 10 and 50% of mmBCFAs in milk from dams on the low-fat diet dependent on the branched-chain fatty acid species. However, HFD fed mice had significantly decreasedde novosynthesized fatty acids in milk resulting in lower total mmBCFAs and medium chain fatty acid levels. Overall, our findings highlight the diverse fatty acid composition of human milk and that human milk mmBCFA levels differ between gestational weight gain phenotypes. In addition, our data indicates thatde novosynthesis contributes to mmBCFA levels in mice milk and thus may also be a contributory factor to mmBCFA levels in human milk. Given emerging data indicating mmBCFAs may be beneficial components of milk, this study contributes to our knowledge around the phenotypic factors that may impact their levels.
Computing the inducibility of B cell lineages under a context-dependent model of affinity maturation: Applications to sequential vaccine design
Authors: Mathews Joseph , Van Itallie Elizabeth , Wiehe Kevin , Schmidler Scott C.
Published: October 2023

A key challenge in B cell lineage-based vaccine design is understanding theinducibilityof target neutralizing antibodies. We approach this problem through the use of detailed stochastic modeling of the somatic hypermutation process that occurs during affinity maturation. Under such a model, sequence mutation rates arecontext-dependent, rendering standard probability calculations for sequence evolution intractable. We develop an algorithmic approach to rapid, accurate approximation of key marginal sequence likelihoods required to inform modern sequential vaccine design strategies. These calculated probabilities are used to define an inducibility index for selecting among potential targets for immunogen design. We apply this approach to the problem of choosing targets for the design of boosting immunogens aimed at elicitation of the HIV broadly-neutralizing antibody DH270min11.

Author summary

Vaccine effectiveness relies on inducing the immune system to generate protective antibodies. Because antibodies are generated by random processes coupled to positive selection, the ability to induce certain rare but desirable antibodies can be limited by the inherent probability of occurrence. We use computational modeling to estimate the probability of antibody occurrence, and demonstrate the use of these estimates in designing vaccine regimens which maximize the probability of induction of broadly neutralizing antibodies.