bluuebunny/crossref_metadata_2025 huggingface dataset:
Protection Conferred by Delta and BA.1/BA.2 Infection Against BA.4/BA.5 Infection and Hospitalization: A Retrospective Cohort Study
Authors: Winchester Nicole E , Shrestha Nabin K , Kim Priscilla , Tereshchenko Larisa G , Rothberg Michael B
Published: January 2023

Background

Severe acute respiratory syndrome coronavirus 2 immunity has declined with subsequent waves and accrual of viral mutations. In vitro studies raise concern for immune escape by BA.4/BA.5, and a study in Qatar showed moderate protection, but these findings have yet to be reproduced.

Methods

This retrospective cohort study included individuals tested for coronavirus disease 2019 by polymerase chain reaction during Delta or BA.1/BA.2 and retested during BA.4/BA.5. The preventable fraction (PF) was calculated as ratio of the infection to the hospitalization rate for initially positive patients divided by the ratio for initially negative patients, stratified by age and adjusted for age, sex, comorbid conditions, and vaccination using logistic regression.

Results

A total of 20 987 patients met inclusion criteria. Prior Delta infection provided no protection against BA.4/BA.5 infection (adjusted PF, 11.9% [95% confidence interval, .8%–21.8%]); P = .04) and minimal protection against hospitalization (10.7% [4.9%–21.7%]; P = .003). In adjusted models, prior BA.1/BA.2 infection provided 45.9% (95% confidence interval, 36.2%–54.1%; P < .001) protection against BA.4/BA.5 reinfection and 18.8% (10.3%–28.3%; (P < .001) protection against hospitalization. Up-to-date vaccination provided modest protection against reinfection with BA.4/BA.5 and hospitalization.

Conclusions

Prior infection with BA.1/BA.2 and up-to-date vaccination provided modest protection against infection with BA.4/BA.5 and hospitalization, while prior Delta infection provided minimal protection against hospitalization and none against infection.
Enhanced Automated Online Immunoaffinity Liquid Chromatography–Fluorescence Method for the Determination of Aflatoxin M1 in Dairy Products
Authors: Wood Jackie E , Gill Brendon D , McGrail Iain J , Indyk Harvey E
Published: January 2023

Background

Aflatoxin M1 (AFM1) is found in the milk of cows exposed to feed spoiled by Aspergillus fungi species. These fungi may produce the secondary metabolite aflatoxin B1, which is converted in the cow liver by hydroxylation to AFM1 and is then expressed in milk. AFM1 is regulated in milk and other dairy products because it can cause serious health issues, such as liver and kidney cancers, in humans and is an immunosuppressant.

Objective

To optimize the chromatographic protocol and to extend the matrix scope to include a wider range of dairy products: whey powder, whey protein concentrate, whey protein isolate, liquid milk, skim milk powder, whole milk powder, adult nutritional products, and yogurt.

Methods

AFM1 is extracted using 1% acetic acid in acetonitrile incorporating ionic salts. The AFM1 in the resulting extract is concentrated using an automated RIDA®CREST IMMUNOPREP® online cartridge coupled to quantification by HPLC–fluorescence.

Results

The method was shown to be accurate, with acceptable recovery (81.2–97.1%) from spiked samples. Acceptable precision was confirmed, with a relative standard deviation (RSD) for repeatability of 6.6–11.2% and an RSD for intermediate precision of 7.5–16.7%. Method LOD and robustness experiments further demonstrated the suitability of this method for routine compliance testing. Analysis of an international proficiency trial sample generated results that were comparable with the value assigned from alternative independent methods.

Conclusion

A method with improved chromatography for high-throughput, routine testing of AFM1 in an extended range of dairy products is described. The method was subjected to single-laboratory validation and was found to be accurate, precise, and fit for purpose.

Highlights

Single-laboratory validation of an automated online immunoaffinity cleanup fluorescence HPLC method for AFM1 in whey proteins, milk powders, nutritional products, liquid milk, and yogurt. Allows for high-throughput analysis of AFM1 with enhanced chromatographic performance. Method applicable to the analysis of AFM1 in an extended range of milk and milk-based products.
The UN and the Protection of Civilians: Sustaining the Momentum
Authors: Gilder Alexander
Published: January 2023

The protection of civilians (PoC) concept remains contested twenty-three years after the first PoC mandate. Current PoC frameworks used by the United Nations (UN) do not assist with determining applicable legal standards. They lead the UN down an unsustainable path that risks diminishing political support for PoC, especially within intense conflicts and following well-documented protection failures. With ever-rising expectations from communities under protection, the UN’s ‘Three Tiers of PoC Action’, and the complexity and dilution of PoC mandates under a whole-of-mission approach, it becomes challenging to determine what missions must do to protect individuals. Undertaking a major re-evaluation of PoC, this article charts the progression of PoC mandates drawing on examples from several missions drawing out the diverse nature of PoC and subsequent activities. The article then argues that current definitions and practical applications of PoC have cast the net too wide, presented uncertainties, and leave PoC open to attack from Member States amidst a political climate of weakened support for collective security action. Instead, the discussion must shift towards a concise and shared understanding of what protection mandates entail for UN peace operations. The article suggests how PoC can be reconceptualised to distinguish a narrow and easily communicated minimum obligation to be placed on UN peacekeepers.
Male microbiota-associated metabolite restores macrophage efferocytosis in female lupus-prone mice via activation of PPARγ/LXR signaling pathways
Authors: Harder James W , Ma Jing , Alard Pascale , Sokoloski Kevin J , Mathiowitz Edith , Furtado Stacia , Egilmez Nejat K , Kosiewicz Michele M
Published: January 2023

Systemic lupus erythematosus development is influenced by both sex and the gut microbiota. Metabolite production is a major mechanism by which the gut microbiota influences the immune system, and we have previously found differences in the fecal metabolomic profiles of lupus-prone female and lupus-resistant male BWF1 mice. Here we determine how sex and microbiota metabolite production may interact to affect lupus. Transcriptomic analysis of female and male splenocytes showed genes that promote phagocytosis were upregulated in BWF1 male mice. Because patients with systemic lupus erythematosus exhibit defects in macrophage-mediated phagocytosis of apoptotic cells (efferocytosis), we compared splenic macrophage efferocytosis in vitro between female and male BWF1 mice. Macrophage efferocytosis was deficient in female compared to male BWF1 mice but could be restored by feeding male microbiota. Further transcriptomic analysis of the genes upregulated in male BWF1 mice revealed enrichment of genes stimulated by PPARγ and LXR signaling. Our previous fecal metabolomics analyses identified metabolites in male BWF1 mice that can activate PPARγ and LXR signaling and identified one in particular, phytanic acid, that is a very potent agonist. We show here that treatment of female BWF1 splenic macrophages with phytanic acid restores efferocytic activity via activation of the PPARγ and LXR signaling pathways. Furthermore, we found phytanic acid may restore female BWF1 macrophage efferocytosis through upregulation of the proefferocytic gene CD36. Taken together, our data indicate that metabolites produced by BWF1 male microbiota can enhance macrophage efferocytosis and, through this mechanism, could potentially influence lupus progression.
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

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

Despite 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

This 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

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

Microfold (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

Synthetic 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

Precise 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

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

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

The 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 >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 >4 wt%, low oxygen fugacity (<ΔNNO-1.5), and low temperatures (<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

Purpose

To describe gender differences in experienced types of bullying, and resulting personal consequences, among internal medicine (IM) residents.

Methods

Participants 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.

Results

Female 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 < .001) and sexual (5% versus 2%, P < .001), whereas male trainees were more likely to experience physical (6% versus 4%, P = .03) and “other” bullying types (27% versus 22%, P < .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 < .001).

Conclusion

Gender 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

Hepatojugular 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

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.
Acute activation of SERCA with CDN1163 attenuates IgE‐mediated mast cell activation through selective impairment of ROS and p38 signaling
Authors: Hunter Katie D. , Crozier Robert W. E. , Braun Jessica L. , Fajardo Val A. , MacNeil Adam J.
Published: January 2023

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE‐mediated mast cell activation leads to a rapid mobilization of Ca2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca2+ concentrations. Among these is sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA), which functions to maintain low cytosolic Ca2+ concentrations by actively transporting cytosolic Ca2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen‐activated mast cells using IgE‐sensitized bone marrow‐derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL‐6, IL‐13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation.
Circadian disruption in lung fibroblasts enhances NF‐κB activity to exacerbate neutrophil recruitment
Authors: Cox Shannon L. , O'Siorain James R. , He Yan , Lordan Ronan , Naik Amruta , Tang Soon Yew , Sengupta Shaon , FitzGerald Garret A. , Carroll Richard G. , Curtis Annie M.
Published: January 2023

Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung‐specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro‐inflammatory cytokine IL‐1β and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1−/− lung fibroblasts also displayed increased Cxcl5 expression under IL‐1β stimulation. Conditioned media obtained from IL‐1β‐stimulated Bmal1−/− immortalized fibroblasts‐induced greater neutrophil migration compared with Bmal1+/+ lung fibroblast controls. Phosphorylation of the NF‐κB subunit, p65, was enhanced in IL‐1β‐stimulated Bmal1−/− lung fibroblasts, and pharmacological inhibition of NF‐κB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF‐κB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response.
A universal method to analyze cellular internalization mechanisms via endocytosis without non‐specific cross‐effects
Authors: Itagaki Mai , Nasu Yoshinori , Sugiyama Chiaki , Nakase Ikuhiko , Kamei Noriyasu
Published: January 2023

Endocytosis is an essential biological process for nutrient absorption and intercellular communication; it can also be used to accelerate the cellular internalization of drug delivery carriers. Clarifying the cellular uptake mechanisms of unidentified endogenous and exogenous molecules and designing new effective drug delivery systems require an accurate, specific endocytosis analysis methodology. Therefore, we developed a method to specifically evaluate cellular internalization via three main endocytic pathways: clathrin‐ and caveolae‐mediated endocytosis, and macropinocytosis. We first revealed that most known endocytosis inhibitors had no specific inhibitory effect or were cytotoxic. Second, we successfully established an alternative method using small interfering RNA to knock down dynamin‐2 and caveolin‐1, which are necessary for clathrin‐ and caveolae‐mediated endocytosis, in HeLa cells. Third, we established another method to specifically analyze macropinocytosis using rottlerin on A431 cells. Finally, we validated the proposed methods by testing the cellular internalization of a biological molecule (insulin) and carriers (nanoparticles and cell‐penetrating peptides). Through this study, we established versatile methods to precisely and specifically evaluate endocytosis of newly developed biopharmaceuticals or drug delivery systems.
The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma
Authors: Patrich Tomas , Wang Yaqun , Elshaikh Mohamed A. , Zhu Simeng , Damast Shari , Li Jessie Y. , Fields Emma C. , Beriwal Sushil , Keller Andrew , Kidd Elizabeth A. , Usoz Melissa , Jolly Shruti , Jaworski Elizabeth , Leung Eric W. , Taunk Neil K. , Chino Junzo , Russo Andrea L. , Lea Jayanthi S. , Lee Larissa J. , Albuquerque Kevin V. , Hathout Lara
Published: January 2023

Objective:

To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma.

Materials and Methods:

A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27.

Results:

The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively (P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 (P value=0.045) for OS and 1.487 (P value=0.116) for RFS. After PSM, black patients were more likely to receive the “Sandwich” approach and concurrent chemoradiotherapy compared with non-black (P=0.013) patients.

Conclusions:

Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the “Sandwich” approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.
Longitudinal Exposure to Tacrolimus and New-Onset Diabetes Mellitus in Renal Transplant Patients
Authors: Destere Alexandre , Premaud Aurélie , Monchaud Caroline , Marquet Pierre , Woillard Jean-Baptiste
Published: January 2023

Purpose:

Tacrolimus is an immunosuppressant widely used in transplantations requiring mandatory concentration-controlled dosing to prevent acute rejection or adverse effects, including new-onset diabetes mellitus (NODM). However, no relationship between NODM and tacrolimus exposure has been established. This study aimed to evaluate the relationship between cumulative tacrolimus exposure and NODM occurrence.

Methods:

A total of 452 kidney transplant patients were included in this study. Sixteen patients developed NODM during the first 3 months after transplant. We considered all tacrolimus concentration (C0) values collected until the diagnosis of NODM in these patients and until 3 months after transplant in the others. New tacrolimus cumulative exposure metrics were derived from the time profile of the tacrolimus morning predose concentration, C0: the percentage of C0 values > cutoff, the average of C0 values above the cutoff, and the percentage of the area under C0 versus time curve, AUCC0, above the cutoff. The cutoff chosen was 15 ng/mL, corresponding to the higher end of the therapeutic range for the early post-transplant period. The influence of these metrics on NODM and other clinical and biological characteristics was investigated using the Cox models.

Results:

The percentage of C0 > 15 mcg/L was statistically different between patients with and without NODM (P = 0.01). Only these tacrolimus C0-derived metrics were significantly associated with an increased risk of NODM [HR: 1.73 (1.43–2.10, P < 0.001)].

Conclusion:

This study shows that tacrolimus concentrations >15 mcg/L affect the incidence of NODM.
What Is the Role of COVID-19 Monoclonal Antibody Programs in Promoting Posttreatment Vaccination?
Authors: Cowman Kelsie , Golia Austin , Guo Yi , Simpson Roxanne , Braithwaite Claire , Sunu Evans , Ros Theary , Rodriguez Maria , Brown Nativida , Laboy Eric , Bard Linda , Alsina Leslie , Cintron Angelica , Andrews Erin , Bao Hongkai , Chang Mei H. , McSweeney Terrence , Nori Priya
Published: January 2023

Background

In addition to highly efficacious mRNA vaccines, there are multiple therapeutic tools to prevent COVID-19, reduce the severity of illness, and prevent death among high-risk patients. Monoclonal antibodies (mAb) are vital to prevent and to manage acute illness, but subsequent vaccination is essential to mitigate risk of reinfection. The objective of our study was to assess vaccination status after mAb treatment.

Methods

We conducted a retrospective, observational cohort study of high-risk adults who were treated with bamlanivimab for mild-moderate COVID-19 between December 2020 and March 2021 at an ambulatory infusion center or 3 emergency departments in the Bronx, NY. Demographics, mAb treatment information, and vaccination status as of February 28, 2022, were collected from the electronic medical record. Patient outreach phone calls were made to obtain information missing in the electronic medical record.

Results

A total of 722 adults were included. Forty patients (6%) were vaccinated before mAb treatment. Of patients who were unvaccinated at time of treatment (n = 682), 569 (83%) were subsequently vaccinated, 35 (5%) remained unvaccinated, and 78 (11%) had an unknown vaccination status as of March 2022. The mean age of vaccinated patients was 59 years and unvaccinated patients was 54 years (P = 0.05). Median time to vaccination was 99 days (interquartile range, 90–142 days). As of March 2022, 307 patients (43%) had received at least 1 vaccine booster dose.

Conclusions

Most patients who were unvaccinated at time of treatment were subsequently vaccinated. Ambulatory COVID-19 encounters are valuable opportunities to provide vaccine education and counseling.
Bacteroides faecium sp. nov. isolated from human faeces
Authors: Kim Juseok , Song Hye Seon , Kim Joon Yong , Whon Tae Woong , Chung Won-Hyong , Nam Young-Do , Choi Yoon-E , Roh Seong Woon
Published: January 2023

A novel bacterial strain, CBA7301T, was isolated from human faeces and was characterised using a polyphasic taxonomic approach. A phylogenetic analysis based on 16S rRNA gene sequences revealed that CBA7301Trepresented a member of the genusBacteroides, in the familyBacteroidaceae. The similarity between the 16S rRNA gene sequence of CBA7301Tand that of its most closely related species,Bacteroides faecichinchillaeJCM 17102T, was 96.2 %, and the average nucleotide identity between these two strains was 77.9 %. The genome size was 6 782 182 bp, and the DNA G+C content was 42.5 mol%. Cells of CBA7301Twere Gram-stain-negative, strictly anaerobic and rod-shaped. The optimal growth of this organism occurred at 30–35 °C, pH 7.0 and 0.5 % (w/v) NaCl. The respiratory quinone was menaquinone 10. The predominant polar lipids were phosphatidylethanolamine, phospholipids and aminophospholipids. The major cellular fatty acid was anteiso-C15 : 0. According to the results of the polyphasic taxonomic analysis, CBA7301Trepresents a novel species of the genusBacteroides, which we namedBacteroides faeciumsp. nov. The type strain is CBA7301T(=KCCM 43355T=ATCC TSD-227T).
Superhydrophobic Rotation-Chip for Computer-Vision Identification of Drug-Resistant Bacteria
Authors: He Jiacheng , Peng Ruonan , Yuqing Henry , Karim Rafi , Chen Juhong , Lu Guoyu , Du Ke
Published: January 2023

The transport, distribution, and mixing of microfluidics often require additional instruments, such as pumps and valves, which are not feasible when operated in point-of-care (POC) settings. Here, we present a simple microfluidic pathogen detection system known as Rotation-Chip that transfers the reagents between wells by manually rotating two concentric layers without using external instruments. The Rotation-Chip is fabricated by a simple computer numerical control (CNC) machining process and is capable of carrying out 60 multiplexed reactions with a simple 30-degree or 60-degree rotation. Leveraging superhydrophobic coating, a high fluid transport efficiency of 92.78% is achieved without observable leaking. Integrated with an intracellular fluorescent assay, an on-chip detection limit of 1.8×106CFU/mL is achieved for ampicillin-resistantEscherichia coli (E. coli), which is similar to our off-chip results. We also develop a computer vision method to automatically distinguish positive and negative samples on the chip, showing 100% accuracy. Our Rotation-Chip is simple, low-cost, high-throughput, and can display test results with a single chip image, ideal for various multiplexing POC applications in resource-limited settings.
Loss of PTPMT1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice
Authors: Zheng Hong , Li Qianjin , Li Shanhu , Li Zhiguo , Brotto Marco , Weiss Daiana , Prosdocimo Domenick , Xu Chunhui , Reddy Ashruth , Puchowicz Michelle , Zhao Xinyang , Weitzmann M. Neale , Jain Mukesh K. , Qu Cheng-Kui
Published: January 2023

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here we report that the deletion ofPTPMT1,a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced.PTPMT1knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly,PTPMT1deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that PTPMT1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.
Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities
Authors: Whitman Ethan T. , Knodt Annchen R. , Elliott Maxwell L. , Abraham Wickliffe C. , Cheyne Kirsten , Hogan Sean , Ireland David , Keenan Ross , Lueng Joan H. , Melzer Tracy R. , Poulton Richie , Purdy Suzanne C. , Ramrakha Sandhya , Thorne Peter R. , Caspi Avshalom , Moffitt Terrie E. , Hariri Ahmad R.
Published: January 2023

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.