bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOD-scid IL2rγnull mice lacking TLR4 support human immune system development and the study of human-specific innate immunity
Authors: Aryee Ken-Edwin , Shultz Leonard D , Burzenski Lisa M , Greiner Dale L , Brehm Michael A 
Published: January 2023

Abstract
Agents that induce inflammation have been used since the 18th century for the treatment of cancer. The inflammation induced by agents such as Toll-like receptor agonists is thought to stimulate tumor-specific immunity in patients and augment control of tumor burden. While NOD-scid IL2rγnull mice lack murine adaptive immunity (T cells and B cells), these mice maintain a residual murine innate immune system that responds to Toll-like receptor agonists. Here we describe a novel NOD-scid IL2rγnull mouse lacking murine TLR4 that fails to respond to lipopolysaccharide. NSG-Tlr4null mice support human immune system engraftment and enable the study of human-specific responses to TLR4 agonists in the absence of the confounding effects of a murine response. Our data demonstrate that specific stimulation of TLR4 activates human innate immune systems and delays the growth kinetics of a human patient-derived xenograft melanoma tumor.
The interplay among HIV, monocytes/macrophages, and extracellular vesicles: a systematic review
Authors: Adhikari Romin , Witwer Kenneth W , Wiberg Kjell J , Chen Yun-Chi 
Published: January 2023

AbstractDespite effective antiretroviral therapies, chronic inflammation and spontaneous viral “blips” occur in HIV-infected patients. Given the roles for monocytes/macrophages in HIV pathogenesis and extracellular vesicles in intercellular communication, we performed this systematic review to delineate the triad of HIV, monocytes/macrophages, and extracellular vesicles in the modulation of immune activation and HIV activities. We searched PubMed, Web of Science, and EBSCO databases for published articles, up to 18 August 2022, relevant to this triad. The search identified 11,836 publications, and 36 studies were deemed eligible and included in this systematic review. Data were extracted for the characteristics of HIV, monocytes/macrophages, and extracellular vesicles used for experiments and the immunologic and virologic outcomes in extracellular vesicle recipient cells. Evidence for the effects on outcomes was synthesized by stratifying the characteristics by outcomes. In this triad, monocytes/macrophages were potential producers and recipients of extracellular vesicles, whose cargo repertoires and functionalities were regulated by HIV infection and cellular stimulation. Extracellular vesicles derived from HIV-infected monocytes/macrophages or the biofluid of HIV-infected patients enhanced innate immune activation and HIV dissemination, cellular entry, replication, and latency reactivation in bystander or infected target cells. These extracellular vesicles could be synthesized in the presence of antiretroviral agents and elicit pathogenic effects in a wide range of nontarget cells. At least eight functional types of extracellular vesicles could be classified based on the diverse extracellular vesicle effects, which were linked to specific virus- and/or host-derived cargos. Thus, the monocyte/macrophage–centered multidirectional crosstalk through extracellular vesicles may help sustain persistent immune activation and residual viral activities during suppressed HIV infection.
Physical and biological dosimetric margin according to prescription method for stereotactic body radiation therapy
Authors: Kawahara Daisuke , Saito Akito , Nagata Yasushi 
Published: January 2023

AbstractThis study aimed to expand the biological conversion factor (BCF) model, which converts the physical dosimetric margin (PDM) to the biological dosimetric margin (BDM) for point prescription with 3-dimensional conformal radiation therapy (3DCRT) and the marginal prescription method with volumetric-modulated arc radiotherapy (VMAT). The VMAT of the marginal prescription and the 3DCRT of the point prescription with lung stereotactic body radiation therapy (SBRT) by using RayStation were planned. The biological equivalent dose (BED) for a dose per fraction (DPF) of 3–20 Gy was calculated from these plans. The dose was perturbed with the calculation using a 1-mm step isocenter shift. The dose covering 95% of the target was greater than or equal to 90% of the prescribed physical dose, and the BED were defined as the PDM and BDM, respectively. The BCF was created as a function of the DPF. The PDM and BDM for all DPFs were larger with the point prescription method than with the marginal prescription method. The marginal prescription method with a 60% isodose line had a larger PDM and BDM. The BCF with the point prescription was smaller than that with the marginal prescription in the left–right (LR), anterior–posterior (AP) and cranio–caudal (CC) directions. In the marginal prescription method, the 60% isodose line had a higher BCF. In conclusion, the improved BCF method could be converted to BDM for point prescription with 3DCRT and marginal prescription method with VMAT, which is required for stereotactic radiation therapy in radiobiology-based treatment planning.
Giant retroperitoneal liposarcoma measuring 27 × 29 × 36 cm: a case report
Authors: Gutu Catalina , Butnari Valentin , Schiopu Victor 
Published: January 2023

Abstract
Retroperitoneal tumors are rare neoplasms that can reach great dimensions due to a slow growth pattern. Although these tumors rarely metastasize, they have a great risk of recurrence, and majority of times these lesions are a challenge for the surgeon. We report the case of a 63-year-old woman who presented with symptoms of large bowel obstruction and was diagnosed with a large heterogenous mass located in the retroperitoneal space. The fine needle biopsy revealed the histology of liposarcoma. The purpose of this article is to report our approach in management of this kind of tumor. Tumor size (27.1 × 29.1 × 36.1 cm) and involvement to the adjacent organs was a challenge for us in order to reach safe oncological margins. In these cases, the risk of recurrence is high; therefore, the patient should be screened at 6, 12 and 24 months post procedure. Chemotherapy or radiotherapy for this tumor is not yet defined, and if operable, surgery is the treatment of choice.
ONECUT2 regulates RANKL-dependent enterocyte and microfold cell differentiation in the small intestine; a multi-omics study
Authors: Luna Velez Maria V , Neikes Hannah K , Snabel Rebecca R , Quint Yarah , Qian Chen , Martens Aniek , Veenstra Gert Jan C , Freeman Michael R , van Heeringen Simon J , Vermeulen Michiel 
Published: January 2023

AbstractMicrofold (M) cells reside in the intestinal epithelium of Peyer's patches (PP). Their unique ability to take up and transport antigens from the intestinal lumen to the underlying lymphoid tissue is key in the regulation of the gut-associated immune response. Here, we applied a multi-omics approach to investigate the molecular mechanisms that drive M cell differentiation in mouse small intestinal organoids. We generated a comprehensive profile of chromatin accessibility changes and transcription factor dynamics during in vitro M cell differentiation, allowing us to uncover numerous cell type-specific regulatory elements and associated transcription factors. By using single-cell RNA sequencing, we identified an enterocyte and M cell precursor population. We used our newly developed computational tool SCEPIA to link precursor cell-specific gene expression to transcription factor motif activity in cis-regulatory elements, uncovering high expression of and motif activity for the transcription factor ONECUT2. Subsequent in vitro and in vivo perturbation experiments revealed that ONECUT2 acts downstream of the RANK/RANKL signalling axis to support enterocyte differentiation, thereby restricting M cell lineage specification. This study sheds new light on the mechanism regulating cell fate balance in the PP, and it provides a powerful blueprint for investigation of cell fate switches in the intestinal epithelium.
Synthetic circular RNA switches and circuits that control protein expression in mammalian cells
Authors: Kameda Shigetoshi , Ohno Hirohisa , Saito Hirohide 
Published: January 2023

AbstractSynthetic messenger RNA (mRNA) has been focused on as an emerging application for mRNA-based therapies and vaccinations. Recently, synthetic circular RNAs (circRNAs) have shown promise as a new class of synthetic mRNA that enables superior stability and persistent gene expression in cells. However, translational control of circRNA remained challenging. Here, we develop ‘circRNA switches’ capable of controlling protein expression from circRNA by sensing intracellular RNA or proteins. We designed microRNA (miRNA) and protein-responsive circRNA switches by inserting miRNA-binding or protein-binding sequences into untranslated regions (UTRs), or Coxsackievirus B3 Internal Ribosome Entry Site (CVB3 IRES), respectively. Engineered circRNAs efficiently expressed reporter proteins without inducing severe cell cytotoxicity and immunogenicity, and responded to target miRNAs or proteins, controlling translation levels from circRNA in a cell type-specific manner. Moreover, we constructed circRNA-based gene circuits that selectively activated translation by detecting endogenous miRNA, by connecting miRNA and protein-responsive circRNAs. The designed circRNA circuits performed better than the linear mRNA-based circuits in terms of persistent expression levels. Synthetic circRNA devices provide new insights into RNA engineering and have a potential for RNA synthetic biology and therapies.
Controlling therapeutic protein expression via inhalation of a butter flavor molecule
Authors: Bertschi Adrian , Stefanov Bozhidar-Adrian , Xue Shuai , Charpin-El Hamri Ghislaine , Teixeira Ana Palma , Fussenegger Martin 
Published: January 2023

AbstractPrecise control of the delivery of therapeutic proteins is critical for gene- and cell-based therapies, and expression should only be switched on in the presence of a specific trigger signal of appropriate magnitude. Focusing on the advantages of delivering the trigger by inhalation, we have developed a mammalian synthetic gene switch that enables regulation of transgene expression by exposure to the semi-volatile small molecule acetoin, a widely used, FDA-approved food flavor additive. The gene switch capitalizes on the bacterial regulatory protein AcoR fused to a mammalian transactivation domain, which binds to promoter regions with specific DNA sequences in the presence of acetoin and dose-dependently activates expression of downstream transgenes. Wild-type mice implanted with alginate-encapsulated cells transgenic for the acetoin gene switch showed a dose-dependent increase in blood levels of reporter protein in response to either administration of acetoin solution via oral gavage or longer exposure to acetoin aerosol generated by a commercial portable inhaler. Intake of typical acetoin-containing foods, such as butter, lychees and cheese, did not activate transgene expression. As a proof of concept, we show that blood glucose levels were normalized by acetoin aerosol inhalation in type-I diabetic mice implanted with acetoin-responsive insulin-producing cells. Delivery of trigger molecules using portable inhalers may facilitate regular administration of therapeutic proteins via next-generation cell-based therapies to treat chronic diseases for which frequent dosing is required.
A Qualitative Study of the Implementation and Continued Delivery of Complete and Partial Smoke-Free Policies Across England’s Prison Estate
Authors: Jayes Leah , Waddingham Jessica , Britton John , Murray Rachael 
Published: January 2023

Abstract

Introduction
In the United Kingdom, smoking among prisoners is up to five times more prevalent than the national average. Between 2015 and 2018, HMPPS introduced a complete smoke-free policy in all closed prisons, and a partial policy permitting smoking only in smoking shelters in open prisons.

Aims and Methods
This study aimed to explore the views of stakeholders regarding the implementation and continuation of smoke-free policies, including the management of nicotine addiction during imprisonment and after release. Individuals with key strategic and/or operational roles in delivering smoke-free prison policies across England were purposively sampled to complete a semi-structured interview. Twenty-eight interviews were analyzed thematically.

Results
The smoke-free implementation across the closed prison estate was viewed as a success, though there were reports of reduced availability of smoking cessation support since the roll out. Participants thought the majority of tobacco smokers living in closed prison environments were now using an electronic cigarette, typically as a temporary means to manage nicotine addiction until release. In open prisons the partial policy has been less successful; high rates of smoking resumption on moving from closed to open conditions were reported, with many participants arguing that the open estate should also go completely smoke free. It was envisaged that most prisoners would resume smoking on community release.

Conclusions
The smoke-free policies provide a unique opportunity to promote lifelong cessation in this highly disadvantaged group. However more could be done to adopt a consistent smoke-free policy across all prisons, and to support prisoners in quitting smoking and nicotine use during and after imprisonment.

Implications
Our results identify the urgent need for more work to explore rates and reasons for relapse to smoking on transfer to the open estate and after release. With the majority of smokers in the closed prison estate now using e-cigarettes to manage their nicotine addiction, one way to support long-term tobacco abstinence could be to place greater emphasis on this switching behavior as a way of reducing tobacco-related harm within this population.
Scottish Firefighters Occupational Cancer and Disease Mortality Rates: 2000-2020
Authors: Stec A A , Robinson A , Wolffe T A M , Bagkeris E 
Published: January 2023

Abstract

Background
Increased mortality from cancers and other diseases has been reported in USA, Canadian, and Nordic firefighters. However, UK firefighters are understudied.

Aims
To determine whether UK firefighters suffer increased mortality from cancers and other diseases when compared with the general population.

Methods
Mortality from cancer and other diseases in Scottish male firefighters between 2000 and 2020 was compared with the general Scottish male population and expressed as standardized mortality ratios (SMRs) (with 95% confidence intervals, CI).

Results
Significant overall excess cancer mortality was found for Scottish firefighters compared with the general population (SMR 1.61, CI 1.42-1.81). Scottish firefighters were nearly three times more likely to die of malignant neoplasms (unspecified sites) (SMR 2.71, CI 1.71-4.00). Excess cancer mortality was also found for several site-specific cancers, including prostate (SMR 3.80, CI 2.56-5.29), myeloid leukaemia (SMR 3.17, CI 1.44-5.58), oesophagus (SMR 2.42, CI 1.69-3.29) and urinary system (kidney and bladder) (SMR 1.94, CI 1.16-2.91). Mortality from neoplasms of unknown behaviour was over six times greater in Scottish firefighters (SMR 6.37, CI 2.29-12.49). Additionally, significantly higher mortality was found for: acute ischaemic heart diseases (SMR 5.27, CI 1.90-10.33), stroke (SMR 2.69, CI 1.46-4.28), interstitial pulmonary diseases (SMR 3.04, CI 1.45-5.22), renal failure (SMR 3.28, CI 1.18-6.44) and musculoskeletal system diseases (SMR 5.64, CI 1.06-13.83).

Conclusions
UK firefighters suffer significant excess mortality from cancer and other diseases when compared with the general population. Preventative health monitoring and presumptive legislation are urgently required to protect UK firefighters’ health.
Extreme Differentiation along Multiple Liquid Lines of Descent in Strongly Peralkaline Magma Series at Pantelleria (Italy)
Authors: White John C , Macdonald Ray , Bagiński Bogusław , Liszewska Katarzyna M 
Published: January 2023

AbstractThe liquid line of descent from trachyte to pantellerite is controlled primarily by fractional crystallization of alkali feldspar, with whole-rock compositions following a fractionation path along the ‘thermal valley’ in the peralkaline haplogranite system Qz-Ab-Or-Ac-Ns and terminating at a minimum on the feldspar-quartz cotectic. Although whole-rock compositions for different pantelleritic suites follow nearly identical paths in a Qz-Ab-Or projection that terminate near the experimental minimum (Qz40.5Or34.5Ab25 at 100 MPa, projected from Ac-Ns), matrix glass from samples with near-minimum compositions record extreme differentiation and form a ‘cotectic delta’ beyond the terminus of the ‘thermal valley’. Although each glass trend shows a continuing increase in Zr to &gt;3000 μg/g, the most evolved compositions in each suite differ in peralkalinity (mol [Na + K] / Al) and in the proportions of FeOT, Qz, Ab, Or, and other components, which are related to subtle variations in the mafic phases controlled mainly by differences in oxygen fugacity (fO2) and pressure (P). To determine the controls over mafic mineral crystallization in pantelleritic magmas and the various paths these suites take beyond the apparent (whole-rock) minimum, amphibole-phyric suites from the ~159 ka Cala dell’Altura and Cala Gadir volcanic centres and the ~8–10 ka Cuddia Mida volcanic centre on Pantelleria have been analyzed and compared with each other and with the well-characterized and amphibole-free, compositionally zoned Green Tuff, the ~46 ka caldera-forming ignimbrite of the Cinque Denti caldera. Differences between the extended fractionation trends may be ultimately attributed to variations in oxygen fugacity, depth of emplacement, and water saturation. Shallower (lower pressure) magma reservoirs such as the one for the Green Tuff are water-saturated and undergo degassing, which leads to an increase in relative oxygen fugacity. Deeper (higher pressure) magma reservoirs remain water-undersaturated and retain water in the melt, which both maintains lower relative oxygen fugacities and enables the crystallization of amphibole. Amphibole formation appears to require melt water contents &gt;4 wt%, low oxygen fugacity (&lt;ΔNNO-1.5), and low temperatures (&lt;700°C), although fluorine may stabilize it at higher temperatures in some rocks.
Gender differences in bullying among internal medicine residents
Authors: Ayyala Manasa S , Rios Rebeca , Wright Scott M 
Published: January 2023

AbstractPurposeTo describe gender differences in experienced types of bullying, and resulting personal consequences, among internal medicine (IM) residents.MethodsParticipants in this cross-sectional study included 21 212 IM trainees who completed a voluntary survey with their 2016 in-training exam that assessed bullying during residency training. The 2875 (13.6% of) trainees who reported experiencing bullying on a screening question were asked for additional details about types of bullying experienced and resulting personal consequences.ResultsFemale and male trainees experienced bullying at similar rates (47% versus 53%, P = .08). Gender differences were seen in both the type of bullying experienced and the resulting personal consequences. Female trainees were more likely than their male counterparts to report bullying characterized as verbal (83% versus 77%, P &lt; .001) and sexual (5% versus 2%, P &lt; .001), whereas male trainees were more likely to experience physical (6% versus 4%, P = .03) and “other” bullying types (27% versus 22%, P &lt; .001). Female trainees were more likely to report negative personal consequences than male trainees, and the most common resultant sequela reported was feeling burned out (63% versus 51%, P &lt; .001).ConclusionGender differences exist in both the types and consequences of bullying experienced among this national sample of IM residents. These results should be considered by programs and institutions that are hoping to optimize the culture of their workplace and enhance safety in the learning environment.
Hepatojugular ‘reflex’ or ‘reflux’? A tale of two vowels
Authors: Mostafa Omar 
Published: January 2023

AbstractSummaryHepatojugular reflux is an important, prognostic clinical sign in the field of medicine. The majority of medical students or clinicians may attempt to elicit this sign during abdominal or cardiovascular examinations. However, some individuals may incorrectly call it the hepatojugular ‘reflex’ rather than a ‘reflux’. In the first instance, that may not pose a problem to either patient or clinician—however, it may reflect a lack of basic understanding of how the human body works.Relevance
Measuring light regularity: sleep regularity is associated with regularity of light exposure in adolescents
Authors: Hand Anthony J , Stone Julia E , Shen Lin , Vetter Céline , Cain Sean W , Bei Bei , Phillips Andrew J K 
Published: January 2023

Abstract

Study Objectives
Light is the main time cue for the human circadian system. Sleep and light are intrinsically linked; light exposure patterns can influence sleep patterns and sleep can influence light exposure patterns. However, metrics for quantifying light regularity are lacking, and the relationship between sleep and light regularity is underexplored. We developed new metrics for light regularity and demonstrated their utility in adolescents, across school term and vacation.

Methods
Daily sleep/wake and light patterns were measured using wrist actigraphy in 75 adolescents (54% male, 17.17 ± 0.83 years) over 2 weeks of school term and a subsequent 2-week vacation. The Sleep Regularity Index (SRI) and social jetlag were computed for each 2-week block. Light regularity was assessed using (1) variation in mean daily light timing (MLiT); (2) variation in daily photoperiod; and (3) the Light Regularity Index (LRI). Associations between SRI and each light regularity metric were examined, and within-individual changes in metrics were examined between school and vacation.

Results
Higher SRI was significantly associated with more regular LRI scores during both school and vacation. There were no significant associations of SRI with variation in MLiT or daily photoperiod. Compared to school term, all three light regularity metrics were less variable during the vacation.

Conclusions
Light regularity is a multidimensional construct, which until now has not been formally defined. Irregular sleep patterns are associated with lower LRI, indicating that irregular sleepers also have irregular light inputs to the circadian system, which likely contributes to circadian disruption.