bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling the impact of treatment adherence on the transmission of HIV drug resistance
Authors: Lai Hao , Li Rui , Li Zengbin , Zhang Baoming , Li Chao , Song Chang , Zhao Quanbi , Huang Jinghua , Zhu Qiuying , Liang Shujia , Chen Huanhuan , Li Jianjun , Liao Lingjie , Shao Yiming , Xing Hui , Ruan Yuhua , Lan Guanghua , Zhang Lei , Shen Mingwang
Published: June 2023

Introduction

A lower adherence rate (percentage of individuals taking drugs as prescribed) to ART may increase the risk of emergence and transmission of HIV drug resistance, decrease treatment efficacy, and increase mortality rate. Exploring the impact of ART adherence on the transmission of drug resistance could provide insights in controlling the HIV epidemic.

Methods

We proposed a dynamic transmission model incorporating the CD4 cell count-dependent rates of diagnosis, treatment and adherence with transmitted drug resistance (TDR) and acquired drug resistance. This model was calibrated and validated by 2008–2018 HIV/AIDS surveillance data and prevalence of TDR among newly diagnosed treatment-naive individuals from Guangxi, China, respectively. We aimed to identify the impact of adherence on drug resistance and deaths during expanding ART.

Results

In the base case (ART at 90% adherence and 79% coverage), we projected the cumulative total new infections, new drug-resistant infections, and HIV-related deaths between 2022 and 2050 would be 420 539, 34 751 and 321 671. Increasing coverage to 95% would reduce the above total new infections (deaths) by 18.85% (15.75%). Reducing adherence to below 57.08% (40.84%) would offset these benefits of increasing coverage to 95% in reducing infections (deaths). Every 10% decrease in adherence would need 5.07% (3.62%) increase in coverage to avoid an increase in infections (deaths). Increasing coverage to 95% with 90% (80%) adherence would increase the above drug-resistant infections by 11.66% (32.98%).

Conclusions

A decrease in adherence might offset the benefits of ART expansion and exacerbate the transmission of drug resistance. Ensuring treated patients’ adherence might be as important as expanding ART to untreated individuals.
Clinical use and effectiveness of dolutegravir and lamivudine: a long-term, real-world, retrospective study
Authors: Martínez-Serra Adrián , De Lazzari Elisa , Berrocal Leire , Foncillas Alberto , De La Mora Lorena , Inciarte Alexy , Chivite Iván , González-Cordón Ana , Martínez-Rebollar María , Torres Berta , Laguno Montserrat , Blanco José Luis , Martínez Esteban , Mallolas Josep , Ambrosioni Juan
Published: June 2023

Background

The use of dolutegravir/lamivudine is based on solid clinical trials; however, real-world data remain limited.

Objectives

To provide data on the clinical use and effectiveness of dolutegravir/lamivudine in persons with HIV in a real-world scenario.

Patients and methods

Retrospective, single-centre and observational study. We included all adults starting dolutegravir/lamivudine since November 2014. We reported all demographic, virological and immunological variables at baseline and assessed effectiveness [on treatment (OT), modified ITT (mITT) and ITT in those persons who reached 6 and 12 month follow-ups (M6 and M12).

Results

Of the 1058 persons, 9 were treatment-naive; the final analysis included 1049 treatment-experienced people with HIV. Median (IQR) follow-up was 1 (0.3–1.6) years, with 81% and 63% persons reaching M6 and M12, respectively. The longest use of dolutegravir/lamivudine was 7.4 years. Per OT, mITT and ITT, HIV-RNA < 50 copies/mL was 97%, 92% and 81% (M6) and 98%, 90% and 80% (M12), respectively. Females [adjusted risk ratio, aRR (95% CI): 1.69 (1.19–2.40)]; immediate, previous PI-based regimen [aRR (95% CI): 1.67 (1.09–2.56)]; and viral load (VL) ≥ 50 copies/mL at dolutegravir/lamivudine initiation [aRR (95% CI): 3.36 (2.32–4.88)] were independently associated with lack of effectiveness at M12; other demographic, immunological and virological variables like previous M184V/I substitutions or virological failure, were unrelated. Of the total, 944 (90%) continued dolutegravir/lamivudine. The most frequent known reason for discontinuation was toxicity [48 (46%) cases].

Conclusions

In our real-world experience, virological suppression rates were high for treatment-experienced persons on dolutegravir/lamivudine; however, we identified subgroups with a higher risk of lack of effectiveness at M12, who may benefit from closer follow-ups.
The case for expressing nursing theories using ontologies
Authors: Umberfield Elizabeth E , Ball Dunlap Patricia A , Harris Marcelline R
Published: June 2023

Nursing and informatics share a common strength in their use of structured representations of domains, specifically the underlying notion of ‘things’ (ie, concepts, constructs, or named entities) and the relationships among those things. Accurate representation of nursing knowledge in machine-interpretable formats is a necessary next step for leveraging contemporary technologies. Expressing validated nursing theories in ontologies, and in particular formal ontologies, would serve not only nursing, but also investigators from other domains, clinical information system developers, and the users of advanced technologies such as artificial intelligence that seek to learn from the real-world data and evidence generated by nurses and others. Such efforts will enable sharing knowledge and conceptualizations about phenomena across the domains of nursing and generating, testing, revising, and providing theoretically-based perspectives when leveraging contemporary technologies. Nursing is well situated for this work, leveraging intentional and focused collaborations among nurse informaticists, scientists, and theorists.
Vitamin D3 decreases myoblast fusion during the growth and increases myogenic gene expression during the differentiation phase in muscle satellite cells from Korean native beef cattle
Authors: Lee Jun Hee , Peng Dong Qiao , Jin Xue Cheng , Smith Stephen B , Lee Hong Gu
Published: June 2023

The process of myogenesis, which involves the growth and differentiation of muscle cells, is a crucial determinant of meat yield and quality in beef cattle. Essential nutrients, such as vitamins D and A, play vital roles in the development and maintenance of various tissues, including muscle. However, limited knowledge exists regarding the specific effects of vitamins A and D in bovine muscle. Therefore, the aim of this study was to investigate the impact of vitamins A and D treatment on myogenic fusion and differentiation in bovine satellite cells (BSC). BSC were isolated from Korean native beef cattle, specifically from four female cows approximately 30 mo old. These individual cows were used as biological replicates (n = 3 or 4), and we examined the effects of varying concentrations of vitamins A (All-trans retinoic acid; 100 nM) and D (1,25-dihydroxy-vitamin D3; 1 nM, 10 nM, and 100 nM), both individually and in combination, on myoblast fusion and myogenic differentiation during the growth phase (48 h) or differentiation phase (6 d). The results were statistically analyzed using GLM procedure of SAS with Tukey’s test and t-tests or one-way ANOVA where appropriate. The findings revealed that vitamin A enhanced the myoblast fusion index, while vitamin D treatment decreased the myoblast fusion index during the growth phase. Furthermore, vitamin A treatment during the differentiation phase promoted terminal differentiation by regulating the expression of myogenic regulatory factors (Myf5, MyoD, MyoG, and Myf6) and inducing myotube hypertrophy compared to the control satellite cells (P < 0.01). In contrast, vitamin D treatment during the differentiation phase enhanced myogenic differentiation by increasing the mRNA expression of MyoG and Myf6 (P < 0.01). Moreover, the combined treatment of vitamins A and D during the growth phase increased myoblast fusion and further promoted myogenic differentiation and hypertrophy of myotubes during the differentiation phase (P < 0.01). These results suggest that vitamin A and D supplementation may have differential effects on muscle development in Korean native beef cattle during the feeding process.
A temporal–spatiotemporal domain transformation-based modeling method for nonlinear distributed parameter systems
Authors: Jin Xi , Wu Daibiao , Yang Haidong , Zhu Chengjiu , Shen Wenjing , Xu Kangkang
Published: June 2023

Complex nonlinear distributed parameter systems (DPSs) exist widely in advanced industrial thermal processes. The modeling of such highly nonlinear systems is a challenge for traditional time/space-separation-based methods since they employ linear methods for the model reduction and spatiotemporal reconstruction, which may lead to an inefficient application of the nonlinear spatial structure features represented by the spatial basis functions. To overcome this problem, a novel spatiotemporal modeling framework composed of nonlinear temporal domain transformation and nonlinear spatiotemporal domain reconstruction is proposed in this paper. Firstly, local nonlinear dimension reduction based on the locally linear embedding technique is utilized to perform nonlinear temporal domain transformation of the spatiotemporal output of nonlinear DPSs. In this step, the original spatiotemporal data can be directly transformed into low-order time coefficients. Then, the extreme learning machine (ELM) method is utilized to establish a temporal model. Finally, through the spatiotemporal domain reconstruction based on the kernel-based ELM method, the prediction of the temporal dynamics obtained from the temporal model can be reconstructed back to the spatiotemporal output. The effectiveness and performance of the proposed method are demonstrated in experiments on the thermal processes of a snap curing oven and a lithium-ion battery.
Current topics and management of head and neck sarcomas
Authors: Kobayashi Kenya , Hanai Nobuhiro , Yoshimoto Seiichi , Saito Yuki , Homma Akihiro
Published: June 2023

Given the low incidence, variety of histological types, and heterogeneous biological features of head and neck sarcomas, there is limited high-quality evidence available to head and neck oncologists. For resectable sarcomas, surgical resection followed by radiotherapy is the principle of local treatment, and perioperative chemotherapy is considered for chemotherapy-sensitive sarcomas. They often originate in anatomical border areas such as the skull base and mediastinum, and they require a multidisciplinary treatment approach considering functional and cosmetic impairment. Moreover, head and neck sarcomas may exhibit different behaviour and characteristics than sarcomas of other areas. In recent years, the molecular biological features of sarcomas have been used for the pathological diagnosis and development of novel agents. This review describes the historical background and recent topics that head and neck oncologists should know about this rare tumour from the following five perspectives: (i) epidemiology and general characteristics of head and neck sarcomas; (ii) changes in histopathological diagnosis in the genomic era; (iii) current standard treatment by histological type and clinical questions specific to head and neck; (iv) new drugs for advanced and metastatic soft tissue sarcomas; and (v) proton and carbon ion radiotherapy for head and neck sarcomas.
Aging modulates homeostatic leukocyte trafficking to the peritoneal cavity in a sex-specific manner
Authors: Hopkin Sophie J , Pezhman Laleh , Begum Jenefa , Kavanagh Dean , McGettrick Helen M , Iqbal Asif J , Chimen Myriam
Published: June 2023

Aging is associated with exacerbated systemic inflammation (inflammaging) and the progressive loss of immune system function (immunosenescence). Leukocyte migration is necessary for effective immunity; however, dysregulated trafficking of leukocytes into tissue contributes to inflammaging and the development of age-related inflammatory diseases. Aging modulates leukocyte trafficking under inflammatory conditions; however, whether aging modulates leukocyte trafficking under homeostatic conditions remains to be elucidated. Although immune responses are evidently sexually dimorphic, limited studies have investigated the effect of sex on age-related changes to leukocyte trafficking processes. Here, we investigated age-related and sex-specific changes to the leukocyte populations within the peritoneal cavity of young (3-mo), middle-aged (18-mo) and old (21-mo) male and female wild-type mice in the steady state. We found an age-related increase in the number of leukocytes within the peritoneal cavity of female mice, predominantly B cells, which may reflect increased trafficking through this tissue with age. This was accompanied by an increased inflammatory environment within the aged cavity, including increased levels of chemoattractants, including B cell chemoattractants CXCL13 and CCL21, soluble adhesion molecules, and proinflammatory cytokines, which was more pronounced in aged female mice. Intravital microscopy techniques revealed altered vascular structure and increased vascular permeability within the peritoneal membrane of aged female mice, which may support increased leukocyte trafficking to the cavity with age. Together, these data indicate that aging affects homeostatic leukocyte trafficking processes in a sex-specific fashion.
Spatial frequency–based correction of the spherical aberration in living brain imaging
Authors: Gohma Aoi , Adachi Naoya , Yonemaru Yasuo , Horiba Daiki , Higuchi Kaori , Nishiwaki Daisuke , Yokoi Eiji , Ue Yoshihiro , Miyawaki Atsushi , Monai Hiromu
Published: June 2023

Optical errors, including spherical aberrations, hinder high-resolution imaging of biological samples due to biochemical components and physical properties. We developed the Deep-C microscope system to achieve aberration-free images, employing a motorized correction collar and contrast-based calculations. However, current contrast-maximization techniques, such as the Brenner gradient method, inadequately assess specific frequency bands. The Peak-C method addresses this issue, but its arbitrary neighbor selection and susceptibility to the noise limit its effectiveness. In this paper, we emphasize the importance of a broad spatial frequency range for accurate spherical aberration correction and propose Peak-F. This spatial frequency–based system utilizes a fast Fourier transform as a bandpass filter. This approach overcomes Peak-C’s limitations and comprehensively covers the low-frequency domain of image spatial frequencies.
Computationally modeling mood management theory: a drift-diffusion model of people’s preferential choice for valence and arousal in media
Authors: Gong Xuanjun , Huskey Richard , Eden Allison , Ulusoy Ezgi
Published: June 2023

Mood management theory (MMT) hypothesizes that people select entertainment content to maintain affective homeostasis. However, this hypothesis lacks a formal quantification of each affective attributes’ separate impact on an individual’s media content selection, as well as an integrated cognitive mechanism explaining media selection. Here we present a computational decision-making model that mathematically formalizes this affective media decision-making process. We empirically tested this formalization with the drift-diffusion model using three decision-making experiments. Contrary to MMT, all three studies showed that people prefer negatively valenced and high-arousal media content and that prevailing mood does not shape media selection as predicted by MMT. We also discovered that people are less cautious when choices have larger valence differences. Our results support the proposed mathematical formalization of affective attributes’ influence on media selection, challenge core predictions drawn from MMT, and introduce a new mechanism (response caution) for media selection.
Diffuse sources, clustering, and the excess anisotropy of the radio synchrotron background
Authors: Cowie F J , Offringa A R , Gehlot B K , Singal J , Heston S , Horiuchi S , Lucero D M
Published: June 2023

We present the largest low frequency (120 MHz) arcminute resolution image of the radio synchrotron background (RSB) to date, and its corresponding angular power spectrum of anisotropies (APS) with angular scales ranging from 3° to 0.3 arcmin. We show that the RSB around the north celestial pole has a significant excess anisotropy power at all scales over a model of unclustered point sources based on source counts of known source classes. This anisotropy excess, which does not seem attributable to the diffuse Galactic emission, could be linked to the surface brightness excess of the RSB. To better understand the information contained within the measured APS, we model the RSB varying the brightness distribution, size, and angular clustering of potential sources. We show that the observed APS could be produced by a population of faint clustered point sources only if the clustering is extreme and the size of the Gaussian clusters is ≲1 arcmin. We also show that the observed APS could be produced by a population of faint diffuse sources with sizes ≲1 arcmin, and this is supported by features present in our image. Both of these cases would also cause an associated surface brightness excess. These classes of sources are in a parameter space not well probed by even the deepest radio surveys to date.
A quantitative description of comet 67P’s dust and gas production remains enigmatic
Authors: Bischoff D , Schuckart C , Attree N , Gundlach B , Blum J
Published: June 2023

The mechanism of dust emission from a cometary nucleus is still an open question and thermophysical models have problems reproducing outgassing and dust productions rates simultaneously. In this study, we investigate the capabilities of a rather simple thermophysical model to match observations from Rosetta instruments at comet 67P/Churyumov–Gerasimenko and the influence of model variations. We assume a macroporous surface structure composed of pebbles and investigate the influence of different model assumptions. Besides the scenario in which dust layers are ejected when the vapour pressure overcomes the tensile strength, we use artificial ejection mechanisms, depending on ice depletion of layers. We find that dust activity following the pressure criterion is only possible for reduced tensile strength values or reduced gas diffusivity and is inconsistent with observed outgassing rates, because activity is driven by CO2. Only when we assume that dust activity is triggered when the layer is completely depleted in H2O, the ratio of CO2 to H2O outgassing rates is in the expected order of magnitude. However, the dust-to-H2O ratio is never reproduced. Only with decreased gas diffusivity, the slope of the H2O outgassing rate is matched, however absolute values are too low. To investigate maximum reachable pressures, we adapted our model equivalent to a gas-impermeable dust structure. Here, pressures exceeding the tensile strength by orders of magnitude are possible. Maximum activity distances of $3.1$, $8.2$, and $74 \, \mathrm{au}$ were estimated for H2O-, CO2-, and CO-driven activity of $1\hbox{-}\mathrm{cm}$-sized dust, respectively. In conclusion, the mechanism behind dust emission remains unclear.
Parameter estimation of LAMOST Medium-Resolution Stellar Spectra
Authors: Li Xiangru , Zhang Xiaoyu , Xiong Shengchun , Zheng Yulong , Li Hui
Published: June 2023

This paper investigates the problem of estimating three stellar atmospheric physical parameters and 13 elemental abundances for medium-resolution spectra from Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST). Typical characteristics of these spectra are their huge scale, wide range of spectral signal-to-noise ratio (S/N), and uneven distribution in parameter space. These characteristics lead to unsatisfactory results on the spectra with low temperature, high temperature, or low metallicity. To this end, this paper proposes a stellar parameter estimation method based on multiple regions (SPEMR) that effectively improves parameter estimation accuracy. On the spectra with S/N ≥ 10, the precisions are 47 K, 0.08 dex, 0.03 dex, respectively, for the estimations of (Teff, $\log \, g$, and $\rm [Fe/H]$), 0.03–0.06 dex for elements C, Mg, Al, Si, Ca, Mn, and Ni, 0.07–0.13 dex for N, O, S, K, and Ti, while that of Cr is 0.16 dex. For the reference of astronomical science researchers and algorithm researchers, we released a catalogue for 4.19 million medium-resolution spectra from the LAMOST DR8, experimental code, trained model, training data, and test data.
The role of baryons in self-interacting dark matter mergers
Authors: Fischer Moritz S , Durke Nils-Henrik , Hollingshausen Katharina , Hammer Claudius , Brüggen Marcus , Dolag Klaus
Published: June 2023

Mergers of galaxy clusters are promising probes of dark matter (DM) physics. For example, an offset between the DM component and the galaxy distribution can constrain DM self-interactions. We investigate the role of the intracluster medium (ICM) and its influence on DM–galaxy offsets in self-interacting dark matter models. To this end, we employ Smoothed Particle Hydrodynamics  + N-body simulations to study idealized setups of equal- and unequal-mass mergers with head-on collisions. Our simulations show that the ICM hardly affects the offsets arising shortly after the first pericentre passage compared to DM-only simulations. But later on, e.g. at the first apocentre, the offsets can be amplified by the presence of the ICM. Furthermore, we find that cross-sections small enough not to be excluded by measurements of the core sizes of relaxed galaxy clusters have a chance to produce observable offsets. We found that different DM models affect the DM distribution and also the galaxy and ICM distribution, including its temperature. Potentially, the position of the shock fronts, combined with the brightest cluster galaxies, provides further clues to the properties of DM. Overall our results demonstrate that mergers of galaxy clusters at stages about the first apocentre passage could be more interesting in terms of DM physics than those shortly after the first pericentre passage. This may motivate further studies of mergers at later evolutionary stages.
Genome-wide analysis of histone modifications that underlie the dynamic changes in gene expression during decidualization in human endometrial stromal cells
Authors: Tamura Isao , Shiroshita Amon , Fujimura Taishi , Tanaka-Doi Yumiko , Shirafuta Yuichiro , Maekawa Ryo , Taketani Toshiaki , Sato Shun , Sugino Norihiro
Published: June 2023

Human endometrial stromal cells (hESCs) undergo a differentiation process with dramatic changes in cell functions during the menstrual cycle, which is called decidualization. This is an important event for implantation of the embryo and successful pregnancy. Defective decidualization can cause implantation failure, miscarriage, and unexplained infertility. A number of genes are upregulated or downregulated during decidualization. Recent studies have shown that epigenetic mechanisms are involved in the regulation of decidualization-related genes and that histone modifications occur throughout the genome during decidualization. The present review focuses on the involvement of genome-wide histone modifications in dramatic changes in gene expression during decidualization. The main histone modifications are the increases of H3K27ac and H3K4me3, which activate transcription. C/EBPβ works as a pioneer factor throughout the genome by recruiting p300. This is the main cause of the genome-wide acetylation of H3K27 during decidualization. Histone modifications were observed in both the proximal promoter and distal enhancer regions. Genome editing experiments show that the distal regions have transcriptional activities, which suggests that decidualization induces the interactions between proximal promoter and distal enhancer regions. Taken together, these findings show that gene regulation during decidualization is closely associated with genome-wide changes of histone modifications. This review provides new insights regarding the cases of implantation failure in terms of decidualization insufficiency owing to epigenetic dysregulation, and may lead to novel treatment options for women with implantation failure.
Shell drilling and gonad biopsies provide a rapid, nonlethal method for in situ assessment of reproductive periodicity in a turbinid gastropod
Authors: Seinor Kate , Benkendorff Kirsten
Published: June 2023

Reproductive data on marine molluscs are imperative for informing conservation and management strategies. Most methods for assessing reproductive periodicity are lethal, which could be unfavourable for fragile populations. This study aimed to trial a nonlethal, drill-biopsy technique for assessing the reproductive cycle in the turbinid gastropod, Turbo militaris. This technique was tested in the laboratory, where a small hole was drilled into the shell, from where a biopsy of the gonad was taken. The procedures resulted in zero mortalities and rapid recovery of the animals when returned to seawater. Sex was identified by viewing the gonad colour through the shell hole and confirmed by viewing gametes from a biopsy. Preservation of the female biopsy was investigated, with buffered formalin found to be the most suitable solution. The drill-biopsy method was also tested in the field; five (out of six) recaptured T. militaris had repaired the shell hole after 6 weeks, and two were recaptured on multiple occasions up to the end of this study, 10 months later. The size–frequency distributions of oocytes from female biopsies suggested an increase in mode size over 2 months with a shift towards a higher number of larger oocytes, supporting the practicality of this nonlethal approach to evaluate reproductive periodicity and sex determination. Nonlethal sampling is recommended for broad-scale studies and populations under stress; methods, such as the drill-biopsy technique, facilitate reproductive sampling without detriment to the target populations.
A unique mRNA decapping complex in trypanosomes
Authors: Kramer Susanne , Karolak Natalia Katarzyna , Odenwald Johanna , Gabiatti Bernardo , Castañeda Londoño Paula Andrea , Zavřelová Anna , Freire Eden Ribeiro , Almeida Kayo Schemiko , Braune Silke , Moreira Claudia , Eder Amelie , Goos Carina , Field Mark , Carrington Mark , Holetz Fabiola , Górna Maria Wiktoria , Zoltner Martin
Published: June 2023

Removal of the mRNA 5′ cap primes transcripts for degradation and is central for regulating gene expression in eukaryotes. The canonical decapping enzyme Dcp2 is stringently controlled by assembly into a dynamic multi-protein complex together with the 5′-3′exoribonuclease Xrn1. Kinetoplastida lack Dcp2 orthologues but instead rely on the ApaH-like phosphatase ALPH1 for decapping. ALPH1 is composed of a catalytic domain flanked by C- and N-terminal extensions. We show that T. brucei ALPH1 is dimeric in vitro and functions within a complex composed of the trypanosome Xrn1 ortholog XRNA and four proteins unique to Kinetoplastida, including two RNA-binding proteins and a CMGC-family protein kinase. All ALPH1-associated proteins share a unique and dynamic localization to a structure at the posterior pole of the cell, anterior to the microtubule plus ends. XRNA affinity capture in T. cruzi recapitulates this interaction network. The ALPH1 N-terminus is not required for viability in culture, but essential for posterior pole localization. The C-terminus, in contrast, is required for localization to all RNA granule types, as well as for dimerization and interactions with XRNA and the CMGC kinase, suggesting possible regulatory mechanisms. Most significantly, the trypanosome decapping complex has a unique composition, differentiating the process from opisthokonts.
Activity, substrate preference and structure of the HsMCM8/9 helicase
Authors: McKinzey David R , Li Chuxuan , Gao Yang , Trakselis Michael A
Published: June 2023

The minichromosomal maintenance proteins, MCM8 and MCM9, are more recent evolutionary additions to the MCM family, only cooccurring in selected higher eukaryotes. Mutations in these genes are directly linked to ovarian insufficiency, infertility, and several cancers. MCM8/9 appears to have ancillary roles in fork progression and recombination of broken replication forks. However, the biochemical activity, specificities and structures have not been adequately illustrated, making mechanistic determination difficult. Here, we show that human MCM8/9 (HsMCM8/9) is an ATP dependent DNA helicase that unwinds fork DNA substrates with a 3′–5′ polarity. High affinity ssDNA binding occurs in the presence of nucleoside triphosphates, while ATP hydrolysis weakens the interaction with DNA. The cryo-EM structure of the HsMCM8/9 heterohexamer was solved at 4.3 Å revealing a trimer of heterodimer configuration with two types of interfacial AAA+ nucleotide binding sites that become more organized upon binding ADP. Local refinements of the N or C-terminal domains (NTD or CTD) improved the resolution to 3.9 or 4.1 Å, respectively, and shows a large displacement in the CTD. Changes in AAA+ CTD upon nucleotide binding and a large swing between the NTD and CTD likely implies that MCM8/9 utilizes a sequential subunit translocation mechanism for DNA unwinding.
Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma
Authors: Benada Jan , Bulanova Daria , Azzoni Violette , Petrosius Valdemaras , Ghazanfar Saba , Wennerberg Krister , Sørensen Claus Storgaard
Published: June 2023

Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low-dose approach utilizing joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. We found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted CDK activation. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. These findings suggest a new multiple low-dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.
Leveraging Influenza Virus Surveillance From 2012 to 2015 to Characterize the Burden of Respiratory Syncytial Virus Disease in Canadian Adults ≥50 Years of Age Hospitalized With Acute Respiratory Illness
Authors: ElSherif May , Andrew Melissa K , Ye Lingyun , Ambrose Ardith , Boivin Guy , Bowie William , David Marie-Pierre , Gruselle Olivier , Halperin Scott A , Hatchette Todd F , Johnstone Jennie , Katz Kevin , Langley Joanne M , Loeb Mark , MacKinnon-Cameron Donna , McCarthy Anne , McElhaney Janet E , McGeer Allison , Poirier Andre , Pirçon Jean-Yves , Powis Jeff , Richardson David , Semret Makeda , Smith Stephanie , Smyth Daniel , Trottier Sylvie , Valiquette Louis , Webster Duncan , McNeil Shelly A , LeBlanc Jason J ,   for the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) and the Toronto Invasive Bacterial Diseases Network (TIBDN), ElSherif May , Andrew Melissa K , Ye Lingyun , Ambrose Ardith , Boivin Guy , Bowie William , David Marie-Pierre , Gruselle Olivier , Halperin Scott A , Hatchette Todd F , Johnstone Jennie , Katz Kevin , Langley Joanne M , Loeb Mark , MacKinnon-Cameron Donna , McCarthy Anne , McElhaney Janet E , McGeer Allison , Poirier Andre , Pirçon Jean-Yves , Powis Jeff , Richardson David , Semret Makeda , Smith Stephanie , Smyth Daniel , Trottier Sylvie , Valiquette Louis , Webster Duncan , McNeil Shelly A , LeBlanc Jason J
Published: June 2023

Background

Respiratory syncytial virus (RSV) disease in older adults is undercharacterized. To help inform future immunization policies, this study aimed to describe the disease burden in Canadian adults aged ≥50 years hospitalized with RSV.

Methods

Using administrative data and nasopharyngeal swabs collected from active surveillance among adults aged ≥50 years hospitalized with an acute respiratory illness (ARI) during the 2012–2013, 2013–2014, and 2014–2015 influenza seasons, RSV was identified using a respiratory virus multiplex polymerase chain reaction test to describe the associated disease burden, incidence, and healthcare costs.

Results

Of 7797 patients tested, 371 (4.8%) were RSV positive (2.2% RSV-A and 2.6% RSV-B). RSV prevalence varied by season from 4.2% to 6.2%. Respiratory virus coinfection was observed in 11.6% (43/371) of RSV cases, with influenza A being the most common. RSV hospitalization rates varied between seasons and increased with age, from 8–12 per 100 000 population in adults aged 50–59 years to 174–487 per 100 000 in adults aged ≥80 years. The median age of RSV cases was 74.9 years, 63.7% were female, and 98.1% of cases had ≥1 comorbidity. Among RSV cases, the mean length of hospital stay was 10.6 days, 13.7% were admitted to the intensive care unit, 6.4% required mechanical ventilation, and 6.1% died. The mean cost per RSV case was $13 602 (Canadian dollars) but varied by age and Canadian province.

Conclusions

This study adds to the growing literature on adult RSV burden by showing considerable morbidity, mortality, and healthcare costs in hospitalized adults aged ≥50 years with ARIs such as influenza.
Clinical Risk Scores to Predict Nonsusceptibility to Trimethoprim-Sulfamethoxazole, Fluoroquinolone, Nitrofurantoin, and Third-Generation Cephalosporin Among Adult Outpatient Episodes of Complicated Urinary Tract Infection
Authors: Lodise Thomas P , Chen Lie Hong , Wei Rong , Im Theresa M , Contreras Richard , Bruxvoort Katia J , Rodriguez Mauricio , Friedrich Larry , Tartof Sara Y
Published: June 2023

Background

Clinical risk scores were developed to estimate the risk of adult outpatients having a complicated urinary tract infection (cUTI) that was nonsusceptible to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolone, nitrofurantoin, or third-generation cephalosporin (3-GC) based on variables available on clinical presentation.

Methods

A retrospective cohort study (1 December 2017–31 December 2020) was performed among adult members of Kaiser Permanente Southern California with an outpatient cUTI. Separate risk scores were developed for TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC. The models were translated into risk scores to quantify the likelihood of nonsusceptibility based on the presence of final model covariates in a given cUTI outpatient.

Results

A total of 30 450 cUTIs (26 326 patients) met the study criteria. Rates of nonsusceptibility to TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC were 37%, 20%, 27%, and 24%, respectively. Receipt of prior antibiotics was the most important predictor across all models. The risk of nonsusceptibility in the TMP-SMX model exceeded 20% in the absence of any risk factors, suggesting that empiric use of TMP-SMX may not be advisable. For fluoroquinolone, nitrofurantoin, and 3-GC, clinical risk scores of 10, 7, and 11 predicted a ≥20% estimated probability of nonsusceptibility in the models that included cumulative number of prior antibiotics at model entry. This finding suggests that caution should be used when considering these agents empirically in patients who have several risk factors present in a given model at presentation.

Conclusions

We developed high-performing parsimonious risk scores to facilitate empiric treatment selection for adult outpatients with cUTIs in the critical period between infection presentation and availability of susceptibility results.
Variations in Genomic Testing in Non-small Cell Lung Carcinoma: A Healthcare Professional Survey of Current Practices in the UK
Authors: Baijal Shobhit , Crosbie Philip , Fenemore Jackie , Desai Ketul
Published: June 2023

This survey aims to understand the current UK practice for non-small cell lung carcinoma (NSCLC) and identify barriers that may impact patient treatment and outcomes. In March–June 2021, 57 interviews were conducted with healthcare professionals involved in the secondary care management of patients with NSCLC. Most respondents performed genetic testing at onsite and non-genomic laboratory hub (GLH) offsite locations. The most common genetic tests were EGFR T790M variant (100%), EGFR exon 18-21 covered (95%) and BRAF (93%). No targeted therapy (TT) available (69%), lack of access to a TT (54%) or excessive molecular testing turnaround times (39%) were the most common reasons for using an immuno-oncology therapy over a TT in the first-line setting. The survey highlights variation in mutation testing practices across the UK, which may impact treatment decisions and contribute to health outcome inequality.
Avelumab in Patients With Metastatic Colorectal Cancer
Authors: Redman Jason M , O’Sullivan Coyne Geraldine , Reed Clay T , Madan Ravi A , Strauss Julius , Steinberg Seth J , Marté Jennifer , Cordes Lisa , Heery Christopher , Gulley James L
Published: June 2023

Background

Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab.

Methods

Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate.

Results

Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1).

Conclusion

As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
Diagnosis, Treatment, and Prognosis of Patients with Primary Familial Gastrointestinal Stromal Tumor: A Case Report and Literature Review
Authors: Yan Miao , Lin Jianghua , Shu Man , Luo Yanji , Sun Kaiyu , Yang Shaohua , Zhang Xinhua
Published: June 2023

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.
Plastid dsRNA transgenes trigger phased small RNA-based gene silencing of nuclear-encoded genes
Authors: Bélanger Sébastien , Kramer Marianne C , Payne Hayden A , Hui Alice Y , Slotkin R Keith , Meyers Blake C , Staub Jeffrey M
Published: June 2023

Plastid transformation technology has been widely used to express traits of potential commercial importance, though the technology has been limited to traits that function while sequestered in the organelle. Prior research indicates that plastid contents can escape from the organelle, suggesting a possible mechanism for engineering plastid transgenes to function in other cellular locations. To test this hypothesis, we created tobacco (Nicotiana tabacum cv. Petit Havana) plastid transformants that express a fragment of the nuclear-encoded Phytoene desaturase (PDS) gene capable of catalyzing post-transcriptional gene silencing if RNA escapes into the cytoplasm. We found multiple lines of direct evidence that plastid-encoded PDS transgenes affect nuclear PDS gene silencing: knockdown of the nuclear-encoded PDS mRNA and/or its apparent translational inhibition, biogenesis of 21-nucleotide (nt) phased small interfering RNAs (phasiRNAs), and pigment-deficient plants. Furthermore, plastid-expressed dsRNA with no cognate nuclear-encoded pairing partner also produced abundant 21-nt phasiRNAs in the cytoplasm, demonstrating that a nuclear-encoded template is not required for siRNA biogenesis. Our results indicate that RNA escape from plastids to the cytoplasm occurs generally, with functional consequences that include entry into the gene silencing pathway. Furthermore, we uncover a method to produce plastid-encoded traits with functions outside of the organelle and open additional fields of study in plastid development, compartmentalization, and small RNA biogenesis.
On the evolution of the plant phytochrome chromophore biosynthesis
Authors: Frascogna Federica , Ledermann Benjamin , Hartmann Jana , Pérez Patallo Eugenio , Zeqiri Fjoralba , Hofmann Eckhard , Frankenberg-Dinkel Nicole
Published: June 2023

Phytochromes are biliprotein photoreceptors present in plants, algae, certain bacteria, and fungi. Land plant phytochromes use phytochromobilin (PΦB) as the bilin chromophore. Phytochromes of streptophyte algae, the clade within which land plants evolved, employ phycocyanobilin (PCB), leading to a more blue-shifted absorption spectrum. Both chromophores are synthesized by ferredoxin-dependent bilin reductases (FDBRs) starting from biliverdin IXα (BV). In cyanobacteria and chlorophyta, BV is reduced to PCB by the FDBR phycocyanobilin:ferredoxin oxidoreductase (PcyA), whereas, in land plants, BV is reduced to PФB by phytochromobilin synthase (HY2). However, phylogenetic studies suggested the absence of any ortholog of PcyA in streptophyte algae and the presence of only PФB biosynthesis-related genes (HY2). The HY2 of the streptophyte alga Klebsormidium nitens (formerly Klebsormidium flaccidum) has already indirectly been indicated to participate in PCB biosynthesis. Here, we overexpressed and purified a His6-tagged variant of K. nitens HY2 (KflaHY2) in Escherichia coli. Employing anaerobic bilin reductase activity assays and coupled phytochrome assembly assays, we confirmed the product and identified intermediates of the reaction. Site-directed mutagenesis revealed 2 aspartate residues critical for catalysis. While it was not possible to convert KflaHY2 into a PΦB-producing enzyme by simply exchanging the catalytic pair, the biochemical investigation of 2 additional members of the HY2 lineage enabled us to define 2 distinct clades, the PCB-HY2 and the PΦB-HY2 clade. Overall, our study gives insight into the evolution of the HY2 lineage of FDBRs.
ALBINO EMBRYO AND SEEDLING is required for RNA splicing and chloroplast homeostasis in Arabidopsis
Authors: An Hongqiang , Ke Xiaolong , Li Lu , Liu Yantong , Yuan Sihui , Wang Qiuyu , Hou Xin , Zhao Jie
Published: June 2023

Pentatricopeptide repeat (PPR) proteins form a large protein family and have diverse functions in plant development. Here, we identified an ALBINO EMBRYO AND SEEDLING (AES) gene that encodes a P-type PPR protein expressed in various tissues, especially the young leaves of Arabidopsis (Arabidopsis thaliana). Its null mutant aes exhibited a collapsed chloroplast membrane system, reduced pigment content and photosynthetic activity, decreased transcript levels of PEP (plastid-encoded polymerase)–dependent chloroplast genes, and defective RNA splicing. Further work revealed that AES could directly bind to psbB-psbT, psbH-petB, rps8-rpl36, clpP, ycf3, and ndhA in vivo and in vitro and that the splicing efficiencies of these genes and the expression levels of ycf3, ndhA, and cis-tron psbB-psbT-psbH-petB-petD decreased dramatically, leading to defective PSI, PSII, and Cyt b6f in aes. Moreover, AES could be transported into the chloroplast stroma via the TOC–TIC channel with the assistance of Tic110 and cpSRP54 and may recruit HCF244, SOT1, and CAF1 to participate in the target RNA process. These findings suggested that AES is an essential protein for the assembly of photosynthetic complexes, providing insights into the splicing of psbB operon (psbB-psbT-psbH-petB-petD), ycf3, and ndhA, as well as maintaining chloroplast homeostasis.
Pectin modifications promote haustoria development in the parasitic plantPhtheirospermum japonicum
Authors: Leso Martina , Kokla Anna , Feng Ming , Melnyk Charles W
Published: June 2023

Parasitic plants are globally prevalent pathogens with important ecological functions but also potentially devastating agricultural consequences. Common to all parasites is the formation of the haustorium which requires parasite organ development and tissue invasion into the host. Both processes involve cell wall modifications. Here, we investigated a role for pectins during haustorium development in the facultative parasitic plant Phtheirospermum japonicum. Using transcriptomics data from infected Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), we identified genes for multiple P. japonicum pectin methylesterases (PMEs) and their inhibitors (PMEIs) whose expression was upregulated by haustoria formation. Changes in PME and PMEI expression were associated with tissue-specific modifications in pectin methylesterification. While de-methylesterified pectins were present in outer haustorial cells, highly methylesterified pectins were present in inner vascular tissues, including the xylem bridge that connects parasite to host. Specifically blocking xylem bridge formation in the haustoria inhibited several PME and PMEI genes from activating. Similarly, inhibiting PME activity using chemicals or by overexpressing PMEI genes delayed haustoria development. Our results suggest a dynamic and tissue-specific regulation of pectin contributes to haustoria initiation and to the establishment of xylem connections between parasite and host.