bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice
Authors: Hanna Jason A , Langdon Casey G , Garcia Matthew R , Benton Annaleigh , Lanman Nadia A , Finkelstein David , Rehg Jerold E , Hatley Mark E
Published: January 2022

Angiosarcomas are aggressive vascular sarcomas that arise from endothelial cells and have an extremely poor prognosis. Because of the rarity of angiosarcomas, knowledge of molecular drivers and optimized treatment strategies is lacking, highlighting the need for in vivo models to study the disease. Previously, we generated genetically engineered mouse models of angiosarcoma driven by aP2‐Cre‐mediated biallelic loss of Dicer1 or conditional activation of KrasG12D with Cdkn2a loss that histologically and genetically resemble human tumors. In the present study, we found that DICER1 functions as a potent tumor suppressor and its deletion, in combination with either KRASG12D expression or Cdkn2a loss, is associated with angiosarcoma development. Independent of the genetic driver, the mTOR pathway was activated in all murine angiosarcoma models. Direct activation of the mTOR pathway by conditional deletion of Tsc1 with aP2‐Cre resulted in tumors that resemble intermediate grade human kaposiform hemangioendotheliomas, indicating that mTOR activation was not sufficient to drive the malignant angiosarcoma phenotype. Genetic dissection of the spectrum of vascular tumors identified genes specifically regulated in the aggressive murine angiosarcomas that are also enriched in human angiosarcoma. The genetic dissection driving the transition across the malignant spectrum of endothelial sarcomas provides an opportunity to identify key determinants of the malignant phenotype, novel therapies for angiosarcoma, and novel in vivo models to further explore angiosarcoma pathogenesis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
The multitargeted receptor tyrosine kinase inhibitor sunitinib induces resistance of HER2 positive breast cancer cells to trastuzumab-mediated ADCC
Authors: Guti Eliza , Regdon Zsolt , Sturniolo Isotta , Kiss Alexandra , Kovács Katalin , Demény Máté , Szöőr Árpád , Vereb György , Szöllősi János , Hegedűs Csaba , Polgár Zsuzsanna , Virág László
Published: January 2022

Despite recent advances in the development of novel personalized therapies, breast cancer continues to challenge physicians with resistance to various advanced therapies. The anticancer action of the anti-HER2 antibody, trastuzumab, involves antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. Here, we report a repurposing screen of 774 clinically used compounds on NK-cell + trastuzumab-induced killing of JIMT-1 breast cancer cells. Using a calcein-based high-content screening (HCS) assay for the image-based quantitation of ADCC that we have developed and optimized for this purpose, we have found that the multitargeted tyrosine kinase inhibitor sunitinib inhibits ADCC in this model. The cytoprotective effect of sunitinib was also confirmed with two other assays (lactate dehydrogenase release, and electric cell substrate impedance sensing, ECIS). The drug suppressed NK cell activation as indicated by reduced granzyme B deposition on to the target cells and inhibition of interferon-γ production by the NK cells. Moreover, sunitinib induced downregulation of HER2 on the target cells' surface, changed the morphology and increased adherence of the target cells. Moreover, sunitinib also triggered the autophagy pathway (speckled LC3b) as an additional potential underlying mechanism of the cytoprotective effect of the drug. Sunitinib-induced ADCC resistance has been confirmed in a 3D tumor model revealing the prevention of apoptotic cell death (Annexin V staining) in JIMT-1 spheroids co-incubated with NK cells and trastuzumab. In summary, our HCS assay may be suitable for the facile identification of ADCC boosting compounds. Our data urge caution concerning potential combinations of ADCC-based immunotherapies and sunitinib.
Curcumin sensitizes response to cytarabine in acute myeloid leukemia by regulating intestinal microbiota
Authors: Liu Junmin , Luo Wei , Chen Qiuru , Chen Xing , Zhou Gang , Sun Hongbo
Published: January 2022

Purpose

To address whether Curcumin has synergistic effect with cytarabine (Ara-C) in treating acute myeloid leukemia (AML).

Methods

A xenograft AML mouse model was established by injecting HL-60 cells into tail vein of mice to assess the function of Curcumin. Mononuclear cells (MNCs) isolated from AML mice and AML cell lines were used to examine the effect of Curcumin. Metagenomics and metabolomics were used to evaluate the alteration of intestinal microbiota and the change of metabolites in MNCs.

Results

Curcumin treatment sensitized response to Ara-C in MNCs of AML mice, but had no direct effect on AML cell lines. Metagenomics revealed an alteration of intestinal microbiota with Curcumin treatment, which contributes to sensitized response to Ara-C. Curcumin treatment led to enhanced intestinal intact to sensitize response to Ara-C in AML mice, through reducing mucus degrading bacteria. Metabolomics demonstrated that Curcumin treatment led to decreased cholesterol in MNCs of AML mice. Further study proved that Curcumin treatment resulted in inhibition of SQLE, a key enzyme of cholesterol biosynthesis, to increase sensitivity to Ara-C.

Conclusion

Curcumin sensitizes response to Ara-C through regulating microbiota, highlighting the importance of intestinal intact strengthening in chemoresistant therapy. Moreover, aiming at cholesterol synthesis is promising in AML treatment.
Single photon sources for quantum radiometry: a brief review about the current state-of-the-art
Authors: Kück Stefan , López Marco , Hofer Helmuth , Georgieva Hristina , Christinck Justus , Rodiek Beatrice , Porrovecchio Geiland , Šmid Marek , Götzinger Stephan , Becher Christoph , Fuchs Philipp , Lombardi Pietro , Toninelli Costanza , Trapuzzano Marco , Colautti Maja , Margheri Giancarlo , Degiovanni Ivo Pietro , Traina Paolo , Rodt Sven , Reitzenstein Stephan
Published: January 2022

Single-photon sources have a variety of applications. One of these is quantum radiometry, which is reported on in this paper in the form of an overview, specifically of the current state of the art in the application of deterministic single photon sources to the calibration of single photon detectors. To optimize single-photon sources for this purpose, extensive research is currently carried out at the European National Metrology Institutes (NMIs), in collaboration with partners from universities. Single-photon sources of different types are currently under investigation, including sources based on defect centres in (nano-)diamonds, on molecules and on semiconductor quantum dots. We will present, summarise, and compare the current results obtained at European NMIs for single-photon sources in terms of photon flux, single-photon purity, and spectral power distribution as well as the results of single-photon detector calibrations carried out with this type of light sources.
Association of sweetened carbonated beverage consumption during pregnancy and ADHD symptoms in the offspring: a study from the Norwegian Mother, Father and Child Cohort Study (MoBa)
Authors: Kvalvik Liv Grimstvedt , Klungsøyr Kari , Igland Jannicke , Caspersen Ida Henriette , Brantsæter Anne Lise , Solberg Berit Skretting , Hartman Catharina , Schweren Lizanne Johanna Stephanie , Larsson Henrik , Li Lin , Forthun Ingeborg , Johansson Stefan , Arias Vasquez Alejandro , Haavik Jan
Published: January 2022

Purpose

Intrauterine exposures influence offspring health and development. Here we investigated maternal intake of sweetened carbonated beverages (SCB) during pregnancy and its association with ADHD symptoms in the offspring.

Methods

This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. Maternal diet mid-pregnancy was assessed using a food frequency questionnaire (FFQ). All mothers who responded to the FFQ and a questionnaire when their child was 8 years of age were included (n = 39,870). The exposure was defined as maternal intake (daily servings) of SCB, using no daily intake as reference. Outcome was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less. Associations were analysed using log-binomial regression and linear mixed regression models with adjustment for covariates.

Results

The adjusted regression coefficients for the standardized ADHD offspring symptom score were 0.31 [95% confidence intervals (0.001, 0.62)] and 0.46 (0.15, 0.77) for maternal daily intake of ≥ 1 glasses of SCB, when the models included adjustments for total energy intake or energy intake from other sources than SCBs and sweet drinks, respectively. The corresponding adjusted relative risks were 1.16 (1.004, 1.34) and 1.21. (1.05, 1.39) for drinking ≥ 1 glasses daily.

Conclusion

In a large pregnancy cohort with offspring followed until 8 years of age, we found an association between maternal daily intake of SCB and offspring ADHD symptoms. These results suggest a weak positive relationship between prenatal exposure to SCB and offspring ADHD.
Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort
Authors: Todd Jamie L. , Neely Megan L. , Overton Robert , Mulder Hillary , Roman Jesse , Lasky Joseph A. , de Andrade Joao A. , Gulati Mridu , Huang Howard , Leonard Thomas B. , Hesslinger Christian , Noth Imre , Belperio John A. , Flaherty Kevin R. , Palmer Scott M. ,   the IPF-PRO Registry investigators
Published: January 2022

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, correctedp ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.
Orexin A peptidergic system: comparative sleep behavior, morphology and population in brains between wild type and Alzheimer’s disease mice
Authors: Zhao Peng , You Yaqian , Wang Zhe , Zhou Yanjun , Chai Gaoshang , Yan Gen , Jin Zhewu , Wang Qing , Sun Hongxu
Published: January 2022

Sleep disturbance is common in patients with Alzheimer’s disease (AD), and orexin A is a pivotal neurotransmitter for bidirectionally regulating the amyloid-β (Aβ) deposition of AD brain and poor sleep. In the present study, we examined the characteristic of sleep–wake architecture in APPswe/PSldE9 (APP/PS1) and Aβ-treated mice using electroencephalogram (EEG) and electromyographic (EMG) analysis. We compared the expression of orexin A, distribution, and morphology of the corresponding orexin A-positive neurons using innovative methods including three-dimensional reconstruction and brain tissue clearing between wild type (WT) and APP/PS1 mice. Results from our study demonstrated that increased wakefulness and reduced NREM sleep were seen in APP/PS1 and Aβ treated mice, while the expression of orexin A was significantly upregulated. Higher density and distribution of orexin A-positive neurons were seen in APP/PS1 mice, with a location of 1.06 mm–2.30 mm away from the anterior fontanelle compared to 1.34 mm–2.18 mm away from the anterior fontanelle in WT mice. These results suggested that the population and distribution of orexin A may play an important role in the progression of AD.
The changing face of maxillofacial trauma during the 2020 COVID-19 lockdowns in Melbourne, Australia
Authors: Nhongo Sipho Simon , Sklavos Anton , Lee Kai , Chan Steven T. F. , Austin Stephen
Published: January 2022

Purpose

To compare the incidence, aetiology, and patterns of maxillofacial fracture presentations during the various stages of the 2020 Melbourne COVID-19 lockdown restrictions to periods outside lockdown in 2019 and 2020.

Methods

This is a retrospective study of 344 subjects. The patterns of facial trauma presentations to a tertiary hospital in metropolitan Melbourne during the 2020 COVID-19 restrictions were compared to periods with no restrictions over 22 months from March 2019 to December 2020.

Results

The incidence of maxillofacial fractures decreased by 28% during lockdown (0.41 vs. 0.57 injuries/day, P = 0.0003). Falls overtook interpersonal violence as the leading cause of fractures (44% of lockdown presentations vs. 25.7% of presentations outside lockdown, P = 0.002), while sporting injuries dropped drastically (4% vs. 17.1%, P = 0.005). Lockdowns saw an increase in the proportion of female patients (40% vs. 26.8%, P = 0.03) and a fivefold increase in proportion of domestic violence-related fractures (6.7% vs. 1.1%, P = 0.006). Alcohol-related injuries decreased significantly (11% vs. 21%, P = 0.03).

Conclusions

While restrictions reduced rates of interpersonal violence and alcohol-related maxillofacial trauma, there was a higher proportion of injuries to females, increased falls, and domestic violence-related injuries.
Study of the biological characteristics of human umbilical cord mesenchymal stem cells after long-time cryopreservation
Authors: Zhang Mingqi , Zhao Yan , Wang Le , Zheng Yuqiang , Yu Hui , Dong Xiaoming , He Wei , Yin Zhengqin , Wang Zhuoshi
Published: January 2022

Human umbilical cord mesenchymal stem cells (hUC-MSCs) have considerable potential in cell therapy. Cryopreservation represents the gold standard in cell storage, but its effect on hUC-MSCs is still not well understood. The aim of this study was to investigate the effect of one year of cryopreservation and thawing on the biological characteristics of hUC-MSCs from the same donors. Fresh hUC-MSCs were cryopreserved in commercial freezing medium (serum-free CellBanker 2) at passage 2. After one year of cryopreservation, the hUC-MSCs were thawed and subcultured to passage 4. The comparison was performed in terms of followings: cell count, viability, morphology, proliferation capacity, differentiation potential and chromosomal stability. The total cell count and viability of hUC-MSCs before and after one year of cryopreservation were 1 × 107 and 96.34% and 0.943 × 107 and 93.81%, respectively. Cryopreserved and fresh hUC-MSCs displayed a similar cell doubling times, expressed the markers CD73, CD90, CD105 and were negative for the markers CD34, CD45, and HLA-DR. Karyotypes were found to be normal after one year of cryopreservation. The trilineage differentiation properties were maintained after cryopreservation. However, when compared to freshly isolated hUC-MSCs from the same donor, cryopreserved hUC-MSCs exhibited decreased expression of osteogenesis- and chondrogenesis-related genes including Runx2, Sox9, and Col1a1, and increased expression of adipogenesis-related genes. These results demonstrated that cryopreservation did not affect cell morphology, surface marker expression, cell viability, proliferative capacity, or chromosomal stability. However, the osteogenic and chondrogenic differentiation capacities of cryopreserved hUC-MSCs were slightly reduced compared with those of fresh cells from the same donor.

Graphical abstract
Importance of IGF-I levels in IVF: potential relevance for growth hormone (GH) supplementation
Authors: Gleicher Norbert , Darmon Sarah K. , Molinari Emanuela , Patrizio Pasquale , Barad David. H.
Published: January 2022

Purpose

Growth hormone (GH) supplementation in association with in vitro fertilization (IVF) is worldwide again increasing, even though study outcomes have been discrepant. Since GH acts via insulin-like growth factor-1 (IGF-1), its utilization in IVF would only seem to make sense with low IGF-1. We, therefore, determined whether IGF-I levels affect IVF outcomes.

Methods

Retrospectively, 302 consecutive first fresh, non-donor IVF cycles were studied, excluding patients on GH supplementation. Patients were divided into 3 subgroups: IGF-1 in lower 25th percentile (group A, < 132 ng/mL,n = 64); 25th–75th percentile (B, 133–202 ng/mL,n = 164), and upper 25th percentile (C, > 202 ng/mL,n = 74). IGF-1 was tested immunochemiluminometric with normal range at 78–270 ng/mL. Because of the study patients’ adverse selection and low pregnancy chances, the main outcome measure for the study was cycle cancellation. Secondary outcomes were oocyte numbers, embryos transferred, pregnancies, and live births.

Results

Group A was significantly older than B and C (P = 0.019). IGF-1 decreased with increasing age per year by 2.2 ± 0.65 ng/mL (P = 0.0007). FSH was best in group B and worst in A (trend,P = 0.085); AMH was best in B and worst in A (N.S.). Cycle cancellations were lowest in C (11.6%) and highest in A (25.0%;P = 0.042). This significance further improved with age adjustment (P = 0.021). Oocytes, embryo numbers, pregnancies, and live birth rates did not differ, though oocyte numbers trended highest in B.

Conclusions

Here presented results support the hypothesis that IGF-1 levels affect IVF outcomes. GH treatments, therefore, may be effective only with low IGF-1.
Spontaneous Fluctuation-Symmetry Breaking and the Landauer Principle
Authors: Buffoni Lorenzo , Campisi Michele
Published: January 2022

We study the problem of the energetic cost of information erasure by looking at it through the lens of the Jarzynski equality. We observe that the Landauer bound, $$\langle W \rangle \ge kT \ln 2$$

⟨
W
⟩
≥
k
T
ln
2

, on average dissipated work $$\langle W \rangle $$

⟨
W
⟩

associated to an erasure process, literally emerges from the underlying second law bound as formulated by Kelvin, $$\langle W \rangle \ge 0$$

⟨
W
⟩
≥
0

, as consequence of a spontaneous breaking of the Crooks–Tasaki fluctuation-symmetry, that accompanies logical irreversibility. We illustrate and corroborate this insight with numerical simulations of the process of information erasure performed on a 2D Ising ferromagnet.
Detection and Sequencing of Multiple Human Norovirus Genotypes from Imported Frozen Raspberries Linked to Outbreaks in the Province of Quebec, Canada, in 2017
Authors: Raymond Philippe , Paul Sylvianne , Perron André , Bellehumeur Christian , Larocque Émilie , Charest Hugues
Published: January 2022

Human noroviruses are among the main causes of acute gastroenteritis worldwide. Frozen raspberries have been linked to several norovirus food-related outbreaks. However, the extraction of norovirus RNA from frozen raspberries remains challenging. Recovery yields are low and PCR inhibitors limit the sensitivity of the detection methodologies. In 2017, 724 people from various regions of the Province of Quebec, Canada, were infected by noroviruses and the outbreak investigation pointed to frozen raspberries as a putative source. A new magnetic silica bead approach was used for the extraction of viruses from different outbreak samples. The RNA extracts were tested by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and five samples were confirmed positive for norovirus by RT-qPCR amplicon sequencing. A multiplex long-range two-step RT-PCR approach was developed to amplify norovirus ORF2 and ORF3 capsid genes from the positive frozen raspberry RNA extracts and other sequencing strategies were also explored. These capsid genes were sequenced by Next-Generation Sequencing. Phylogenetic analyses confirmed the presence of multiple genotypes (GI.3, GI.6, and GII.17) and intra-genotype variants in some of the frozen raspberry samples. Variants of genotype GI.3 and GI.6 had 100% homology with sequences from patient samples. Similar strains were also reported in previous outbreaks. Confirmation approaches based on sequencing the norovirus capsid genes using Next-Generation Sequencing can be applied at trace level contaminations and could be useful to assess risk and assist in source tracking.
A novel compact 4-channel beam splitter based on a Kösters-type prism
Authors: Greiner J. , Laux U.
Published: January 2022

We introduce a novel compact 4-channel beam splitter which is based on a combination of dichroic coatings and internal total reflection, similar in concept to the interference double prism invented by Kösters 90 years ago [1]. Used with a rapidly-slewing 50 cm telescope in space, this would allow to double the presently known gamma-ray bursts at high (> 5) redshift within 2 years.
Migraine Is Associated with High Risk of Erectile Dysfunction: A Systematic Review and Cumulative Analysis
Authors: He Weicheng , Yang Yi , Liang Hongyi , Huang Zhonghua , Jiang Jiehong
Published: January 2022

Background

Migraine, a common chronic primary headache, has been found to be associated with a high risk of erectile dysfunction (ED).

Aim

The present study aims to summarize all the evidence related to this topic and demonstrate a quantified result on the association between migraine and ED, which has not been reported in the literature.

Methods

MEDLINE, Excerpta Medica Database, and Cochrane Library were systematically searched for identifying the eligible studies (2000–2021). This study was registered in the PROSPERO (ID: CRD42021248013).

Outcomes

The combined effects were synthesized with the relative risks (RR) or standard mean differences (SMD) with 95% confidence intervals (CI).

Results

6 trials with a total of 51,657 participants were included, of which 6,175 were men with migraine. The pooled analysis indicated that migraine was associated with a significantly higher risk of ED as compared to the non-migraine general population (RR = 1.63, 95%CI: 1.34 to 2.0, P < .001). Consistently, men with migraine have a significantly lower IIEF-5 score than healthy controls (SMD = -3.64, 95%CI: -6.4 to -0.89, P = .01). Stratification analysis on the mean age indicated that the association between migraine and ED was much stronger in the migraine patients with age < 40 years (RR = 32.29, 95% CI: 6.41–162.64, P < .001; I2 = 0.0 %, P = .837) than in those with age > 40 years (RR = 1.75, 95% CI: 1.11–2.78, P = .017; I2 = 89.2%, P = .002). Sensitivity analysis indicated that no single study had dominated the combined RR and the heterogeneity.

Clinical Implications

ED is a common disease among migraine men, especially those patients whose age is under 40 years old. It shows a 32-fold increased risk of ED compared to the healthy controls. Migraine-induced ED may be correlated with multiple factors, that is, chronic illnesses, chronic pain, and psychosocial causes (like anxiety and depression). Since phosphodiesterase-5 inhibitors (ie, sildenafil) might induce or exacerbate migraine, thus it is not recommended to prescribe these drugs for patients with migraine-mediated ED.

Conclusion

The present study provides evidence that migraine is associated with a significantly high risk of ED, especially in those aged < 40 years. The pathophysiological mechanisms of this action deserve further study.
Reversible data hiding for JPEG images with a cascaded structure
Authors: Zhan Wuyue , Yao Heng
Published: January 2022

Since Joint Photographic Experts Group is a typical image compression standard, so the reversible data hiding research on Joint Photographic Experts Group has received a lot of attention. There are two main research methods in Joint Photographic Experts Group‐reversible data hiding: the method based on modifying DCT coefficients and the method based on variable length coding mapping. The disadvantage of the first one is that the visual loss is always inevitable during the DCT‐coefficient modification process, while the second method often has insufficient embedding capacity and excessive file expansion. In order to solve the above problems, this paper proposes a cascaded reversible data hiding scheme, which builds a distortion minimisation scheme based on the DCT coefficients, and then cascades a file expansion suppression scheme based on the variable length coding mapping. For a particular case during the payload distribution, in this paper, all the secret information is embedded into DCT coefficients with a distortion minimisation scheme, and then the auxiliary information generated in the previous process is embedded in the variable length coding sequence with a scheme to optimise the file size expansion. The experimental results demonstrate the superiority of the proposed method in high‐quality factor circumstances in terms of visual quality and file expansion.
Ende gut, alles gut?
Authors: Heeser Alexandra-Corinna
Published: January 2022

Lernen hat sich aufgrund von Corona verändert – digitales Lernen ist seit der Pandemie gefragter denn je. Doch ist diese Form besser oder schlechter als die altehrwürdigen Präsenzveranstaltungen? Sowohl als auch.
Optimized Flow Cytometry Strategy for Phenotyping Intramuscular Leukocytes: Application to the Evaluation of Myopathological Processes
Authors: Saidj Tassadit , Baba Amer Yasmine , Plonquet Anne , Henry Adeline , Souvannanorath Sarah , Relaix Frederic , Beldi-Ferchiou Asma , Authier François Jérôme
Published: January 2022

Phenotyping intramuscular immune cells is essential for the characterization of dysimmune/inflammatory myopathies (DIM). Flow cytometry (FC) is the most reliable technique for analyzing leukocyte subpopulations and evaluating their activation levels. We developed a purely mechanical protocol for extracting cells from muscle tissue allowing us to preserve cell surface epitopes and determined its applicability to experimental pathology in mice and myopathological diagnosis in human. Skeletal muscle regeneration in mice was associated with a transient enrichment of macrophages (CD11bhighGr-1+), myeloid dendritic cells (CD3−C8+CD11bhigh), CD8+ T cells (CD3+C8+), and NK cells (CD3− CD11bhighNKp46+). In murine models of inherited muscle dystrophies, leukocytes represented 23%–84% of intramuscular mononuclear cells, with a percentage of CD8+ T cells (4%–17%) mirroring that of all CD45+ cells, while MDCs remained a minority. In human 16 samples (DIM: n = 9; nonimmune conditions: n = 7), DIM was associated with intramuscular recruitment of CD8+ T cells, but not CD4+ T cells and NK cells. FC allowed concomitant quantification of HLA-DR, CD25, CD38, and CD57 activation/differentiation biomarkers and showed increased activation levels of CD4+ and CD8+ T cells in DIM. In conclusion, FC is an appropriate method for quantifying intramuscular leukocyte subpopulations and analyzing their activation states.
Inhibition of Ferroptosis Attenuates Glutamate Excitotoxicity and Nuclear Autophagy in a CLP Septic Mouse Model
Authors: Xie Zhenxing , Xu Mang , Xie Jie , Liu Tao , Xu Xie , Gao Wei , Li Zhanfei , Bai Xiangjun , Liu Xinghua
Published: January 2022

Sepsis-associated encephalopathy (SAE) often manifests in severe diffuse cerebral dysfunction due to an aberrant systemic immune response to infection. The underlying pathophysiology of SAE is not entirely understood but is likely a multifactorial process that involves disruption in cell death mechanism. Ferroptosis is a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, leading to inflammatory cascade and glutamate release. We hypothesized that ferroptosis is involved in the glutamate-mediated excitotoxic neuron injury during the uncontrolled neural inflammatory process of SAE. Inhibiting ferroptosis with ferrostatin-1 (Fer-1) could alleviate glutamate excitotoxicity and reduce neuron death of SAE, potentially improving prognosis. We found that in the cecal ligation and puncture (CLP) sepsis model, ferroptosis occurred increasingly in the cerebrum, characterized by glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4) inactivation, transferrin upregulation, mitochondria shrink and malondialdehyde (MDA) increased. Fer-1 treatment downregulated cerebral ferroptosis and alleviated glutamate excitotoxicity via dampening system xc-(SXC) and glutamate receptor N-methyl-D-asperate receptor subunit 2. Combined with an observed reduction in calcium transporter PLCG and PLCB activation, these processes ultimately protected the integrities of synapses and neurons during SAE. Fer-1 treatment also rescued sepsis-induced nuclear autophagy and improved the behaviors of tail suspension test and novel object recognition test in septic mice. Conclusively, our results suggested that inhibition of ferroptosis could attenuate glutamate excitotoxicity and SAE outcomes.
Clinical Characteristics and Outcomes of Neutropenic Sepsis: A Multicenter Cohort Study
Authors: Na Soo Jin , Oh Dong Kyu , Park Sunghoon , Lee Yeon Joo , Hong Sang-Bum , Park Mi-Hyun , Ko Ryoung-Eun , Lim Chae-Man , Jeon Kyeongman
Published: January 2022

Background:

Sepsis is a leading cause of mortality in patients with neutropenia; however, data on whether neutropenic sepsis is associated with distinct clinical characteristics and outcomes are limited. Thus, this study was designed to clarify the clinical characteristics and outcomes of patients with neutropenic sepsis compared with those of patients without neutropenic sepsis diagnosed based on the Third International Consensus Definitions for Sepsis and Septic Shock criteria.

Methods:

We analyzed data from the Korean Sepsis Alliance, a nationwide prospective multicenter cohort study evaluating the clinical characteristics, management, and outcomes of patients with sepsis from September 2019 to February 2020. Eligible patients were divided into the neutropenic (absolute neutrophil count of less than 1,500/mL) and non- neutropenic groups. The characteristics and outcomes were compared between the two groups.

Results:

During the study period, 2,074 patients were enrolled from 16 tertiary referral or university-affiliated hospitals. Of them, 218 (10.5%) had neutropenia. The neutropenia group was younger and had a lower proportion of patients with chronic diseases compared with the non-neutropenia group. However, solid tumors (50.0% vs. 34.1%; P 
> 0.001) and hematological malignancies (40.8% vs. 3.8%; P 
< 0.001) were more common in the neutropenia group. The neutropenia group had a higher incidence of septic shock (43.6% vs. 22.9%; P 
< 0.001) and higher Sequential Organ Failure Assessment score (7 vs. 5; P 
< 0.001) than the nonneutropenia group. However, no significant differences in microbiologically confirmed infections and its pathogen distribution and the incidence of multidrug resistance were observed between the two groups. The neutropenic group had a higher hospital mortality than the non-neutropenic group (42.2% vs. 26.3%; P 
< 0.001), and the Kaplan-Meier survival curve demonstrated a significant difference in survival within 1 week after diagnosing sepsis (log-rank test, P = 0.002). The incidence of adverse events during intensive care unit admission was not different between the two groups. Among hospital survivors, the neutropenic group was more frequently discharged to home (72.2% vs. 57.8%; P = 0.002).

Conclusions:

Neutropenic sepsis is associated with a higher-grade organ dysfunction during the diagnosis of sepsis and higher mortality without difference in the pathogen isolated.
Overestimated Polygenic Prediction due to Overlapping Subjects in Genetic Datasets
Authors: Park David Keetae , Chen Mingshen , Kim Seungsoo , Joo Yoonjung Yoonie , Loving Rebekah K. , Kim Hyoung Seop , Cha Jiook , Yoo Shinjae , Kim Jong Hun
Published: January 2022

Recently, polygenic risk score (PRS) has gained significant attention in studies involving complex genetic diseases and traits. PRS is often derived from summary statistics, from which the independence between discovery and replication sets cannot be monitored. Prior studies, in which the independence is strictly observed, report a relatively low gain from PRS in predictive models of binary traits. We hypothesize that the independence assumption may be compromised when using the summary statistics, and suspect an overestimation bias in the predictive accuracy. To demonstrate the overestimation bias in the replication dataset, prediction performances of PRS models are compared when overlapping subjects are either present or removed. We consider the task of Alzheimer’s disease (AD) prediction across genetics datasets, including the International Genomics of Alzheimer’s Project (IGAP), AD Sequencing Project (ADSP), and Accelerating Medicine Partnership - Alzheimer’s Disease (AMP-AD). PRS is computed from either sequencing studies for ADSP and AMP-AD (denoted as rPRS) or the summary statistics for IGAP (sPRS). Two variables with the high heritability in UK Biobank, hypertension, and height, are used to derive an exemplary scale effect of PRS. Based on the scale effect, the expected performance of sPRS is computed for AD prediction. Using ADSP as a discovery set for rPRS on AMP-AD, ΔAUC and ΔR2(performance gains in AUC and R2by PRS) record 0.069 and 0.11, respectively. Both drop to 0.0017 and 0.0041 once overlapping subjects are removed from AMP-AD. sPRS is derived from IGAP, which records ΔAUC and ΔR2of 0.051±0.013 and 0.063±0.015 for ADSP and 0.060 and 0.086 for AMP-AD, respectively. On UK Biobank, rPRS performances for hypertension assuming a similar size of discovery and replication sets are 0.0036±0.0027 (ΔAUC) and 0.0032±0.0028 (ΔR2). For height, ΔR2is 0.029±0.0037. Considering the high heritability of hypertension and height of UK Biobank, we conclude that sPRS results from AD databases are inflated. The higher performances relative to the size of the discovery set were observed in PRS studies of several diseases. PRS performances for binary traits, such as AD and hypertension, turned out unexpectedly low. This may, along with the difference in linkage disequilibrium, explain the high variability of PRS performances in cross-nation or cross-ethnicity applications, i.e., when there are no overlapping subjects. Hence, for sPRS, potential duplications should be carefully considered within the same ethnic group.
PRICE COVID19 Data Report December 2021 Pakistan Registry of Intensive Care
Authors: farooq Ahmed , Arsalan Rahatullah , Aisha Mufti Kulsoom , Muhammad Asim , Hayat Muhammad , Altaf Aneela , Taqi Arshad , Kumar Ashok , Rehman Attaur , Haidri Fakhir Raza , Hussain Iqbal , Chaudhry Mobin , Rehman Safdar , Malik Irfan , Saleem Jodat , Ali Liaquat , Zia Muhammad Ashraf , Khan Maria Ali , Sheikh Mohiuddin , Ashraf Muhammad Sheharyar , Rana Muhammad Asim , Khoso Muhammad Nasir , Rizvi Saadiya , Shaikh Naseem Ali , Salahuddin Nawal , Khan Qurat-ul-Ain , Sikander Rana Imran , Ali Syed Muneeb , Khan Rashid Nasim , Babar Sairah , Beane Abigail , Dondorp Arjen M , Kodippily Chamira , Priyadarshani Dilanthi , Udayanga Ishara , Ishani Pramodya , Darshana Sri , Rashan Thalha , Haniffa Rashan , Murthy Srinivas , Hashmi Madiha
Published: January 2022

Abstract
Pakistan Registry of Intensive Care (PRICE) is a platform that has enabled standardized COVID-19 clinical data collection based on ISARIC/WHO Clinical Characterization Protocol. The near real-time data platform includes epidemiology, severity of illness, microbiology, treatment and outcomes of patients admitted with suspected or laboratory confirmed COVID19 infection to 67 intensive care and high dependency units across the country. Data has been extracted and analysed at regular intervals to inform stakeholders and improve care practices. This is our 28th report including all patients with suspected or confirmed COVID-19 from 26th March 2020 to 26th December 2021.

Key findings from 8624 patients who met eligibility criteria, are as follows:
● Median age of 60 years (IQR 50-70).
● The most common symptoms were shortness of breath (n = 6428, 77.8%), fever (n = 6091, 73.8%), and Cough (n = 3354, 38.9%)
● The most common comorbidity was hypertension followed by diabetes.
● During the course of illness 2804 (32.6%) patients received non-invasive ventilation, whereas 2474 (28.8%) patients had mechanical ventilation as their highest organ support. In addition, 2246 (26.1%) patients needed haemodynamic support and 1249 (14.7%) patients required renal replacement therapy as their highest organ support.
● Median APACHE II score was 18
● Overall mortality at ICU discharge was 39.2%
● Increasing age and requirement for invasive mechanical ventilation were independent risk factors for mortality increased the risk of death
Multiscale computer modeling of spreading depolarization in brain slices
Authors: Kelley Craig , Newton Adam JH , Hrabetova Sabina , McDougal Robert A. , Lytton William W
Published: January 2022

Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and associated with several neurological conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (2 voltage-gated ion channels; 3 leak channels; 3 ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thickness) with ion (K+, Cl−, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+ pumps. SD propagated through the slices at realistic speeds of 2–4 mm/min, which increased by as much as 50% in models incorporating the effects of hypoxia or propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make testable predictions, including: 1. SD can be inhibited by enlarging ECS volume; 2. SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; 3. SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; 4. Slice thickness influences SD due to relative hypoxia in the slice core, exacerbated by SD in a pathological cycle; 5. SD and high neuronal spike rates will be observed in the core of the slice. Cells in the periphery of the slice near an oxygenated bath will resist SD.

Significance

Spreading depolarization (SD) is a slow moving wave of electrical and ionic imbalances in brain tissue and is a hallmark of several neurological disorders. We developed a multiscale computer model of brain slices with realistic neuronal densities, ions, and oxygenation. Our model shows that SD is exacerbated by and causes hypoxia, resulting in strong SD dependence on slice thickness. Our model also predicts that the velocity of SD propagation is not dependent on its initiation, but instead on tissue properties, including the amount of extracellular space and the total area of neuronal membrane, suggesting faster SD following ischemic stroke or traumatic brain injury.
Predicting Response to McGurk Illusion Based on Periodic and Aperiodic Prestimulus EEG Activity
Authors: Singh Vinsea A V , Kumar Vinodh G , Banerjee Arpan , Roy Dipanjan
Published: January 2022

Studies have reported that prestimulus brain oscillations guide perceptual experiences during AV speech perception. However, ’what’ features of these prestimulus activity drives perception remains unknown. In this electroencephalography (EEG) study, we investigated the relationship between prestimulus periodic oscillations and aperiodic components with subsequent perception of the McGurk illusion at single-trial levels. Using logistic mixed-effect models, we determined which spectral features from different sensor regions predicted response to the illusory perception. We found that lower alpha (8-12 Hz) and beta (15-30 Hz) band oscillations over parieto-occipital sensors predicted illusion perception. We also found lower aperiodic offset values over parieto-temporal sensors, and lower ‘global’ effect of exponent over the scalp, that predicted the response to McGurk illusion. We conclude that the predominant source of the prestimulus oscillatory state is aperiodic background activity, and that variations in these arrhythmic components account for inter-trial and inter-individual variability in perception of the McGurk illusion.
Outcomes of SARS-CoV-2 Omicron infection in residents of Long-Term Care
Authors: Krutikov Maria , Stirrup Oliver , Nacer-Laidi Hadjer , Azmi Borscha , Fuller Chris , Tut Gokhan , Palmer Tom , Shrotri Madhumita , Irwin-Singer Aidan , Baynton Verity ,   The COVID-19 Genomics UK (COG-UK) consortium, Hayward Andrew , Moss Paul , Copas Andrew , Shallcross Laura
Published: January 2022

Background

Recently there has been a rapid, global increase in SARS-CoV-2 infections associated with the Omicron variant (B.1.1.529). Although severity of Omicron cases may be reduced, the scale of infection suggests hospital admissions and deaths may be substantial. Definitive conclusions about disease severity require evidence from populations with the greatest risk of severe outcomes, such as residents of Long-Term Care Facilities (LTCFs).

Methods

We used a cohort study to compare the risk of hospital admission or death in LTCF residents in England who had tested positive for SARS-CoV-2 in the period shortly before Omicron emerged (Delta dominant) and the Omicron-dominant period, adjusting for age, sex, vaccine type, and booster vaccination. Variants were confirmed by sequencing or spike-gene status in a subset.

Results

Risk of hospital admission was markedly lower in 1241 residents infected in the Omicron-period (4.01% hospitalised, 95% CI: 2.87-5.59) compared to 398 residents infected in the pre-Omicron period (10.8% hospitalised, 95% CI: 8.13-14.29, adjusted Hazard Ratio 0.50, 95% CI: 0.29-0.87, p=0.014); findings were similar in residents with confirmed variant. No residents with previous infection were hospitalised in either period. Mortality was lower in the Omicron versus the pre-Omicron period, (p<0.0001).

Conclusions

Risk of severe outcomes in LTCF residents with the SARS-CoV-2 Omicron variant was substantially lower than that seen for previous variants. This suggests the current wave of Omicron infections is unlikely to lead to a major surge in severe disease in LTCF populations with high levels of vaccine coverage and/or natural immunity.

Trial Registration Number

ISRCTN 14447421
Modelling Quarantine Effects on SARS-CoV-2 Epidemiological Dynamics in Chilean Communes and their Relationship with the Social Priority Index
Authors: Salinas Dino G. , Bustamante María Leonor , Gallardo Mauricio O.
Published: January 2022

An epidemiological model [Susceptible, Un-quarantined infected, Quarantined infected, Confirmed infected (SUQC)] has previously been developed and applied to incorporate quarantine measures and calculate COVID-19 contagion dynamics and pandemic control in some Chinese regions. Here, we generalized this model to incorporate the disease recovery rate and applied our model to records of the total number of confirmed cases of people infected with the SARS-CoV-2 virus in some Chilean communes. In each commune, two consecutive stages were considered: a stage without quarantine and an immediately subsequent quarantine stage imposed by the Ministry of Health. To adjust the model, typical epidemiological parameters were determined, such as the confirmation rate and the quarantine rate. The latter allowed us to calculate the reproduction number. The mathematical model adequately reproduced the data, indicating a higher quarantine rate when quarantine was imposed by the health authority, with a corresponding decrease in the reproduction number of the virus down to values that prevent or decrease its exponential spread. In general, during this second stage, the communes with the lowest social priority indices had the highest quarantine rates, and therefore, the lowest effective viral reproduction numbers. This study provides useful evidence to address the health inequity of pandemics. The mathematical model applied here can be used in other regions or easily modified for other cases of infectious disease control by quarantine.
Waning of Vaccine-Conferred Protection against SARS-CoV-2 Infection: Matched Case-Control Test-Negative Design Study in Two High-Risk Populations
Authors: Goldhaber-Fiebert Jeremy D. , Prince Lea , Chin Elizabeth T. , Leidner David , Studdert David M. , Salomon Joshua A. , Andrews Jason R.
Published: January 2022

To distinguish waning of vaccine responses from differential variant protection, we performed a test-negative case-control analysis during a Delta variant-dominant period in California’s prisons. We found that infection odds increased each 28-day period post-vaccination, reaching 3.4-fold (residents) to 4.7-fold (staff) increased odds of infection after 180 days.
Population dynamics of epithelial-mesenchymal heterogeneity in cancer cells
Authors: Jain Paras , Bhatia Sugandha , Thompson Erik W , Jolly Mohit Kumar
Published: January 2022

Phenotypic heterogeneity is a hallmark of aggressive cancer behaviour and a clinical challenge. Despite much characterisation of this heterogeneity at a multi-omics level in many cancers, we have a limited understanding of how this heterogeneity emerges spontaneously in an isogenic cell population. Some longitudinal observations of dynamics in epithelial-mesenchymal heterogeneity, a canonical example of phenotypic heterogeneity, have offered us opportunities to quantify the rates of phenotypic switching that may drive such heterogeneity. Here, we offer a mathematical modeling framework that explains the salient features of population dynamics noted in PMC42-LA cells: a) predominance of EpCAMhigh subpopulation, b) re-establishment of parental distributions from the EpCAMhigh and EpCAMlow subpopulations, and c) enhanced heterogeneity in clonal populations established from individual cells. Our framework proposes that fluctuations or noise in content duplication and partitioning of SNAIL – an EMT-inducing transcription factor – during cell division can explain spontaneous phenotypic switching and consequent dynamic heterogeneity in PMC42-LA cells observed experimentally at both single-cell and bulk level analysis. Together, we propose that asymmetric cell division can be a potential mechanism for phenotypic heterogeneity.
CRISPR-based targeted haplotype-resolved assemblies of a megabase region
Authors: Li Taotao , Du Duo , Zhang Dandan , Ma Jiakang , Zhou Mengyu , Meng Weida , Jin Zelin , Lin Yicheng , Chen Ziqiang , Yuan Haozhe , Wang Jue , Dong Shulong , Sun Shaoyang , Ye Wenjing , Li Boshen , Zhang Zhao , Xie Zhi , Qiu Wenqing , Liu Yun
Published: January 2022

Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved de novo assemblies of targeted genomic regions with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assemblies, our targeted approach achieved comparable completeness and accuracy with greatly reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.