bluuebunny/crossref_metadata_2025 huggingface dataset:
Finding his Feet, Finding a Role
Authors: Gehring David Scott
Published: May 2024

This chapter moves from 1563 to 1569 and discusses Beale’s activity in Germany and France during these years. It investigates Beale’s first real ‘job’ in working for the earl of Hertford regarding the legitimacy of his marriage to Katherine Grey and, accordingly, claim in the royal succession. John Hales, Beale’s step-uncle, played a major role in the drama both by way of his activity in the House of Commons and in corresponding with Beale while Beale was in Germany surveying legal opinion on the matter. Beale’s connections with civil lawyers in high places are examined, including the Reichskammergericht (Imperial Chamber Court) at Speyer. His subsequent work in the English embassy in Paris is discussed, as are his contact with William Cecil and his continued knowledge and expertise in German affairs. Beale’s most significant work to 1569, ‘the State of Germany’, is contexualized and analysed.
Diplomatic Interlude
Authors: Gehring David Scott
Published: May 2024

In 1576 and 1577 Beale was sent abroad as Queen Elizabeth’s formal ambassador, first to the Netherlands to negotiate the release of English ships, and second to Germany to persuade the Protestant princes away from hardline Lutheran doctrines in the Formula of Concord condemning other Protestants. Beale was climbing the ladder of government service, but he was still largely recognized as a specialist in diplomacy and with the relevant languages. In both cases, Beale achieved a degree of success, but he also was the victim of piracy and incurred enormous financial losses. One of several ambassadors on each occasion, Beale followed in the footsteps of Philip Sidney and worked closely with Daniel Rogers, a friend from years previous and close colleague for years to come. Looking towards the future, Beale collected and retained as much of his paperwork possible, which added to his working personal archive.
The Highest Highs and Lowest Lows
Authors: Gehring David Scott
Published: May 2024

Beale did not slow down between 1585 and 1593. He had more children, and split time between the City of London and Barnes, in Surrey. Beale’s worked on further negotiations regarding Mary Queen of Scots, culminating in his role in her execution at Fotheringhay in 1587. He served again in Parliament and in additional roles in the Council of the North and petty custom in London. He also became a member of the Elizabethan Society of Antiquaries. His part in Mary’s demise was recognized overseas, to Beale’s chagrin, but he was soon abroad again in the Netherlands, this time as an English sitting member of the Dutch Council of State when Leicester was governor general. Beale also worked again with Henry Killigrew. Upon his return Beale was asked to negotiate with the Hanseatic League of merchants, with whom English relations were souring. In 1593 Beale was dismissed from Parliament.
England in Europe
Authors: Gehring David Scott
Published: May 2024

The final chapter of the biography recounts Beale’s life in broad strokes and draws several themes together, both within his own life and across the age. Beale’s merits, shortcomings, personal idiosyncrasies, and principles are considered. Attention is paid to his archive and how it relates to archival practices both in England and elsewhere, and his networks of friends and associates near and far are noted. The limitations of the voluminous sources used in the study are discussed. Readers are invited to think about the ways in which Englishmen like Beale and English affairs more broadly mattered to a broader European theatre, especially though not exclusively regarding the wars of religion. Just as the introductory chapter considered the ways in which mainland Europe could affect and influence sixteenth-century England, the concluding chapter considers the inverse and accordingly recognizes the relative rise of Elizabethan England in Reformation Europe.
Incorporating temporal dynamics of mutations to enhance the prediction capability of antiretroviral therapy’s outcome for HIV-1
Authors: Di Teodoro Giulia , Pirkl Martin , Incardona Francesca , Vicenti Ilaria , Sönnerborg Anders , Kaiser Rolf , Palagi Laura , Zazzi Maurizio , Lengauer Thomas
Published: May 2024

Motivation

In predicting HIV therapy outcomes, a critical clinical question is whether using historical information can enhance predictive capabilities compared with current or latest available data analysis. This study analyses whether historical knowledge, which includes viral mutations detected in all genotypic tests before therapy, their temporal occurrence, and concomitant viral load measurements, can bring improvements. We introduce a method to weigh mutations, considering the previously enumerated factors and the reference mutation-drug Stanford resistance tables. We compare a model encompassing history (H) with one not using this information (NH).

Results

The H-model demonstrates superior discriminative ability, with a higher ROC-AUC score (76.34%) than the NH-model (74.98%). Wilcoxon test results confirm significant improvement of predictive accuracy for treatment outcomes through incorporating historical information. The increased performance of the H-model might be attributed to its consideration of latent HIV reservoirs, probably obtained when leveraging historical information. The findings emphasize the importance of temporal dynamics in acquiring mutations. However, our result also shows that prediction accuracy remains relatively high even when no historical information is available.

Availability and implementation

This analysis was conducted using the Euresist Integrated DataBase (EIDB). For further validation, we encourage reproducing this study with the latest release of the EIDB, which can be accessed upon request through the Euresist Network.
Efficient data integration under prior probability shift
Authors: Huang Ming-Yueh , Qin Jing , Huang Chiung-Yu
Published: May 2024

Conventional supervised learning usually operates under the premise that data are collected from the same underlying population. However, challenges may arise when integrating new data from different populations, resulting in a phenomenon known as dataset shift. This paper focuses on prior probability shift, where the distribution of the outcome varies across datasets but the conditional distribution of features given the outcome remains the same. To tackle the challenges posed by such shift, we propose an estimation algorithm that can efficiently combine information from multiple sources. Unlike existing methods that are restricted to discrete outcomes, the proposed approach accommodates both discrete and continuous outcomes. It also handles high-dimensional covariate vectors through variable selection using an adaptive least absolute shrinkage and selection operator penalty, producing efficient estimates that possess the oracle property. Moreover, a novel semiparametric likelihood ratio test is proposed to check the validity of prior probability shift assumptions by embedding the null conditional density function into Neyman’s smooth alternatives (Neyman, 1937) and testing study-specific parameters. We demonstrate the effectiveness of our proposed method through extensive simulations and a real data example. The proposed methods serve as a useful addition to the repertoire of tools for dealing dataset shifts.
Social considerations for the removal of dams and other aquatic barriers
Authors: Lutter Seth H , Cuppett Scott , Sethi Suresh A , Rahm Brian G
Published: May 2024

Stream connectivity restoration through the removal or mitigation of dams and other anthropogenic barriers is critical for aquatic species conservation. Historically, stream connectivity restoration planning has been focused on biophysical criteria; however, aquatic barriers are embedded in social contexts that can constrain restoration decisions. To support the integration of social considerations into stream connectivity conservation planning, we synthesized the available research involving social criteria linked to barrier removal. We found that the literature has been focused predominantly on the removal of dams and identify four major categories of social considerations for barrier removal: economics, nonmarket social values, safety, and procedural context. We reviewed contemporary barrier removal prioritization efforts and found that existing approaches typically only consider small subsets of social considerations and face issues with data availability. The findings synthesized in the present article establish potential criteria that could be integrated into effective stream connectivity restoration planning and inform future data capture efforts for barrier removal.
Social infrastructure, community organizations, and friendship formation: a scoping review
Authors: Lauer Sean , Wong Karen Lok Yi , Yan Miu Chung
Published: May 2024

Community organizations are a unique part of the local social infrastructure that provides opportunities for social connections and community building. This contribution has been established in research on social capital and the research on social networks. Little research has looked specifically at the processes that lead to forming new relationships within community organizations. In this paper, we address this gap by looking specifically at the situational dynamics at community organizations that contribute to making new friends. We approach this question by conducting a scoping review, a systematic approach to research search and selection when conducting reviews. Our review identified 37 relevant pieces of research. The majority of the research we identify comes from Australia, Canada, the UK, and the USA. We discuss three themes addressing situational dynamics that emerged in the analysis: (1) the importance of structured programs and activities as prompts for connection, (2) creating spaces for informal interactions, and (3) emerging mutuality based on similarities and differences. We conclude with suggestions for how community organizations purposefully create these situational dynamics in their work.
NK-cell receptor modulation in viral infections
Authors: Lenart Marzena , Rutkowska-Zapała Magdalena , Siedlar Maciej
Published: May 2024

Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK-cell receptors are divided into either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK-cell activation requires stimulation of activating receptors. In viral infections, NK-cell interaction with infected cells can result in activation, memory-like NK-cell differentiation, or NK-cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK-cell receptor expression. In this review, we summarize the current knowledge of NK-cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK-cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK-cell receptor activation gives a promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of the application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK-cell receptor biology, a deeper understanding of NK-cell receptors role in viral infections is still needed.
In-situ observation of DL-alanine crystallization from a laser-trapped dense liquid droplet as a heterogeneous nucleation site
Authors: Niinomi Hiromasa , Yoshikawa Hiroshi Y , Kawamura Ryuzo , Yamazaki Tomoya , Oshikiri Tomoya , Nakagawa Masaru
Published: May 2024

Nucleation from an aqueous solution is an important step in crystallization which controls the physicochemical properties of crystalline materials. Although dense liquid droplets are considered as a precursor of a crystal in the two-step nucleation model, their actual role is unclear. Our in-situ microscopic observations of the crystallization of DL-alanine from a dense liquid droplet trapped by laser tweezers show that liquid droplets play the role of a substrate, facilitating heterogeneous nucleation, rather than a precursor of a crystal.
Organic solvent-induced structural changes in a protein confined in a giant coordination cage
Authors: Tamura Hiroyuki , Nakama Takahiro , Rossen Anouk , Ishikita Hiroshi , Fujita Makoto
Published: May 2024

We investigate the molecular mechanism of acetonitrile-induced structural changes in a cutinase-like enzyme in a giant coordination cage using molecular dynamics (MD) simulations. As the acetonitrile content within the cage increases, significant conformational changes of the caged protein occur due to acetonitrile binding to the specific sites, in line with protein denaturation events observed in previous nuclear magnetic resonance studies. Accordingly, employing MD simulations on caged proteins represents an effective strategy for investigating the dynamics of unstable protein structures.
Distinct Clinical Endpoints of Staphylococcus aureus Bacteraemia Complicate Assessment of Outcome
Authors: Russell Clark D , Berry Karla , Cooper George , Sim Wynne , Lee Rui Shian , Gan Tze Yi , Donlon William , Besu Antonia , Heppenstall Emily , Tysall Luke , Robb Andrew , Dewar Simon , Smith Andrew , Fowler Vance G
Published: May 2024

Background

We aimed to test the hypothesis that development of metastatic infection represents a distinct clinical endpoint from death due to Staphylococcus aureus bacteremia (SAB).

Methods

We conducted a retrospective observational study of adults with SAB between 20 December 2019 and 23 August st2022 (n = 464). Simple logistic regression, odds ratios, and z-scores were used to compare host, clinical, and microbiologic features.

Results

Co-occurrence of attributable mortality and metastatic infection was infrequent. Charlson Comorbidity Index and age were strongly associated with attributable mortality, but not metastatic infection. We compared patients with fatal SAB (without clinically-apparent metastatic complications, 14.4% of cohort), metastatic SAB (without attributable mortality, 22.2%), neither complication (56.7%), and overlapping fatal/metastatic SAB (6.7%). Compared to SAB without complications, fatal SAB was specifically associated with older age and multi-morbidity. Metastatic SAB was specifically associated with community acquisition, persistent fever, persistent bacteremia, and recurrence. Endocarditis was over-represented in the fatal/metastatic SAB overlap group, which shared patient characteristics with fatal SAB. In contrast to other (predominantly musculoskeletal) metastatic complications, endocarditis was associated with increased mortality, with death occurring in older multi-morbid patients later after SAB onset.

Conclusions

Patients with SAB experience distinct clinical endpoints: (i) early death, associated with multi-morbidity and age; (ii) metastatic (predominantly musculoskeletal) SAB; (iii) endocarditis, associated with late death occurring in older people with multi-morbidity, and (iv) bacteraemia without complications. These distinctions could be important for selecting appropriate outcomes in clinical trials: different interventions might be required to reduce mortality versus improve clinical response in patients with metastatic SAB.
Magnetic Resonance Imaging Features Indicative of Permanent Colon Damage in Ulcerative Colitis: An Exploratory Study
Authors: Rimola Jordi , Castro-Poceiro Jesús , Sapena Víctor , Aduna Marta , Arevalo Juan , Vera Isabel , Pastrana Miguel Ángel , Gallego Marta , Masamunt Maria Carme , Fernández-Clotet Agnès , Ordás Ingrid , Ricart Elena , Panés Julian
Published: May 2024

Background and Aims

It is uncertain whether ulcerative colitis leads to accumulated bowel damage on cross-sectional image. We aimed to characterise bowel damage in patients with ulcerative colitis using magnetic resonance imaging [MRI], and to determine its relation with duration of disease and the impact on patients’ quality of life.

Methods

In this prospective study, patients with ulcerative colitis [UC] in endoscopic remission underwent MRI without bowel cleansing, and completed quality-of-life questionnaires. Participants’ magnetic resonance findings were analysed considering normal values and thresholds determined in controls with no history of inflammatory bowel disease [n=40], and in patients with Crohn’s disease with no history of colonic involvement [n = 12]. Subjects with UC were stratified according to disease duration [< 7 years vs 7‒14 years vs > 14 years].

Results

We analysed 41 subjects with ulcerative colitis [20 women; Mayo endoscopic subscore 0 in 38 [92.7%] and 1 in three [7.3%]]. Paired segment-by-segment comparison of magnetic resonance findings in colonic segments documented as being affected by ulcerative colitis versus controls showed that patients with ulcerative colitis had decreased cross-sectional area [p ≤ 0.0034] and perimeter [p ≤ 0.0005] and increased wall thickness [p = 0.026] in all segments. Colon damage, defined as wall thickness ≥ 3 mm, was seen in 22 [53.7%] patients. Colon damage was not associated with disease duration or quality of life.

Conclusions

Morphological abnormalities in the colon were highly prevalent in patients with ulcerative colitis in the absence of inflammation. Structural bowel damage was not associated with disease duration or quality of life.
Effectiveness of combined first-line medical treatment in acromegaly with prolactin cosecretion
Authors: Biagetti Betina , Araujo-Castro Marta , Torre Edelmiro Menéndez , Novoa-Testa Iría , Cordido Fernando , Corrales Eider Pascual , Berrocal Víctor Rodríguez , Guerrero-Pérez Fernando , Vicente Almudena , Percovich Juan Carlos , Centeno Rogelio García , González Laura , García María Dolores Ollero , Echarri Ana Irigaray , Rodríguez María Dolores Moure , Novo-Rodríguez Cristina , Calatayud María , Villar-Taibo Rocío , Bernabéu Ignacio , Alvarez-Escola Cristina , Valderrama Pamela Benítez , Tenorio-Jiménez Carmen , Galiana Pablo Abellán , Moreno Eva Venegas , Molero Inmaculada González , Iglesias Pedro , Blanco Concepción , De Lara Fernando Vidal-Ostos , de Miguel Paz , Mezquita Elena López , Hanzu Felicia , Aldecoa Iban , Aznar Silvia , Lamas Cristina , Aulinas Anna , Asla Roca Queralt , Gracia Paola , Córdova José María Recio , Aviles Mariola , Asensio-Wandosel Diego , Sampedro Miguel , Cámara Rosa , Paja Miguel , Ruz-Caracuel Ignacio , Fajardo-Montañana Carmen , Asanza Esteban Cordero , Martinez-Saez Elena , Marazuela Mónica , Puig-Domingo Manel
Published: May 2024

Objective

The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA).

Design

This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment.

Methods

Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality.

Results

Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline.

Conclusion

In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.
A review of the epidemiology of invasive fungal infections in Asian patients with hematological malignancies (2011–2021)
Authors: Iyadorai Thevambiga , Tay Sun Tee , Liong Chee Chiat , Samudi Chandramathi , Chow Lai Chee , Cheong Chin Sum , Velayuthan Rukumani , Tan Sen Mui , Gan Gin Gin
Published: May 2024

The incidence of invasive fungal infection (IFI) is increasing, especially among patients diagnosed with hematological malignancies due to their immunocompromised nature. Other risk factors include advanced age, exposure to immunosuppressants, neutropenia, and catheter use. Some of the most common IFI organisms reported are Candida and Aspergillus species, and other fungal species, including Scedosporium, Trichosporon, Cryptococcus, and Fusarium have also increasingly been reported in the past years. However, the epidemiologic data on IFI among patients with hematological malignancies in Asian countries are lacking. Therefore, we investigated published epidemiologic data on such cases from the past 10 years (2011–2021) and discuss the challenges faced in the diagnosis and management of IFIs in Asia.
Challenges and advances in measuring phenotypic convergence
Authors: Grossnickle David M , Brightly William H , Weaver Lucas N , Stanchak Kathryn E , Roston Rachel A , Pevsner Spencer K , Stayton C Tristan , Polly P David , Law Chris J
Published: May 2024

Tests of phenotypic convergence can provide evidence of adaptive evolution, and the popularity of such studies has grown in recent years due to the development of novel, quantitative methods for identifying and measuring convergence. These methods include the commonly applied C1–C4 measures of Stayton (2015a), which measure morphological distances between lineages, and Ornstein–Uhlenbeck (OU) model-fitting analyses, which test whether lineages converged on shared adaptive peaks. We test the performance of C-measures and other convergence measures under various evolutionary scenarios and reveal a critical issue with C-measures: they often misidentify divergent lineages as convergent. We address this issue by developing novel convergence measures—Ct1–Ct4-measures—that calculate distances between lineages at specific points in time, minimizing the possibility of misidentifying divergent taxa as convergent. Ct-measures are most appropriate when focal lineages are of the same or similar geologic ages (e.g., extant taxa), meaning that the lineages’ evolutionary histories include considerable overlap in time. Beyond C-measures, we find that all convergence measures are influenced by the position of focal taxa in phenotypic space, with morphological outliers often statistically more likely to be measured as strongly convergent. Further, we mimic scenarios in which researchers assess convergence using OU models with a priori regime assignments (e.g., classifying taxa by ecological traits) and find that multiple-regime OU models with phenotypically divergent lineages assigned to a shared selective regime often outperform simpler models. This highlights that model support for these multiple-regime OU models should not be assumed to always reflect convergence among focal lineages of a shared regime. Our new Ct1–Ct4-measures provide researchers with an improved comparative tool, but we emphasize that all available convergence measures are imperfect, and researchers should recognize the limitations of these methods and use multiple lines of evidence to test convergence hypotheses.
Longitudinal Associations of Family Relationship Quality With Chronic Pain Incidence and Persistence Among Aging African Americans
Authors: Woods Sarah B , Roberson Patricia N E , Booker Quiera , Wood Beatrice L  , Booker Staja Q
Published: May 2024

Objectives

This study examines how family relationships convey risk or resilience for pain outcomes for aging African Americans, and to replicate and extend analyses across 2 nationally representative studies of aging health.

Methods

African American participants in Midlife in the United States (MIDUS, N = 755) and the Health and Retirement Study (HRS, N = 2,585) self-reported chronic pain status at 2006 waves and then again 10 years later. Logistic regression was used to estimate the odds of pain incidence and persistence explained by family, intimate partner, and parent–child strain and support, as well as average support and average strain across relationships.

Results

On average, MIDUS participants were younger (M = 52.35, SD = 12.06; 62.1% female) than HRS (M = 66.65, SD = 10.92; 63.7% female). Family support and average support were linked to decreased odds of pain incidence in MIDUS, but only when tested without accounting for strain, whereas parent–child strain was a risk factor for pain incidence in HRS, as was average strain. Family support protected against pain persistence in MIDUS, whereas average support was linked to reduced odds of pain persisting in HRS.

Discussion

Chronic pain outcomes are worse for African Americans for a number of reasons, but parent–child strain may contribute to the risk of new pain developing over time for older adults. Conversely, family support may offer a protective benefit for pain incidence and persistence among aging African Americans. Findings implicate family relationships as a potential target of pain management interventions.
Who’s Worried? Memory, Worries About Dementia, and Marital Strain in Midlife Same- and Different-Sex Marriages: A Dyadic Perspective
Authors: Wang Yiwen
Published: May 2024

Objectives

Prior scholarship has highlighted the importance of marriage for cognition. However, little research has considered how cognition-related concerns may impact marriage. In this study, researchers examine how aging couples view each other’s memory and worry about their potential development of dementia in the future. Additionally, researchers investigate whether these cognition-related concerns may strain marriage, and how these dynamics differ for men and women in same- and different-sex marriages.

Methods

Researchers used 2 waves of dyadic data from the Health and Relationships Project (HARP; 2015–2022), including 594 respondents from 297 same- and different-sex married couples (aged 41–71 at Time 2). Researchers employed the Actor–Partner Interdependence Model (APIM) to explore associations between actor and partner reports of memory and dementia worry with marital strain.

Results

Men and women in same- and different-sex marriages were equally likely to report worries about their own potential development of dementia. However, women reported more concerns about their spouse developing dementia in the future than men did, regardless of whether they were married to a man or a woman. Both partners’ reports of memory and dementia worry played a complex role in influencing marital strain, with variations observed across couple types.

Discussion

Concerns about cognitive decline and dementia are common in older populations, and for married couples, spouses have concerns about their own memory as well as that of their partner. Researchers finding identified the significance of concerns about a spouse’s memory on marital dynamics among aging couples.
The three-sided right-handed β-helix is a versatile fold for glycan interactions
Authors: Burnim Audrey A , Dufault-Thompson Keith , Jiang Xiaofang
Published: May 2024

Interactions between proteins and glycans are critical to various biological processes. With databases of carbohydrate-interacting proteins and increasing amounts of structural data, the three-sided right-handed β-helix (RHBH) has emerged as a significant structural fold for glycan interactions. In this review, we provide an overview of the sequence, mechanistic, and structural features that enable the RHBH to interact with glycans. The RHBH is a prevalent fold that exists in eukaryotes, prokaryotes, and viruses associated with adhesin and carbohydrate-active enzyme (CAZyme) functions. An evolutionary trajectory analysis on structurally characterized RHBH-containing proteins shows that they likely evolved from carbohydrate-binding proteins with their carbohydrate-degrading activities evolving later. By examining three polysaccharide lyase and three glycoside hydrolase structures, we provide a detailed view of the modes of glycan binding in RHBH proteins. The 3-dimensional shape of the RHBH creates an electrostatically and spatially favorable glycan binding surface that allows for extensive hydrogen bonding interactions, leading to favorable and stable glycan binding. The RHBH is observed to be an adaptable domain capable of being modified with loop insertions and charge inversions to accommodate heterogeneous and flexible glycans and diverse reaction mechanisms. Understanding this prevalent protein fold can advance our knowledge of glycan binding in biological systems and help guide the efficient design and utilization of RHBH-containing proteins in glycobiology research.
Integrated multi-omics investigation revealed the importance of phenylpropanoid metabolism in the defense response of Lilium regale Wilson to fusarium wilt
Authors: Deng Jie , Che Xiaoli , Gu Yue , Qu Yuan , Liu Diqiu
Published: May 2024

Lilies (genus Lilium) play a significant role in the global cut-flower industry, but they are highly susceptible to fusarium wilt caused by Fusarium oxysporum. However, Lilium regale, a wild lily species, exhibits remarkable resistance to F. oxysporum. To investigate the quantitative resistance of L. regale to fusarium wilt, a comprehensive multi-omics analysis was conducted. Upon inoculation with F. oxysporum, L. regale roots showed a significant accumulation of phenylpropane metabolites, including lignin precursors, flavonoids, and hydroxycinnamic acids. These findings were consistent with the upregulated expression of phenylpropanoid biosynthesis-related genes encoding various enzymes, as revealed by transcriptomics and proteomics analyses. Furthermore, metabolomics and proteomics data demonstrated differential activation of monoterpenoid and isoquinoline alkaloid biosynthesis. Colorimetry and high-performance liquid chromatography analyses revealed significantly higher levels of total flavonoids, lignin, ferulic acid, phlorizin, and quercetin contents in L. regale scales compared with susceptible lily ‘Siberia’ scales during F. oxysporum infection. These phenylpropanes exhibited inhibitory effects on F. oxysporum growth and suppressed the expression of pathogenicity-related genes. Transcriptional regulatory network analysis suggested that ethylene-responsive transcription factors (ERFs) may positively regulate phenylpropanoid biosynthesis. Therefore, LrERF4 was cloned and transiently overexpressed in the fusarium wilt-susceptible Oriental hybrid lily ‘Siberia’. The overexpression of LrERF4 resulted in increased levels of total flavonoids, lignin, ferulic acid, phlorizin, and quercetin, while the silencing of LrERF4 in L. regale through RNAi had the opposite effect. In conclusion, phenylpropanoid metabolism plays a crucial role in the defense response of L. regale against fusarium wilt, with LrERF4 acting as a positive regulator of phenylpropane biosynthesis.
Short-Term Use of Upadacitinib in Combination With Biologic Therapy for Inducing Clinical Remission in Patients With Active Inflammatory Bowel Disease
Authors: Yin Jianyi , El-Najjar Yassin , Cordova Noelle , Touma Mary-Joe , Nguyen Noelle , Boktor Moheb , Burstein Ezra , Fudman David I
Published: May 2024

Lay Summary

We report that upadacitinib intended for short-term use in combination with biologic therapy appeared to be effective in inducing steroid-free clinical remission in patients with active inflammatory bowel disease, but a substantial proportion of patients required extended use.
A Mitochondrial Perspective on the Demands of Reproduction
Authors: Hood Wendy R
Published: May 2024

Synopsis

The cost of supporting traits that increase mating opportunities and maximize the production of quality offspring is paid in energy. This currency of reproduction is enabled by bioenergetic adaptations that underlie the flexible changes in energy utilization that occur with reproduction. This review considers the traits that contribute to variation in the capacity of an organ to produce ATP. Further, it synthesizes findings from studies that have evaluated bioenergetic adaptations to the production of sexually selected traits and performance during reproduction and the role of change in mitochondrial respiratory performance in the tradeoff between reproduction and longevity. Cumulatively, these works provide evidence that in selecting for redder males, female finches will likely mate with a male with high mitochondrial respiratory performance and, potentially, a higher probability of mitonuclear compatibility. Females from diverse taxa allocate more to reproduction when the respiratory performance of mitochondria or density of the inner mitochondrial membrane in the liver or skeletal muscle is higher. Finally, reproduction does not appear to have persistent negative effects on mitochondrial respiratory performance, countering a role for mitochondria in the trade-off between reproduction and longevity. I close by noting that adaptations that improve mitochondrial respiratory performance appear vital for optimizing reproductive fitness.
Symbiotic bacteria and fungi proliferate in diapause and may enhance overwintering survival in a solitary bee
Authors: Christensen Shawn M , Srinivas Sriram N , McFrederick Quinn S , Danforth Bryan N , Buchmann Stephen L , Vannette Rachel L
Published: May 2024

Host–microbe interactions underlie the development and fitness of many macroorganisms, including bees. Whereas many social bees benefit from vertically transmitted gut bacteria, current data suggests that solitary bees, which comprise the vast majority of species diversity within bees, lack a highly specialized gut microbiome. Here, we examine the composition and abundance of bacteria and fungi throughout the complete life cycle of the ground-nesting solitary bee Anthophora bomboides standfordiana. In contrast to expectations, immature bee stages maintain a distinct core microbiome consisting of Actinobacterial genera (Streptomyces, Nocardiodes) and the fungus Moniliella spathulata. Dormant (diapausing) larval bees hosted the most abundant and distinctive bacteria and fungi, attaining 33 and 52 times their initial copy number, respectively. We tested two adaptive hypotheses regarding microbial functions for diapausing bees. First, using isolated bacteria and fungi, we found that Streptomyces from brood cells inhibited the growth of multiple pathogenic filamentous fungi, suggesting a role in pathogen protection during overwintering, when bees face high pathogen pressure. Second, sugar alcohol composition changed in tandem with major changes in fungal abundance, suggesting links with bee cold tolerance or overwintering biology. We find that A. bomboides hosts a conserved core microbiome that may provide key fitness advantages through larval development and diapause, which raises the question of how this microbiome is maintained and faithfully transmitted between generations. Our results suggest that focus on microbiomes of mature or active insect developmental stages may overlook stage-specific symbionts and microbial fitness contributions during host dormancy.
Making Art on a City Wide Scale
Authors: Powell Grant
Published: May 2024

Marin Petkov, founder of MP-STUDIO, talks to Grant Powell MBCS about the work that goes into designing one of the most popular light festivals in Europe.
Vishing in the Age of AI
Authors: Clark Timothy
Published: May 2024

Tim Clark, MBCS, takes a look at vishing attacks using AI and explains why their increasing sophistication demands greater awareness and vigilance.
The Value of Effective Cybersecurity
Authors: Ademola Ojo Emmanuel
Published: May 2024

Professor Ojo Emmanuel Ademola PhD, FBCS explains why effective cybersecurity is not only a necessity, but imperative for long term success.
Addressing the AI Skills Gap
Authors: Powell Grant
Published: May 2024

Grant Powell MBCS spoke to Jon Verrier, former partner and managing director at Accenture, about the impact of AI on business applications development and the skills necessary to succeed in this space.
Invisible Engineers and the History of Computing
Authors: Runciman Brian
Published: May 2024

Dr Roger Johnson has been made a BCS Honorary Fellow. Brian Runciman MBCS spoke to him about his long association with BCS, his contributions, and how he has benefited.
Safe and Reliable Software
Authors: Gupta Pankaj
Published: May 2024

Pankaj Gupta FBCS examines the importance of Memory Safe Programming and why it is increasingly regarded as necessary.
Strengthening the use of artificial intelligence within healthcare delivery organizations: balancing regulatory compliance and patient safety
Authors: Sendak Mark P , Liu Vincent X , Beecy Ashley , Vidal David E , Shaw Keo , Lifson Mark A , Tobey Danny , Valladares Alexandra , Loufek Brenna , Mogri Murtaza , Balu Suresh
Published: May 2024

Objectives

Surface the urgent dilemma that healthcare delivery organizations (HDOs) face navigating the US Food and Drug Administration (FDA) final guidance on the use of clinical decision support (CDS) software.

Materials and Methods

We use sepsis as a case study to highlight the patient safety and regulatory compliance tradeoffs that 6129 hospitals in the United States must navigate.

Results

Sepsis CDS remains in broad, routine use. There is no commercially available sepsis CDS system that is FDA cleared as a medical device. There is no public disclosure of an HDO turning off sepsis CDS due to regulatory compliance concerns. And there is no public disclosure of FDA enforcement action against an HDO for using sepsis CDS that is not cleared as a medical device.

Discussion and Conclusion

We present multiple policy interventions that would relieve the current tension to enable HDOs to utilize artificial intelligence to improve patient care while also addressing FDA concerns about product safety, efficacy, and equity.
Fatally impaired glucose digestion by propylene glycol in Aedes aegypti (Diptera: Culicidae) and co-formulation with terpenoids for enhancing attractive toxic sugar baits
Authors: Maes Gavin , Tintorri Giulia , Nelson Irvane E , Baker Kobi A , Seavey Corey E , Rehbein Michele M , White Gregory S , Faraji Ary , Willenberg Bradley J , Bibbs Christopher S
Published: May 2024

Propylene glycol (PG) demonstrates greater efficacy than other sugar polyols. However, the attributes it confers for toxicity and possible co-formulation with other ingredients are unknown. To evaluate this, α-glucosidase and glucose oxidase reactions were performed in Aedes aegypti (L.) (Diptera: Culicidae) to categorize if PG behaves similarly to prior studied sugar alcohols. A combination of no-choice and choice assays was used to determine effective ratios of PG and sucrose, competitiveness against a control of 10% sucrose, and whether mosquitoes recovered from PG consumption. The final trials included β-cyclodextrin encapsulated cinnamon leaf oil, clove stem oil, patchouli oil, garlic oil, cedarwood oil, and papaya seed oil formulated with 5% sucrose + 5% PG. PG functioned as a linear competitive inhibitor of α-glucosidase. The efficacy of PG was synergized by co-ingestion with equivalent ratios of sucrose. Unlike the high diuretic response to other sugar alcohols, PG resulted in diminished excretion regardless of being co-formulated with sucrose or terpenoids. PG is not especially competitive against unadulterated sugar meals but is likewise not clearly repellent. Although mosquitoes did not recover from ingestion of the glycol meals, there was no indication that mortality would continue to accumulate once the treatments were removed. Of the terpenoids tested, cinnamon and patchouli caused ~50% or less mortality; garlic, cedarwood, and clove caused 80-90% mortality; and papaya seed caused 100% mortality, exceeding all other test groups and the formulation blank. PG is a useful supporting ingredient in attractive toxic sugar bait formulations with flexibility in formulation.
GL-V9 synergizes with oxaliplatin of colorectal cancer via Wee1 degradation mediated by HSP90 inhibition
Authors: Chen Hongyu , Yang Fan , Zhao Qianying , Wang Hongzheng , Zhu Mengyuan , Li Hui , Ge Zheng , Zhang Shuai , Guo Qinglong , Hui Hui
Published: May 2024

Objectives

GL-V9 exhibited anti-tumour effects on various types of tumours. This study aimed to verify if GL-V9 synergized with oxaliplatin in suppressing colorectal cancer (CRC) and to explore the synergistic mechanism.

Methods

The synergy effect was tested by MTT assays and the mechanism was examined by comet assay, western blotting and immunohistochemistry (IHC). Xenograft model was constructed to substantiated the synergy effect and its mechanism in vivo.

Results

GL-V9 was verified to enhance the DNA damage effect of oxaliplatin, so as to synergistically suppress colon cancer cells in vitro and in vivo. In HCT-116 cells, GL-V9 accelerated the degradation of Wee1 and induced the abrogation of cell cycle arrest and mis-entry into mitosis, bypassing the DNA damage response caused by oxaliplatin. Our findings suggested that GL-V9 binding to HSP90 was responsible for the degradation of Wee1 and the vulnerability of colon cancer cells to oxaliplatin. Functionally, overexpression of either HSP90 or WEE1 annulled the synergistic effect of GL-V9 and oxaliplatin.

Conclusions

Collectively, our findings revealed that GL-V9 synergized with oxaliplatin to suppress CRC and displayed a promising strategy to improve the efficacy of oxaliplatin.
Lights, location, action: shade avoidance signalling over spatial scales
Authors: Gautrat Pierre , Matton Sanne E A , Oskam Lisa , Shetty Siddhant S , van der Velde Kyra J , Pierik Ronald
Published: May 2024

Plants growing in dense vegetation need to flexibly position their photosynthetic organs to ensure optimal light capture in a competitive environment. They do so through a suite of developmental responses referred to as the shade avoidance syndrome. Below ground, root development is also adjusted in response to above-ground neighbour proximity. Canopies are dynamic and complex environments with heterogeneous light cues in the far-red, red, blue, and UV spectrum, which can be perceived by photoreceptors in spatially separated plant tissues. Molecular regulation of plant architecture adjustment via PHYTOCHROME-INTERACTING FACTOR transcription factors and growth-related hormones such as auxin, gibberellic acid, brassinosteroids, and abscisic acid were historically studied without much attention to spatial or tissue-specific context. Recent developments and technologies have, however, sparked strong interest in spatially explicit understanding of shade avoidance regulation. Other environmental factors such as temperature and nutrient availability interact with the molecular shade avoidance regulation network, often depending on the spatial location of the signals, and the responding organs. Here, we review recent advances in how plants respond to heterogeneous light cues and integrate these with other environmental signals.
HCN as a probe of the inner disc in a candidate proto-brown dwarf
Authors: Riaz B , Thi W -F , Machida M N
Published: May 2024

The detection of Keplerian rotation is rare among Class 0 protostellar systems. We have investigated the high-density tracer HCN as a probe of the inner disc in a Class 0 proto-brown dwarf candidate. Our ALMA high angular resolution observations show the peak in the HCN (3–2) line emission arises from a compact component near the proto-brown dwarf with a small bar-like structure and a deconvolved size of ∼50 au. Radiative transfer modelling indicates that this HCN feature is tracing the innermost, dense regions in the proto-brown dwarf where a small Keplerian disc is expected to be present. The limited velocity resolution of the observations, however, makes it difficult to confirm the rotational kinematics of this feature. A brightening in the HCN emission towards the core centre suggests that HCN can survive in the gas phase in the inner, dense regions of the proto-brown dwarf. In contrast, modelling of the HCO+ (3–2) line emission indicates that it originates from the outer pseudo-disc/envelope region and is centrally depleted. HCN line emission can reveal the small-scale structures and can be an efficient observational tool to study the inner disc properties in such faint compact objects where spatially resolving the disc is nearly impossible.
Speed, Spectrum, and Satisfaction: Assessment of an Infectious Diseases eConsult Program
Authors: Hofmann Justin , Coe Kelci , Young Jeremy D
Published: May 2024

This report examines the implementation and early functioning of a new infectious diseases (ID) eConsult program. We recorded the reasons for placing ID eConsults, time to eConsult completion, in-person clinic wait times, and referring provider satisfaction following implementation of our outpatient eConsult program. Our data suggest that this ambulatory eConsult program led to improved access to ID subspecialty care, both via eConsults directly, and by reducing clinic wait times for patients who required an in-person evaluation.
Estimating scenarios for survival time in patients with advanced melanoma receiving immunotherapy and targeted therapy
Authors: Smith-Uffen Megan , Park John , Parsonson Andrew , Kiely Belinda E , Vasista Anuradha
Published: May 2024

Background

We aim to provide survival scenario estimates for patients with advanced melanoma starting targeted therapies and immunotherapies.

Materials and Methods

We sought randomized trials of targeted therapies and immunotherapies for advanced melanoma and recorded the following percentiles (represented survival scenario) from each overall survival (OS) curve: 90th (worst-case), 75th (lower-typical), 50th (median), 25th (upper-typical), and 10th (best-case). We tested whether these scenarios can be estimated for each OS curve by multiplying its median by 4 multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case).

Results

We identified 15 trials with 8025 patients. For first-line combination targeted therapy treatment groups, the median (interquartile range, IQR) in months for each percentile was: 90th, 6.2 (6.0-6.5); 75th, 11.3 (11.3-11.4); and median, 24.4 (23.5-25.3). For the first-line combination immunotherapy treatment group, the percentiles in months were: 90th, 3.9 (2.8-4.5); 75th, 13.4 (10.1-15.4), median 73 (not applicable). In targeted therapy groups, simple multiples of the median OS were accurate for estimating the 90th percentile in 80%; 75th percentile in 40%; 25th percentile in 100%. In immunotherapy groups, these multiples were accurate at 0% for the 90th percentile, and 43% for the 75th percentile. The 90th percentile (worst-case scenario) was better estimated as 1/6× median OS, and the 75th percentile (lower-typical) as 1/3× median OS.

Conclusions

Simple multiples of the median OS are a useful framework to estimate scenarios for survival for patients receiving targeted therapies, not immunotherapy. Longer follow-up is required to estimate upper-typical and best-case scenarios.