bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning from health information challenges in the Central African Republic: where documenting health and humanitarian needs requires fresh approaches
Authors: Kuehne Anna , Roberts Leslie 
Published: September 2021

AbstractThe Central African Republic (CAR) is one of the world’s poorest and most fragile countries. Maybe there is no nation on the planet where the official health statistics are so poor. Evidence presented in this Conflict and Health themed collection to document humanitarian needs in CAR, suggests that UN statistics dramatically under-estimate the birth and death rates in conflict settings. To be current and valid, health indicator data in violent settings require more frequent measurement, more triangulation and granular exploration, and creative approaches based on few assumptions. In a world increasingly dependent on model driven data—data often inaccurate in conflict settings—we hope that this collection will allow those service providers and researchers operating in CAR to share their work and help us better learn how to learn. We particularly invite research from professionals working in CAR that documents humanitarian needs and presents indicators of population health where official estimates might not articulate the true extent of the health crisis.
Endosomal traffic and glutamate synapse activity are increased in VPS35 D620N mutant knock-in mouse neurons, and resistant to LRRK2 kinase inhibition
Authors: Kadgien Chelsie A. , Kamesh Anusha , Milnerwood Austen J. 
Published: September 2021

AbstractVacuolar protein sorting 35 (VPS35) regulates neurotransmitter receptor recycling from endosomes. A missense mutation (D620N) in VPS35 leads to autosomal-dominant, late-onset Parkinson’s disease. Here, we study the basic neurobiology of VPS35 and Parkinson’s disease mutation effects in the D620N knock-in mouse and the effect of leucine-rich repeat kinase 2 (LRRK2) inhibition on synaptic phenotypes. The study was conducted using a VPS35 D620N knock-in mouse that expresses VPS35 at endogenous levels. Protein levels, phosphorylation states, and binding ratios in brain lysates from knock-in mice and wild-type littermates were assayed by co-immunoprecipitation and western blot. Dendritic protein co-localization, AMPA receptor surface expression, synapse density, and glutamatergic synapse activity in primary cortical cultures from knock-in and wild-type littermates were assayed using immunocytochemistry and whole-cell patch clamp electrophysiology. In brain tissue, we confirm VPS35 forms complexes with LRRK2 and AMPA-type glutamate receptor GluA1 subunits, in addition to NMDA-type glutamate receptor GluN1 subunits and D2-type dopamine receptors. Receptor and LRRK2 binding was unaltered in D620N knock-in mice, but we confirm the mutation results in reduced binding of VPS35 with WASH complex member FAM21, and increases phosphorylation of the LRRK2 kinase substrate Rab10, which is reversed by LRRK2 kinase inhibition in vivo. In cultured cortical neurons from knock-in mice, pRab10 is also increased, and reversed by LRRK2 inhibition. The mutation also results in increased endosomal recycling protein cluster density (VPS35-FAM21 co-clusters and Rab11 clusters), glutamate transmission, and GluA1 surface expression. LRRK2 kinase inhibition, which reversed Rab10 hyper-phosphorylation, did not rescue elevated glutamate release or surface GluA1 expression in knock-in neurons, but did alter AMPAR traffic in wild-type cells. The results improve our understanding of the cell biology of VPS35, and the consequences of the D620N mutation in developing neuronal networks. Together the data support a chronic synaptopathy model for latent neurodegeneration, providing phenotypes and candidate pathophysiological stresses that may drive eventual transition to late-stage parkinsonism in VPS35 PD. The study demonstrates the VPS35 mutation has effects that are independent of ongoing LRRK2 kinase activity, and that LRRK2 kinase inhibition alters basal physiology of glutamate synapses in vitro.
Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia
Authors: Wang Guoling , Sun Xiaolei , Zuo Shiyu , Li Chuo , Niu Qing , Xia Yonghui , Meng Yuan , Liu Min , Fang Zihao , Yang Xi , Jiang Yanyu , Wang Sheng , Cui Haidong , Huang Huifang , Jiang Erlie , Zhou Dongming , Deng Qi , Pan Jing , Feng Xiaoming 
Published: September 2021

AbstractCD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.
How senior paramedics decide to cease resuscitation in pulseless electrical activity out of hospital cardiac arrest: a mixed methods study
Authors: Coppola Ali , Black Sarah , Endacott Ruth 
Published: September 2021

Abstract
Background
Evidenced-based guidelines on when to cease resuscitation for pulseless electrical activity are limited and support for paramedics typically defaults to the senior clinician. Senior clinicians include paramedics employed to work beyond the scope of clinical guidelines as there may be a point at which it is reasonable to cease resuscitation. To support these decisions, one ambulance service has applied a locally derived cessation of resuscitation checklist. This study aimed to describe the patient, clinical and system factors and examine senior clinician experiences when ceasing resuscitation for pulseless electrical activity.

Design and methods
An explanatory sequential mixed method study was conducted in one ambulance service in the South West of England. A consecutive sample of checklist data for adult pulseless electrical activity were retrieved from 1st December 2015 to 31st December 2018. Unexpected results which required exploration were identified and developed into semi-structured interview questions. A purposive sample of senior clinicians who ceased resuscitation and applied the checklist were interviewed. Content framework analysis was applied to the qualitative findings.

Results
Senior clinicians ceased resuscitation for 50 patients in the presence of factors known to optimise survival: Witnessed cardiac arrest (n = 37, 74%), bystander resuscitation (n = 30, 60%), defibrillation (n = 22, 44%), return of spontaneous circulation (n = 8, 16%). Significant association was found between witnessed cardiac arrest and bystander resuscitation (p = .00). Six senior clinicians were interviewed, and analysis resulted in four themes: defining resuscitation futility, the impact of ceasing resuscitation, conflicting views and clinical decision tools. In the local context, senior clinicians applied their clinical judgement to balance survivability. Multiple factors were considered as the decision to cease resuscitation was not always clear. Senior clinicians deviated from the checklist when the patient was perceived as non-survivable.

Conclusion
Senior clinicians applied clinical judgement to assess patients as non-survivable or when continued resuscitation was considered harmful with no patient benefit. Senior clinicians perceived pre-existing factors with duration of resuscitation and clinical factors known to optimise patient survival. Future practice could look beyond a set criteria in which to cease resuscitation, however, it would be helpful to investigate the value or threshold of factors associated with patient outcome.
ISOlation Procedure vs. conventional procedure during Distal Pancreatectomy (ISOP-DP trial): study protocol for a randomized controlled trial
Authors: Okada Ken-ichi , Kawai Manabu , Hirono Seiko , Sho Masayuki , Tani Masaji , Matsumoto Ippei , Yamada Suguru , Amano Ryosuke , Toyama Hirochika , Yamashita Yo-ichi , Gocho Takeshi , Shibuya Kazuto , Nagai Minako , Maehira Hiromitsu , Kamei Keiko , Ohira Go , Shirai Yoshihiro , Takami Hideki , Kimura Nana , Fukumoto Takumi , Baba Hideo , Kodera Yasuhiro , Nakao Akimasa , Shimokawa Toshio , Katsuda Masahiro , Yamaue Hiroki 
Published: September 2021

Abstract
Background
Radical antegrade modular pancreatosplenectomy (RAMPS) is an isolation procedure in pancreatosplenectomy for pancreatic body/tail cancer. Connective tissues around the bifurcation of the celiac axis are dissected, followed by median-to-left retroperitoneal dissection. This procedure has the potential to isolate blood and lymphatic flow to the area of the pancreatic body/tail and the spleen to be excised. This is achieved by division of the inflow artery, transection of the pancreas, and then division of the outflow vein in the early phases of surgery. In cases of pancreatic ductal adenocarcinoma (PDAC), the procedure has been shown to decrease intraoperative blood loss and increase R0 resection rate by complete clearance of the lymph nodes. This trial investigates whether the isolation procedure can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo distal pancreatosplenectomy (DPS) compared with those that undergo the conventional approach.

Methods/design
Patients with PDAC scheduled to undergo DPS are randomized before surgery to undergo either a conventional procedure (arm A) or to undergo the isolation procedure (arm B). In arm A, the pancreatic body, tail, and spleen are mobilized, followed by removal of the regional lymph nodes. The splenic vein is transected at the end of the procedure. The timing of division of the splenic artery (SA) is not restricted. In arm B, regional lymph nodes are dissected, then we transect the root of the SA, the pancreas, then the splenic vein. At the end of the procedure, the pancreatic body/tail and spleen are mobilized and removed. In total, 100 patients from multiple Japanese high-volume centers will be randomized. The primary endpoint is 2-year recurrence-free survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 resection rate, and overall survival.

Discussion
If this trial shows that the isolation procedures can improve survival with a similar R0 rate and with a similar number of lymph node dissections to the conventional procedure, the isolation procedure is expected to become a standard procedure during DPS for PDAC. Conversely, if there were no significant differences in endpoints between the groups, it would demonstrate justification of either procedure from surgical and oncological points of view.

Trial registration
UMIN Clinical Trials Registry UMIN000041381. Registered on 10 August 2020. ClinicalTrials.gov NCT04600063. Registered on 22 October 2020.
Engineering the substrate binding site of the hyperthermostable archaeal endo-β-1,4-galactanase from Ignisphaera aggregans
Authors: Muderspach Sebastian J. , Fredslund Folmer , Volf Verena , Poulsen Jens-Christian Navarro , Blicher Thomas H. , Clausen Mads Hartvig , Rasmussen Kim Krighaar , Krogh Kristian B. R. M. , Jensen Kenneth , Lo Leggio Leila 
Published: September 2021

Abstract
Background
Endo-β-1,4-galactanases are glycoside hydrolases (GH) from the GH53 family belonging to the largest clan of GHs, clan GH-A. GHs are ubiquitous and involved in a myriad of biological functions as well as being widely used industrially. Endo-β-1,4-galactanases, in particular hydrolyse galactan and arabinogalactan in pectin, a major component of the primary plant cell wall, with important functions in plant defence and application in the food and other industries. Here, we explore the family’s biological diversity by characterizing the first archaeal and hyperthermophilic GH53 galactanase, and utilize it as a scaffold for engineering enzymes with different product lengths.

Results
A galactanase gene was identified in the genome of the anaerobic hyperthermophilic archaeon Ignisphaera aggregans, and the isolated catalytic domain expressed and characterized (IaGal). IaGal presents the typical (βα)8 barrel structure of clan GH-A enzymes, with catalytic carboxylates at the end of the 4th and 7th barrel strands. Its activity optimum of at least 95 °C and melting point over 100 °C indicate extreme thermostability, a very advantageous property for industrial applications. If enzyme depletion is reduced, so is the need for re-addition, and thus costs. The main stabilizing features of IaGal compared to other structurally characterized members are π–π and cation–π interactions. The length of the substrate binding site—and thus produced oligosaccharide products—is intermediate compared to previously characterized galactanases. Variants inspired by the structural diversity in the GH53 family were rationally designed to shorten or extend the substrate binding groove, in order to modulate product length. Subsite-deleted variants produced shorter products than IaGal, as do the fungal galactanases inspiring the design. IaGal variants engineered with a longer binding site produced a less expected degradation pattern, though still different from that of wild-type IaGal. All variants remained extremely stable.

Conclusions
We have characterized in detail the most thermophilic endo-β-1,4-galactanase known to date and successfully engineered it to modify the degradation profile, while maintaining much of its desirable thermostability. This is an important achievement as oligosaccharide products length is an important property for industrial and natural GHs alike.
Predicting the spread and persistence of genetically modified dominant sterile male mosquitoes
Authors: Ickowicz Adrien , Foster Scott D. , Hosack Geoffrey R. , Hayes Keith R. 
Published: September 2021

AbstractBackgroundReproductive containment provides an opportunity to implement a staged-release strategy for genetic control of malaria vectors, in particular allowing predictions about the spread and persistence of (self-limiting) sterile and male-biased strains to be compared to outcomes before moving to (self-sustaining) gene-drive strains.MethodsIn this study, we: (i) describe a diffusion–advection–reaction model of the spread and persistence of a single cohort of male mosquitoes; (ii) elicit informative prior distributions for model parameters, for wild-type (WT) and genetically modified dominant sterile strains (DSM); (iii) estimate posterior distributions for WT strains using data from published mark-recapture-release (MRR) experiments, with inference performed through the Delayed-Rejection Adaptive Metropolis algorithm; and (iv) weight prior distributions, in order to make predictions about genetically modified strains using Bayes factors calculated for the WT strains.ResultsIf a single cohort of 5000 genetically modified dominant sterile male mosquitoes are released at the same location as previous MRR experiments with their WT counterparts, there is a 90% probability that the expected number of released mosquitoes will fall to < 1 in 10 days, and that by 12 days there will be a 99% probability that no mosquitoes will be found more than 150 m from the release location.ConclusionsSpread and persistence models should form a key component of risk assessments of novel genetic control strategies for malaria vectors. Our predictions, used in an independent risk assessment, suggest that genetically modified sterile male mosquitoes will remain within the locality of the release site, and that they will persist for a very limited amount of time. Data gathered following the release of these mosquitoes will enable us to test the accuracy of these predictions and also provide a means to update parameter distributions for genetic strains in a coherent (Bayesian) framework. We anticipate this will provide additional insights about how to conduct probabilistic risk assessments of stage-released genetically modified mosquitoes.Graphical abstract
Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma
Authors: Herviou Laurie , Ovejero Sara , Izard Fanny , Karmous-Gadacha Ouissem , Gourzones Claire , Bellanger Celine , De Smedt Eva , Ma Anqi , Vincent Laure , Cartron Guillaume , Jin Jian , De Bruyne Elke , Grimaud Charlotte , Julien Eric , Moreaux Jérôme 
Published: September 2021

Abstract
Background
Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention.

Results
Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment.

Conclusions
Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.
Comparison of weight per volume and protein nitrogen units in non-standardized allergen extracts: implications for prescribing subcutaneous immunotherapy
Authors: Dua Benny , Park Jane , Kim Harold 
Published: September 2021

AbstractBackgroundAllergen extracts used in subcutaneous immunotherapy can be standardized or non-standardized. Standardized extracts are available in specific biological potencies, presumably making their biological activity more consistent. The majority of allergen extracts are non-standardized and may have less consistent potencies. Non-standardized extracts are labeled as weight per volume or protein nitrogen units (PNUs). Neither method provides direct information regarding the extract’s biologic potency. The purpose of this study was to compare weight per volume versus PNU concentrations for 4 non-standardized allergen extracts prepared by two allergen manufacturers. The potencies were compared to current North American practice recommendations.MethodsThe weight per volume and PNU values were provided for 4 non-standardized extracts—birch, short ragweed, dog hair and Alternaria—from HollisterStier and Stallergenes Greer. Weight per volume and PNU concentrations were compared for each of these extracts from both manufacturers. From the raw data, we calculated the corresponding PNU values for a weight per volume of 1:100 and 1:200 for each extract. Similarly, we calculated the corresponding weight per volume including a range of PNU values, for 1000, 2000, 3000, 4000 and 5000 PNU/ml.ResultsBirch extract has low PNU concentration, below 5000, for a weight per volume of 1:200 for both HollisterStier and Stallergenes Greer. In contrast, for both HollisterStier and Stallergenes Greer ragweed extract, a weight per volume of 1:200 corresponds to a PNU concentration greater than 5000. Dog extract for a weight per volume of 1:200, and even for 1:100, corresponds to very low PNUs for both companies. For Alternaria, corresponding PNU concentrations for HollisterStier is low at only 500 while over 5000 for Stallergenes Greer.ConclusionsOur results show variability when comparing weight per volume and PNU concentrations for both Hollister-Stier and Stallergenes Greer products. We suggest selecting a PNU dose that corresponds to a weight per volume of 1:200 as this may improve patient safety. Our recommendations for starting PNU dose for the four non-standardized extracts are 1500 for birch, 5000 for ragweed, 25 for dog, and 500 for Alternaria when using HollisterStier products; 2300 for birch, 5000 for ragweed, 1200 for dog, and 5000 for Alternaria when using Stallergenes Greer products. If the starting PNU concentration is considerably below 5000 for a weight per volume of 1:200 slow up-titration is advised. Conversely, for PNU concentrations above 5000 for weight per volume of 1:200 we suggest a maintenance dose of 5000 PNU.