bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-obesity effects of agar (Gelidium amansii)-derived oligosaccharides in high-fat diet-treated C57BL/6N mice due to differential regulations of lipogenesis and lipolysis
Authors: Lee Mi Rim , Kim Ji Eun , Jin You Jeong , Roh Yu Jeong , Seol Ayun , Song Hee Jin , Jung Min Wook , Hong Jin Tae , Jang Miran , Hwang Dae Youn
Published: September 2022

To investigate the effects of agar oligosaccharides (AO) on lipid metabolism, changes in obesity phenotypes and related molecular factors were evaluated in C57BL/6N mice fed a high-fat diet (HFD). When HFD-induced obese mice were fed AO, they lost weight. Also, fat accumulation in abdominal and liver tissues was lower in the AO groups than in the Vehicle group. Lipid droplet sizes in tissue sections were reduced by AO, and these observations were mirrored by serum lipid contents. To evaluate the effects of AO on lipid metabolism, lipogenesis and lipolysis-related factors were analyzed. The mRNA expressions of genes involved in lipogenesis, such as adipocyte-protein 2 (aP2) and fatty acid synthase (FAS), were reduced by AO administration, and the expressions of lipolysis-associated proteins, including perilipin, hormone-sensitive lipase (HSL), and fat triglyceride lipase (ATGL), were increased. Taken together, our results suggest that AO should be considered a valuable natural agent that inhibits obesity.
Towards a Synthesised Directional Map of the Stages of Innovation in Children’s Social Care
Authors: Lefevre Michelle , Hampson Martha , Goldsmith Carlie
Published: September 2022

There has been substantial investment by governments and charities in the UK in the development, diffusion and evaluation of innovative practice models and systems to safeguard and support vulnerable children, young people and families. However, understandings of the processes of innovation within the sector are still at a relatively early stage—for example, in relation to what might be expected or planned for at each stage of an innovation journey. As a result, best use may not always be made of opportunities to address deficiencies in provision. To inform this knowledge gap, the literature was reviewed regarding innovation processes and trajectories within children’s social care (statutory and voluntary settings) and within the field of social innovation more widely. Ten modellings of the stages of innovation were identified and synthesised into a directional map of six stages that might be commonly expected: mobilising, designing, developing, integrating, growing and system change. This trajectory framework poses key questions for innovators to consider at each stage to inform planning and determine if, when and how an innovation should progress further.
Strategic Complexity and the Value of Thinking
Authors: Gill David , Prowse Victoria
Published: September 2022

We leverage response-time data from repeated strategic interactions to measure the strategic complexity of a situation by how long people think on average when they face that situation (where we categorise situations according to characteristics of play in the previous round). We find that strategic complexity varies significantly across situations, and we find considerable heterogeneity in how responsive subjects’ thinking times are to complexity. We also study how variation in response times at the individual level affects success: when a subject thinks for longer than she would normally do in a particular situation, she wins less frequently and earns less.
Personalized vascular healthcare: insights from a large international survey
Authors: West Nick E J , Juneja Maneesh , Pinilla Natalia , De Loose Koen R , Henry Timothy D , Baumgard Connie S , Kraineva Olga
Published: September 2022

Fragmentation of healthcare systems through limited cross-speciality communication and intermittent, intervention-based care, without insight into follow-up and compliance, results in poor patient experiences and potentially contributes to suboptimal outcomes. Data-driven tools and novel technologies have the capability to address these shortcomings, but insights from all stakeholders in the care continuum remain lacking. A structured online questionnaire was given to respondents (n = 1432) in nine global geographies to investigate attitudes to the use of data and novel technologies in the management of vascular disease. Patients with coronary or peripheral artery disease (n = 961), physicians responsible for their care (n = 345), and administrators/healthcare leaders with responsibility for commissioning/procuring cardiovascular services (n = 126) were included. Narrative themes arising from the survey included patients’ desire for more personalized healthcare, shared decision-making, and improved communication. Patients, administrators, and physicians perceived and experienced deficiencies in continuity of care, and all acknowledged the potential for data-driven techniques and novel technologies to address some of these shortcomings. Further, physicians and administrators saw the ‘upstream’ segment of the care journey—before diagnosis, at point of diagnosis, and when determining treatment—as key to enabling tangible improvements in patient experience and outcomes. Finally, despite acceptance that data sharing is critical to the success of such interventions, there remains persistent issues related to trust and transparency. The current fragmented care continuum could be improved and streamlined through the adoption of advanced data analytics and novel technologies, including diagnostic and monitoring techniques. Such an approach could enable the refocusing of healthcare from intermittent contacts and intervention-only focus to a more holistic patient view.
Importance of Host Abundance and Microhabitat in Tick Abundance
Authors: Iijima Hayato , Watari Yuya , Furukawa Takuya , Okabe Kimiko
Published: September 2022

To reduce the risk of zoonoses, it is necessary to understand the infection process, including the ecology of animals and vectors (i.e., the ‘One Health’ approach). In temperate climates, ticks are the major vectors of zoonoses, so factors determining their abundance, such as host mammal abundance and microhabitat conditions, should be clarified. Sika deer (Cervus nippon) are a major tick host and are rapidly expanding their distribution in Japan. We established 12 plots along a gradient of sika deer abundance in Tochigi Prefecture, Japan. We monitored the occurrence of mammal species with camera traps and sampled questing ticks on a monthly basis by flagging along three transects (center of a trail, forest edge, and forest interior) at each site from April to November 2018. The camera traps recorded 12 mammal species, predominantly sika deer. Five Haemaphysalis species and three Ixodes species were sampled. The numbers of ticks sampled were explained by the photographic frequency of sika deer, and partly by that of other mammal species, depending on tick species and their developmental stages. The numbers of sampled adult and nymphal ticks were the highest at the forest edge, where vegetation cover was greatest. Thus, vegetation management in tick habitats and the control of sika deer populations may reduce tick abundance.
Use of Host Response to Refine the Diagnosis of Group A Streptococcal Pharyngitis
Authors: Yu Jinsheng , Tycksen Eric , Yang Wei , Mariani Thomas J , Bhattacharya Soumyaroop , Falsey Ann R , Topham David J , Storch Gregory A
Published: September 2022

Background

Current diagnostic tests for pharyngitis do not distinguish between symptomatic group A Streptococcus (GAS) infection and asymptomatic colonization, resulting in over-diagnosis and unnecessary use of antibiotics. We assessed whether measures of host response could make this distinction.

Methods

We enrolled 18 children with pharyngitis having Centor scores of 4 or 5 and 21 controls without pharyngitis or other acute infections. Both groups had throat cultures, molecular tests for GAS and respiratory viruses and IgM serology for Epstein–Barr virus. Host response was evaluated with white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), and sequencing of RNA from peripheral blood leukocytes.

Results

Of 18 cases, 11 had GAS pharyngitis, 3 had adenovirus pharyngitis and 4 had other pharyngitis. Among asymptomatic controls, 5 were positive for GAS. WBC, CRP, and PCT were higher in subjects with pharyngitis compared to asymptomatic controls including those with GAS. Transcriptional profiles from children with symptomatic GAS were clearly distinct from those of children in all other groups. The levels of two genes, CD177 and TLR5 each individually accurately distinguished between symptomatic and asymptomatic GAS. Optimal diagnostic sensitivity and specificity were achieved by the combination of CRP and PCT, and by each of the two gene markers.

Conclusion

In this exploratory study, we showed that traditional measures of inflammation and markers of host gene expression distinguish between symptomatic and asymptomatic GAS. These results point to future rapid molecular approaches for improving the diagnosis of GAS pharyngitis, that may help reduce unnecessary antibiotic use.
Remembering Hodson’s Horse: Commemoration and the Indian Uprising of 1857–58
Authors: Cheshire Jim
Published: September 2022

This article presents analysis of the memorial to William Hodson in Lichfield Cathedral, designed by George Edmund Street between 1859 and 1862, focusing on the iconography of the monument and way that it was influenced by Muscular Christianity and ecclesiology. The attitude of Hodson and his brother George Hodson, who commissioned the monument, is examined through analysis of the publication that presented Hodson’s career to the Victorian public: Twelve Years of a Soldier’s Life in India (1859). The memorial raises urgent questions about the future of Victorian cultural heritage as it demonstrably misrepresents a highly symbolic event within British imperial history. Hodson was represented as a hero by Victorian ecclesiologists but is now seen by many as an unscrupulous and ruthless imperialist. This paper will demonstrate that the extraordinary form of the tomb was determined by an alteration to the design: the inclusion of a sculptural panel representing the ‘Surrender of the King of Delhi’. This change was instigated by the committee of the Ecclesiological Society headed by A. J. Beresford Hope. The panel turns a relatively peripheral event into a symbolic tableau: the surrender of Indian Islam to British Christianity, a distortion typical of British culture in the aftermath of the Indian Uprising of 1857–1858. The historiography of Hodson’s career shows that the tomb has acted as a focus for those wishing to perpetuate a conservative interpretation of Hodson’s career.
Comparing the super-Eddington accretion of SMC X-3 and RX J0209.6−7427 with Swift J0243.6+6124
Authors: Liu Jiren , Vasilopoulos Georgios , Ge MingYu , Ji Long , Weng Shan-Shan , Zhang Shuang-Nan , Hou Xian
Published: September 2022

We study the giant outbursts of SMC X-3 and RX J0209.6−7427 (hereafter RX J0209) to compare their super-Eddington accretion regime with that of Swift J0243.6+6124 (hereafter Swift J0243). The high double-peak profile of SMC X-3 is found to be 0.25 phase offset from that below 2.3 × 1038 erg s−1, which is similar to Swift J0243 (happened around 0.9 × 1038 erg s−1). The profile of RX J0209 shows a similar 0.25 phase offset between high double-peak and low double-peak around 1.25 × 1038 erg s−1. The 0.25 phase offset corresponds to a 90° angle change of the emission beam and strongly supports for a transition from a fan beam to a pencil beam. Their critical luminosities imply a surface magnetic field ∼4 × 1013 and 2 × 1013 G for SMC X-3 and RX J0209, respectively, based on the recently measured cyclotron line of Swift J0243. The spin-up rate and luminosity of SMC X-3 follows a relation of $\dot{\nu }\propto L^{0.94\pm 0.03}$, while that of RX J0209 follows $\dot{\nu }\propto L^{1.00\pm 0.03}$, which are similar to Swift J0243 and consistent with the prediction of a radiation-pressure-dominated disc. These results indicate that accretion columns are indeed formed above Eddington luminosity, and the population of ultraluminous X-ray pulsars likely corresponds to X-ray pulsars of highest magnetic field.
Rise and fall of silicate dust in RS Ophiuchi following the 2006 eruption
Authors: Rushton M T , Woodward C E , Gehrz R D , Evans A , Kaminsky B , Pavlenko Ya V , Eyres S P S
Published: September 2022

We present an analysis of archival Spitzer InfraRed Spectrograph (IRS) observations of the recurrent nova RS Ophiuchi obtained on several occasions, beginning about 7 months after the outburst in 2006. These data show atomic emission lines, absorption bands due to photospheric SiO, and the well-known silicate dust features at 9.7 and $18\, \mu$m. The dust emission, arising in the wind of the secondary star, is fitted by dusty models for mass-loss rates in the range 1.0–1.7 × 10−7 M⊙ yr−1. The silicate features are similar in profile to those seen in circumstellar environments of isolated late-type stars and some dusty symbiotic binaries, although the longer wavelength feature peaks at $17\, \mu$m, instead of the usual $18\, \mu$m, indicating peculiar grain properties. The dust features are variable, appearing stronger in 2006–2007 during outburst than in 2008–2009 when the system was in the quiescent state. This variability is attributed to changes in the ultraviolet output and the reformation of the accretion disc, although a decline in the mass-loss rate of the red giant secondary star could also play a role. Further observations, in the aftermath of the 2021 eruption, could provide a definitive conclusion.
Forecasting the success of the WEAVE Wide-Field Cluster Survey on the extraction of the cosmic web filaments around galaxy clusters
Authors: Cornwell Daniel J , Kuchner Ulrike , Aragón-Salamanca Alfonso , Gray Meghan E , Pearce Frazer R , Aguerri J Alfonso L , Cui Weiguang , Méndez-Abreu J , Peralta de Arriba Luis , Trager Scott C
Published: September 2022

Next-generation wide-field spectroscopic surveys will observe the infall regions around large numbers of galaxy clusters with high sampling rates for the first time. Here, we assess the feasibility of extracting the large-scale cosmic web around clusters using forthcoming observations, given realistic observational constraints. We use a sample of 324 hydrodynamic zoom-in simulations of massive galaxy clusters from TheThreeHundred project to create a mock-observational catalogue spanning 5R200 around 160 analogue clusters. These analogues are matched in mass to the 16 clusters targetted by the forthcoming WEAVE Wide-Field Cluster Survey (WWFCS). We consider the effects of the fibre allocation algorithm on our sampling completeness and find that we successfully allocate targets to 81.7 ${\rm {per \,cent}}\, \pm$ 1.3 of the members in the cluster outskirts. We next test the robustness of the filament extraction algorithm by using a metric, Dskel, which quantifies the distance to the filament spine. We find that the median positional offset between reference and recovered filament networks is Dskel = 0.13 ± 0.02 Mpc, much smaller than the typical filament radius of ∼ 1 Mpc. Cluster connectivity of the recovered network is not substantially affected. Our findings give confidence that the WWFCS will be able to reliably trace cosmic web filaments in the vicinity around massive clusters, forming the basis of environmental studies into the effects of pre-processing on galaxy evolution.
Heavy Rare Earth Elements and the Sources of Continental Flood Basalts
Authors: Heinonen Jussi S , Brown Eric L , Turunen Sanni T , Luttinen Arto V
Published: September 2022

Heavy rare earth elements (HREEs) in mafic and ultramafic volcanic rocks are useful recorders of mantle source processes because their ratios are not easily modified by differentiation. Here we utilize REEBOX PRO, a simulator of adiabatic decompression melting of the mantle, to study the behavior of HREEs in the formation of continental flood basalt (CFB) parental magmas in the mantle. We simulate partial melting of depleted peridotite, pyrolitic peridotite, pyroxenite, and peridotite-pyroxenite mixtures at mantle potential temperatures of 1350–1650°C and lithospheric thicknesses of 50–150 km, and compare the results to natural data. Many large igneous provinces are typified by low-Ti and high-Ti CFBs with contrasting HREE patterns. Our results show that low-Ti CFBs originate mainly from peridotitic sources. Flat mid-ocean ridge basalt-like HREE patterns typical of low-Ti CFBs can be generated beneath thick lithosphere (~100 km), given that mantle potential temperatures are high (>1500°C) and garnet is completely consumed from the source. We thus challenge the common interpretation that flat HREE patterns always indicate shallow sources for CFB parental magmas. High-Ti CFBs require pyroxenite-bearing sources (≥10%). Contrary to a common view, their steep oceanic island basalt-like HREE patterns can be generated beneath quite a thin lithosphere (~50 km), which is due to increased garnet stability in pyroxenite sources. When applied to CFBs of the Karoo large igneous province, the results are compatible with a model where a mantle plume penetrates a progressively thinning Gondwana lithosphere.
Price Uncertainty and Debt Covenants: Evidence from U.S. Oil Producers
Authors: Docgne Sandrine , Duarte Diogo
Published: September 2022

We use an exogenous, forward-looking measure of price uncertainty to examine the effect of uncertainty on the use of covenants in private and public debt contracts. The effect of uncertainty differs significantly in loans versus bonds, suggesting that private and public lenders face different incentives when contracting under high uncertainty. In loans, uncertainty increases the use of performance-based covenants. In contrast, covenant usage decreases in bonds, but firms with low agency conflicts mainly drive this effect. However, bondholders require higher spreads to offset the lack of protection with fewer covenants. Hedging does not affect the covenant-uncertainty relationship for debt contracts. (JEL: G21, G23, G32, D82, D81)
Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate
Authors: Wang Yafei , Madhusudan Shrinidhi , Cotellessa Ludovica , Kvist Jouni , Eskici Nazli , Yellapragada Venkatram , Pulli Kristiina , Lund Carina , Vaaralahti Kirsi , Tuuri Timo , Giacobini Paolo , Raivio Taneli
Published: September 2022

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons. Through trajectory analysis, we identified a specific gene module activated along the GnRH neuron differentiation lineage, and we examined one of the transcription factors, DLX5, expression in human fetal GnRH neurons. Furthermore, we found that Wnt inhibition could increase DLX5 expression and improve the GnRH neuron differentiation efficiency through promoting neurogenesis and switching the differentiation fates of neural progenitors into glutamatergic neurons/GnRH neurons. Our research comprehensively reveals the dynamic cell population transition and gene regulatory network during GnRH neuron differentiation.
Multicountry study of SARS-CoV-2 and associated risk factors among healthcare workers in Côte d'Ivoire, Burkina Faso and South Africa
Authors: Kribi Sarah , Touré Fidèle , Mendes Adriano , Sanou Soufiane , Some Arsène , Aminou Abdoul M , Belarbi Essia , Griessel Rosemary , Hema Arsène , Kabore Firmin , Pitzinger Paul , Strydom Amy , Vietor Ann Christin , Traoré Korotimi , Zongo Arsène , Anoh Etilé A , Grossegesse Marica , Hofmann Natalie , Ouangraoua Soumeya , Poda Armel , Kagone Thérèse , Schubert Grit , Eckmanns Tim , Venter Marietjie , Leendertz Fabian , Akoua-Koffi Chantal , Tomczyk Sara
Published: September 2022

Background

Reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread across Africa have varied, including among healthcare workers (HCWs). This study assessed the comparative SARS-CoV-2 burden and associated risk factors among HCWs in three African countries.

Methods

A multicentre study was conducted at regional healthcare facilities in Côte d’Ivoire (CIV), Burkina Faso (BF) and South Africa (SA) from February to May 2021. HCWs provided blood samples for SARS-CoV-2 serology and nasopharyngeal/oropharyngeal swabs for testing of acute infection by polymerase chain reaction and completed a questionnaire. Factors associated with seropositivity were assessed with logistic regression.

Results

Among 719 HCWs, SARS-CoV-2 seroprevalence was 34.6% (95% confidence interval 31.2 to 38.2), ranging from 19.2% in CIV to 45.7% in BF. A total of 20 of 523 (3.8%) were positive for acute SARS-CoV-2 infection. Female HCWs had higher odds of SARS-CoV-2 seropositivity compared with males, and nursing staff, allied health professionals, non-caregiver personnel and administration had higher odds compared with physicians. HCWs also reported infection prevention and control (IPC) gaps, including 38.7% and 29% having access to respirators and IPC training, respectively, in the last year.

Conclusions

This study was a unique comparative HCW SARS-CoV-2 investigation in Africa. Seroprevalence estimates varied, highlighting distinctive population/facility-level factors affecting COVID-19 burden and the importance of established IPC programmes to protect HCWs and patients.
LASER PROPHYLAXIS IN STICKLER SYNDROME
Authors: Linton Emma , Jalil Assad , Sergouniotis Panagiotis , Moussa George , Black Graeme , Charles Stephen , Ivanova Tsveta
Published: September 2022

Purpose:

Patients with Stickler syndrome are at high risk of giant retinal tears (GRTs) and detachments. Vitreoretinal interventions can reduce this risk, but there is presently no consensus about the optimal prophylactic approach. The aim of our study was to determine whether 360° laser prophylaxis is a safe and effective procedure to prevent GRT detachments in patients with Stickler syndrome.

Methods:

Study subjects were recruited retrospectively through the databases of the vitreoretinal and ophthalmic genetic tertiary services in Manchester, United Kingdom. Clinical data were collected including on prophylactic intervention, the occurrence of retinal detachment, and the presence/type of retinal breaks.

Results:

One hundred thirteen eyes from 63 patients with Stickler syndrome were studied; 72.6% (82/113) of these eyes received 360° laser prophylaxis. Of these, 9% had a retinal detachment, but no GRTs occurred. Among the 27.4% (31/113) of eyes that had no prophylactic treatment, 23% suffered a retinal detachment and 42.9% of these were associated with a GRT.

Conclusion:

Patients who underwent laser prophylaxis had fewer retinal detachments and no GRTs during an average of 6.1 years of follow-up (median 5 years), suggesting that this is a safe and effective approach for individuals with Stickler syndrome.
Activation of HIF-1α/VEGF-A pathway by deferoxamine ameliorates retinal hypoxia in a rat subarachnoid hemorrhage model
Authors: Deji Qu-Zhen , Wang Xue , Zhaba Wang-Dui , Deng Hong-Ji , Han Yan-Ling , Gao Sheng-Qing , Liu Xi-Lin , Zhou Meng-Liang
Published: September 2022

Background and purpose

Subarachnoid hemorrhage (SAH) is associated with sustained vasoconstriction in retinal vessels and vasoconstriction leads to retinal ischemia and hypoxia. Our previous finding also revealed the changes in hypoxia-related elements in the retina after SAH, further lending weight to the hypothesis that retinal vasospasm and hypoxia after SAH. Deferoxamine is a high-affinity iron chelator with reported neuroprotective effects against stroke. Here, we aimed to explore the effects of deferoxamine on retinal hypoxia after SAH.

Methods

SAH was established and deferoxamine was injected intraperitoneally for 3 days in the treatment group. To detect retinal new vessels, platelet endothelial cell adhesion molecule (CD31) was labeled by immunofluorescence and immunohistochemistry. Furthermore, the effects of deferoxamine on the expression of vascular endothelial growth factor A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) were revealed by western blot analysis.

Results

The immunofluorescence and immunohistochemical staining of CD31 revealed a marked increase in new vessels in the retinal ganglion cell layer after deferoxamine treatment. By western blot analysis, HIF-1α and VEGF-A increased gradually in the first day and then rebounded to a new level on day 7. A deferoxamine-induced increase in HIF-1α/VEGF-A expression was also confirmed by western blot.

Conclusions

Our findings suggest that modulating the application of deferoxamine may offer therapeutic approaches to alleviate retinal complications after SAH.
Exploring the effect of group schema therapy and comorbidity on the treatment course of personality disorders
Authors: Koppers David , Van Henricus L. , Peen Jaap , Dekker Jack J.M.
Published: September 2022

Purpose of review

To provide an update of outcome studies of schema group therapy for personality disorders and the effect of comorbidity in order to explore whether schema group therapy might be effective for this patient group and what dosage is required.

Recent findings

Studies of short-term schema group therapy for personality disorders with or without comorbidity show moderately effective results but the majority of patients fail to achieve full remission from global psychological symptom distress. Preliminary findings revealed that those unremitted patients might benefit from 40 to 60 sessions. Patients with severe personality disorders (such as borderline personality disorders) seem to need longer and/or more intensive treatment dosage to recover.

We advocate short-term schema therapy in groups as a valuable first step in a stepped-care programme for patients with moderate personality disorders and comorbidity.

Treatment extension or treatment intensification may be indicated in patients who do not recover. Patients with severe personality disorders seem to require long-term outpatient group treatment, with a combination of group and individual treatment being preferable. High-quality randomized controlled trials are needed in order to determine which treatment dosage is necessary for whom.
Dissociative episode and panic attacks triggered by pitolisant in a narcoleptic patient
Authors: Brunetti Valerio , Marotta Jessica , Simoncini Malucelli Giorgia , Marano Giuseppe , Mazza Marianna , Della Marca Giacomo
Published: September 2022

Pitolisant is a histamine 3-receptor antagonist/inverse agonist effective and safe for the treatment of excessive daytime sleepiness and cataplexy in narcolepsy. We report a 19-year-old woman affected by narcolepsy type 1 who presented panic attacks and dissociative symptoms induced by pitolisant. The patient medical history was unremarkable except that for familiarity for anxiety disorder and chronic insomnia. Moreover, a detailed psychometric evaluation revealed a profile of low resilience, a severe grade of depression, an anxiety trait and a propension to dissociative symptoms. Our report suggests that caution should be used in patients with predisposing factors to psychiatric disorders, especially during the first period of treatment with pitolisant. In consideration of the high prevalence of psychiatric comorbidities in narcolepsy, it seems worth to carefully investigate psychiatric background of narcoleptic patients.
Programmed cell death-1 receptor mediated regulation of Tbet+ NK1.1− Innate Lymphoid Cells within the Tumor Microenvironment
Authors: Lim Jing Xuan , Lai Chester Y. , Mallett Grace E. , McDonald David , Hulme Gillian , Laba Stephanie , Shapanis Andrew , Payne Megan , Patterson Warren , Alexander Michael , Coxhead Jonathan , Filby Andrew , Plummer Ruth , Lovat Penny E. , Sciume Giuseppe , Healy Eugene , Amarnath Shoba
Published: September 2022

Innate Lymphoid Cells (ILCs) play a key role in tissue mediated immunity and can be controlled by co-receptor signaling. Here we define a subset of ILCs that are Tbet+NK1.1− and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet+NK1.1−ILCs. PD-1 significantly controlled the proliferation and function of Tbet+NK1.1−ILCs in multiple murine and human tumors. We found tumor derived lactate enhanced PD-1 expression on Tbet+NK1.1−ILCs within the TME, which resulted in dampened mTOR signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1 deficient Tbet+NK1.1−ILCs expressed significantly increased IFNγ, granzyme B and K. Furthermore, PD1 deficient Tbet+NK1.1− ILCs contributed towards diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate anti-tumor responses of Tbet+NK1.1−ILCs within the tumor microenvironment.

Highlights

Tbet+NK1.1− ILCs are found in WT and PD1 ko mice

PD-1 is expressed on Tbet+NK1.1− ILC1s within multiple TME

PD-1 controls the proliferation and function of Tbet+NK1.1− ILCs within the tumor microenvironment by modulating fatty acid metabolism.

PD-1 regulates the proliferation of human Tbet+ ILC1s in human cutaneous squamous cell carcinoma (cSCC) and melanoma tumor microenvironment.
Microbiome and resistome dynamics along a sewage-effluent-reservoir continuum underline the role of natural attenuation in effluent receiving reservoirs
Authors: Leão Inês , Khalifa Leron , Gallois Nicolas , Vaz-Moreira Ivone , Klümper Uli , Youdkes Daniel , Palmony Shaked , Dagai Lotan , Berendonk Thomas U. , Merlin Christophe , Manaia Célia M. , Cytryn Eddie
Published: September 2022

This study assessed temporal dynamics of total and antibiotic resistant fecal bacterial indicators and antibiotic resistance genes (ARG) along a sewage-effluent-reservoir continuum, in an experimental system consisting of a sewage-fed membrane-aerated bioreactor (MABR) whose effluent fed a 4500 L polypropylene basin that mimicked an effluent storage reservoir. We applied a multidisciplinary approach that coupled physicochemical analyses, cultivation of total and cefotaxime-resistant E. coli, microbiome (bacterial and eukaryotic) analysis and qPCR/ddPCR quantification of selected ARGs. Total and cefotaxime-resistant E. coli loads dropped by approximately 1.5 log units in both the MABR and the reservoir, but the relative reduction (normalized to 16S rRNA genes) in both E. coli and ARGs was higher in the reservoir. Reservoir microbiomes were significantly different from those in the MABR, and were characterized by temporal shifts and periodic algal (Chlorophyta) blooms that were coupled to oxygen and pH fluctuations. Collectively, the data indicates that the decrease in E. coli and ARGs in the MABR was primarily facilitated by sludge removal, whereas in the reservoir, it was predominantly associated with microbial community shifts. The study highlights the capacity of ecological interactions in mitigating antibiotic resistance in both engineered and natural ecosystems.

Importance

Antibiotic resistance is considered one of the most significant public health predicaments of the 21st century, and there is growing evidence that anthropogenically impacted environments such as those receiving raw and treated sewage can contribute to this phenomenon. In this study, we evaluated the dynamics of total and antibiotic resistant fecal pathogen indicators and antibiotic resistance genes along a sewage-treated wastewater-effluent reservoir continuum, concurrent to evaluation of microbial community composition and physicochemical parameters. Results indicate that both the treatment bioreactor and the effluent storage reservoir removed resistant bacteria and antibiotic resistance encoding genes. However, in the reactor removal was primarily linked to physical processes, whereas in the storage reservoir it appeared to be strongly facilitated by ecological interactions. The study highlights the capacity of aquatic ecosystems to alleviate antibiotic resistance, and suggests that ecological processes in aquatic ecosystems can be harnessed to mitigate antibiotic resistance.
Piperacillin-Tazobactam Resistance Mechanisms in Escherichia coli and Identification of a CTX-M-255 β-Lactamase Selectively Conferring Resistance to Penicillin/β-Lactamase Inhibitor Combinations
Authors: Andreasen Minna Rud , Hansen Katrine Hartung , Pedersen Martin Schou , Mollerup Sarah , Jelsbak Lotte , Schønning Kristian
Published: September 2022

Piperacillin/tazobactam (TZP) is a widely used penicillin/β-lactamase inhibitor combination with broad antimicrobial activity. Recently, Escherichia coli strains resistant to TZP but susceptible to third generation cephalosporins (TZP-R/3GC-S isolates) have been increasingly identified. Here, we investigated resistance mechanisms underlying the TZP-R/3GC-S phenotype in clinical E. coli isolates.

A total of 29 TZP-R/3GC-S E. coli isolates were retrieved from urinary cultures and subjected to whole genome sequencing. Resistance to TZP was confirmed by minimum inhibitory concentration determination. β-lactamase activity in the presence and absence of tazobactam was determined to identify hyperproduction of β-lactamase and assess susceptibility to tazobactam inhibition. A previously unrecognized β-lactamase was identified and cloned to determine its resistance profile.

Four different resistance mechanisms underlying the TZP-R/3-GC phenotype were identified: 1) In 18 out of 29 isolates (62%) β-lactamase production was increased and in 16 of these either strong alternative promoters or increased gene copy numbers of blaTEM-1 or blaSHV-1 were identified, 2) seven isolates (24%) produced blaOXA-1, 3) three isolates (10%) produced inhibitor-resistant TEM-β-lactamases, and 4) a single isolate (3%) harboured a blaCTX-M gene as the only β-lactamase present. This β-lactamase, CTX-M-255, only differs from CTX-M-27 by a G239S amino acid substitution. In contrast to CTX-M-27, CTX-M-255 conferred resistance to penicillin/β-lactamase inhibitor combinations but remained susceptible to cephalosporins.

In conclusion, hyperproduction of blaTEM was the most prevalent mechanism of TZP-resistance underlying the TZP-R/3GC-S phenotype followed by production of blaOXA-1 and inhibitor-resistant TEM-β-lactamases. Furthermore, we identified a previously unrecognized CTX-M-β-lactamase, CTX-M-255 that was resistant to β-lactamase inhibitors.
Genome-scale mapping of DNA damage suppressors identifies GNB1L as essential for ATM and ATR biogenesis
Authors: Zhao Yichao , Tabet Daniel , Contreras Diana Rubio , Kousholt Arne Nedergaard , Weile Jochen , Melo Henrique , Hoeg Lisa , Coté Atina G. , Lin Zhen-Yuan , Setiaputra Dheva , Jonkers Jos , Gingras Anne-Claude , Herreros Fernando Gómez , Roth Frederick P. , Durocher Daniel
Published: September 2022

To maintain genome integrity, cells must avoid DNA damage by ensuring the accurate duplication of the genome and by having efficient repair and signaling systems that counteract the genome-destabilizing potential of DNA lesions. To uncover genes and pathways that suppress DNA damage in human cells, we undertook genome-scale CRISPR/Cas9 screens that monitored the levels of DNA damage in the absence or presence of DNA replication stress. We identified 160 genes in RKO cells whose mutation caused high levels of DNA damage in the absence of exogenous genotoxic treatment. This list was highly enriched in essential genes, highlighting the importance of genomic integrity for cellular fitness. Furthermore, the majority of these 160 genes are involved in a limited set of biological processes related to DNA replication and repair, nucleotide biosynthesis, RNA metabolism and iron sulfur cluster biogenesis, suggesting that genome integrity may be insulated from a wide range of cellular processes. Among the many genes identified and validated in this study, we discovered that GNB1L, a schizophrenia/autism-susceptibility gene implicated in 22q11.2 syndrome, protects cells from replication catastrophe promoted by mild DNA replication stress. We show that GNB1L is involved in the biogenesis of ATR and related phosphatidylinositol 3-kinase-related kinases (PIKKs) through its interaction with the TTT co-chaperone complex. These results implicate PIKK biogenesis as a potential root cause for the neuropsychiatric phenotypes associated with 22q11.2 syndrome. The phenotypic mapping of genes that suppress DNA damage in human cells therefore provides a powerful approach to probe genome maintenance mechanisms.
Effects of microtubule length and crowding on active microtubule network organization
Authors: Chew Wei-Xiang , Henkin Gil , Nédélec François , Surrey Thomas
Published: September 2022

Active filament networks can organize into various dynamic architectures driven by crosslinking motors. Densities and kinetic properties of motors and microtubules have been shown previously to determine active microtubule network self-organization, but the effects of other control parameters are less understood. Using computer simulations, we study here how microtubule lengths and crowding effects determine active network architecture and dynamics. We find that attractive interaction mimicking crowding effects or long microtubules both promote the formation of nematic networks of extensile bundles instead of contractile networks. When microtubules are very long and the network is highly percolated, a new isotropically motile network state resembling a ‘crawling mesh’ is predicted. Usingin vitroreconstitutions, we confirm the existence of this crawling mesh experimentally. These results provide a better understanding of how active microtubule network organization can be controlled, with implications for cell biology and active materials in general.
Astrocytic synapse elimination controls ocular dominance plasticity
Authors: Lee Joon-Hyuk , Kim Jinah , Kim Minjin , Shin Chi-Hong , Chung Won-Suk
Published: September 2022

Ocular dominance plasticity (ODP) is a representative form of experience-dependent synaptic plasticity observed in the primary visual cortex (V1). However, the cellular mechanisms and physiological roles of synapse elimination in ODP are largely unknown. Here, we show that astrocytic phagocytosis of thalamo-cortical synapses in V1 is a critical mediator of ODP. We found that astrocytes, but not microglia, start to engulf thalamo-cortical synapses within 24 hours after monocular deprivation and that astrocytic synapse elimination is highly selective for synapses from the deprived eye, as revealed by AAV1-mediated trans-synaptic anterograde tracing of synapse phagocytosis reporters. Importantly, mice without the Megf10 phagocytic receptor in astrocytes exhibit deficits in eliminating the synapses from the deprived eye, leading to the failure to reduce the number of thalamo-cortical synapses after monocular deprivation. Remarkably, Megf10-deficient animals show severe defects in monocular deprivation-induced cortical synapse remodeling and subsequent expansion of the thalamo-cortical circuitry from the nondeprived eye. Taken together, our data show that astrocytic synapse elimination through MEGF10 is one of the key components in ODP, revealing the physiological importance of astrocytic phagocytosis in experience-dependent synaptic plasticity.
ErbB Signalling is a Potential Therapeutic Target for Vascular Lesions with Fibrous Component
Authors: Ilmonen Henna , Jauhiainen Suvi , Vuola Pia , Rasinkangas Heta , Pulkkinen Heidi H , Keränen Sara , Kiema Miika , Liikkanen Jade J , Laham-Karam Nihay , Laidinen Svetlana , Aavik Einari , Lappalainen Kimmo , Lohi Jouko , Aronniemi Johanna , Örd Tiit , Kaikkonen Minna U , Salminen Päivi , Tukiainen Erkki , Ylä-Herttuala Seppo , Laakkonen Johanna P
Published: September 2022

Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to high recurrence of the lesions more effective therapies are needed.
Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth.
Results: We report, for the first time, expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of VEGF-A paracrinally, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts.
Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component.
Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, and Department of Musculosceletal and Plastic Surgery, Helsinki University Hospital.
A genetically-encoded three-colour stress biosensor reveals multimodal response at single cell level and spatiotemporal dynamics of biofilms
Authors: Zoheir Ahmed E. , Sobol Morgan S. , Ordoñez-Rueda Diana , Kaster Anne-Kristin , Niemeyer Christof M. , Rabe Kersten S.
Published: September 2022

The plethora of chemical, physical, and biological factors that can damage microbial cells has triggered the evolution of sophisticated stress response (SR) mechanisms. While individual SR pathways have been monitored with genetically encoded reporters, sensor concepts for the detection of multimodal effects of stressing conditions in living microorganisms are still lacking. Orthogonally detectable red, green, and blue fluorescent proteins combined in a single vector system, dubbed RGB-S reporter, enable the simultaneous, independent and real-time analysis of the stress response in Escherichia coli to physiological stress, genotoxicity, and cytotoxicity. The sensor system can be read out via conventional fluorescence microscopy or microtiter plate analysis and can also be combined with Fluorescent Activated Cell Sorting (FACS) and subsequent transcriptome analysis. Various stressors, such as the biotechnologically relevant 2-propanol, lead to the activation of one, two or all three SRs, which can have a significant impact on non-stress-related metabolic pathways. Implemented in microfluidic cultivation with confocal fluorescence microscopy imaging, the technology enabled spatiotemporal analysis of live biofilms to discover stratified subpopulations of bacteria with heterogeneous stress responses.
R2Dtool: Integration and visualization of isoform-resolved RNA features
Authors: Sethi Aditya J. , Acera Mateos Pablo , Hayashi Rippei , Shirokikh Nikolay , Eyras Eduardo
Published: September 2022

Long-read RNA sequencing enables the mapping of RNA modifications, structures, and protein-interaction sites at the resolution of individual transcript isoforms. To understand the functions of these RNA features, it is critical to analyze them in the context of transcriptomic and genomic annotations, such as open reading frames and splice junctions. To enable this, we have developed R2Dtool, a bioinformatics tool that integrates transcript-mapped information with transcript and genome annotations, allowing for the isoform-resolved analytics and graphical representation of RNA features in their genomic context. We illustrate R2Dtool’s capability to integrate and expedite RNA feature analysis using epitranscriptomics data. R2Dtool facilitates the comprehensive analysis and interpretation of alternative transcript isoforms.

R2Dtool is freely available under the MIT license at:https://github.com/comprna/R2Dtool.
Identification of 2-amino benzothiazoles with bactericidal activity againstMycobacterium tuberculosis
Authors: Bonnett Shilah , Jee Jo-Ann , Chettiar Somsundaram , Ovechkina Yulia , Korkegian Aaron , Greve Eric , Odingo Joshua , Parish Tanya
Published: September 2022

We identified an amino-benzothiazole scaffold from a whole cell screen against recombinantMycobacterium tuberculosisunder expressing the essential signal peptidase LepB. The seed molecule had two-fold higher activity against the LepB hypomorph. Through a combination of purchase and chemical synthesis we explored the structure activity relationship for this series; 34 analogs were tested for anti-tubercular activity and for cytotoxicity against eukaryotic cells. We identified molecules with improved potency and reduced cytotoxicity. However, molecules did not appear to target LepB directly and did not inhibit protein secretion. Key compounds showed good permeability, low protein binding, and lack of CYP inhibition, but metabolic stability was poor with short half-lives. The seed molecule showed good bactericidal activity against both replicating and non-replicating bacteria, as well as potency against intracellularM. tuberculosisin murine macrophages. Overall, the microbiological properties of the series are attractive if metabolic stability can be improved, and identification of the target could assist in development of this series.
Spurious off-target signals from potential lncRNAs by 10X Visium probes
Authors: Prakrithi P. , Juwayria  , Jain Deepali , Malik Prabhat Singh , Gupta Ishaan
Published: September 2022

Spatial transcriptomics has revolutionized molecular profiling of tissues in a spatial context, especially in the study of cancer heterogeneity. 10X Genomics facilitates spatial gene expression profiling platforms to help work with fresh-frozen (FF) and formalin fixed paraffin embedded (FFPE) tissues. FF analysis is based on polyA capture of RNAs while FFPE analysis uses a pre-designed set of probes to capture transcripts of coding genes. Previously, we used FFPE spatial data as a ‘negative control’ in a study to identify novel non-coding RNAs in FF data. Interestingly, we find and report that certain target probes used in FFPE show off-target signals from lncRNAs. The Space Ranger pipeline of 10X Visium counts the expression of these potential off-targets to be that of the corresponding target gene, some of which have known implications in cancer and its diagnosis. Therefore, relying on this technology is not ideal to investigate expression of the genes reported in this study. We hereby recommend excluding those genes in any downstream analysis of FFPE datasets and to design probes with better specificity, considering the sequence similarity between genes and non-coding RNAs.