bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses
Authors: Mao Tianyang , Israelow Benjamin , Suberi Alexandra , Zhou Liqun , Reschke Melanie , Peña-Hernández Mario A , Dong Huiping , Homer Robert J. , Saltzman W. Mark , Iwasaki Akiko 
Published: January 2022

AbstractAs the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.One-sentence summaryBroad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.
Converting non-neutralizing SARS-CoV-2 antibodies targeting conserved epitopes into broad-spectrum inhibitors through receptor blockade
Authors: Weidenbacher Payton A.-B. , Waltari Eric , de los Rios Kobara Izumi , Bell Benjamin N. , Pak John E. , Kim Peter S. 
Published: January 2022

AbstractAll but one of the authorized monoclonal antibody-based treatments for SARS-CoV-2 are largely ineffective against Omicron, highlighting the critical need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective therapeutic antibodies target epitopes that are not highly conserved. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to antibodies that are known to be non-neutralizing, but which target highly conserved epitopes in the viral spike protein. These inhibitors, called Receptor-blocking conserved non-neutralizing Antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOC), including Omicron. Neutralization potency is dependent on both the binding and inhibitory ReconnAb components as activity is lost when the linker joining the two is severed. In addition, a bifunctional ReconnAb, made by linking ACE2 to a bispecific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad- spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
Patients’ satisfaction and quality of clinical laboratory services provision at public health facilities in northeast Ethiopia
Authors: Abebe Daniel Dagne , Temesgen Minwuyelet Maru , Abozin Addisu Tesfie , Zeleke Abebe Eyasu , Hassen Seid Legesse , Gebremichael Hailay Berhe 
Published: January 2022

AbstractPatient satisfaction is a key element of quality measures that has increasingly become acknowledged as an important tool for service improvement. This study aimed to assess the level of patients’ satisfaction and associated factors with clinical laboratory services provided at public health facilities. A cross-sectional study was conducted from May-June 2019 among clients attending 24 health centers and 8 hospitals, northeast Ethiopia. A total of 502 patients were selected using systematic random sampling. Patient’s satisfaction towards multiple aspects of laboratory services was assessed using structured exit interview questionnaire, on a rating scale of 1 (very dissatisfied) to 5 points (very satisfied). We assessed test availability and laboratory practices using facility inventory, stepwise accreditation audit checklist and blinded slide rechecking. Data were entered and analyzed using EpiData ver3.1 and STATA ver14.1. Multivariable logistic regression analysis was used to determine the association of factors with overall satisfaction. Overall, majority of the respondents (73.5%) were found to be satisfied. Lowest mean ratings were obtained for waiting area (3.3), and information provided on specimen collection (3.5) and on how and when to receive results (3.7). Patients were more likely to be satisfied in health centers (75.2%) than in hospitals (68.6%) (AOR=1.9, 95%CI: 1.0-3.6, p=0.036). Patients’ timely receipt of results (p=0.005) and laboratories’ accuracy of results (p< 0.025) also showed significant positive associations with satisfaction. In conclusion, there were specific areas of deficiency that were driving dissatisfaction, particularly in the larger hospital laboratories. Therefore, more and balanced emphasis should be given to the patients’ experiences, alongside technical quality improvements, to reduce the disparities and enhance the overall quality of care.
Functional proteomic profiling links deficient DNA clearance to mortality in patients with severe COVID-19 pneumonia
Authors: Aramburu Iker Valle , Hoving Dennis , Vernardis Spyros I. , Tin Martha , Demichev Vadim , Helbig Elisa Theresa , Lippert Lena , Stahl Klaus , Ioannou Marianna , Temkin Mia I. , White Matthew , Radbruch Helena , Ihlow Jana , Horst David , Chiesa Scott T. , Deanfield John E. , David Sascha , Bode Christian , Kurth Florian , Ralser Markus , Papayannopoulos Venizelos 
Published: January 2022

SummaryHyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Activity-based proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.
Acquired neutralizing breadth against SARS-CoV-2 variants including Omicron after three doses of mRNA COVID-19 vaccination and the vaccine efficacy
Authors: Furukawa Koichi , Tjan Lidya Handayani , Kurahashi Yukiya , Sutandhio Silvia , Nishimura Mitsuhiro , Arii Jun , Mori Yasuko 
Published: January 2022

ABSTRACTTo investigate the induction of neutralizing antibodies against Omicron after two and three vaccine doses in recipients of different ages. Physicians at Kobe University Hospital who had received the second dose of the BNT162b2 mRNA vaccine. At 2 months after the second vaccinations, the positive rate of neutralizing antibody against Omicron was 28%, and the titer was significantly lower than those against other variants, 11.8-fold and 3.6-fold lower than those against D614G and Delta, respectively. Unlike Delta, that positive rates of neutralizing antibody against Omicron were low in all age groups, and there was no significant difference in titers among age groups. Seven months after the 2nd dose, the positive rate of neutralizing antibody against Omicron decreased to 6%, but after the booster,3rd vaccination, it increased to 100%, and the titer was much higher than those at 2 and 7 months post-vaccination, 32-fold and 39-fold respectively. The booster vaccination effect was also observed in the younger at 41-fold, middle-aged at 43-fold, and older at 27-fold groups compared to the 7-month titers. Surprisingly, higher-than-predicted titers of the neutralizing antibodies against Omicron were induced after the booster vaccination regardless of recipient age, while this effect was not observed after two doses, indicating the induction of antibodies against common epitopes by the booster vaccination. Three doses can be confidently recommended to suppress the pandemic.
Historical records of plant-insect interactions in subarctic Finland
Authors: Zoller Leana , Knight Tiffany M. 
Published: January 2022

AbstractHistorical ecological records document the diversity and composition of communities decades or centuries ago and provide a valuable benchmark for modern comparisons. Historical datasets on plant-animal interactions allow for modern comparisons that examine the stability of species and interaction networks over long periods of time and in response to anthropogenic change. Here we present a curated dataset of interactions between plants and insects in subarctic Finland, generated from digitizing a historical document from the late 19th century and updating the taxonomy using currently accepted nomenclature. The resulting dataset contains 654 records of plant-insect interactions observed during the years 1895-1900, and includes 498 unique interactions between 86 plant species and 173 insect taxa. Syrphidae, Apidae and Muscidae were the insect families involved in most interactions, and interactions were most observed with the plant species Angelica archangelica, Salix caprea, and Chaerophyllum prescottii. Interaction data are available as csv-file and provide a valuable resource on plant-insect interactions over 120 years ago in a high latitude ecosystem that is undergoing rapid climate change.
The scotopic band: primate detailed scotopic vision and perceptual uncertainty
Authors: Barash Shabtai , Spivak Oleg , Thier Peter 
Published: January 2022

AbstractPrimates perceive detailed images in photopic (daylight) vision via a preferred-processing, high-acuity pathway, made up of a small photopic center (the fovea), and dedicated eye movements, whose function is to shift images of target objects to the fovea and keep them while foveal cones sense the image. Thus, the preferred processing pathway processes images serially, not in parallel. No such pathway is known for scotopic (night-light) vision or mesopic (twilight) vision – though details are informative in dim light, even vital; it remains unclear whether and how scotopic vision of details is accomplished. Here we show that primates do have a scotopic preferred-processing pathway. It consists of a ‘scotopic center’, located on a ‘scotopic band’, and eye movements that shift target images not to the fovea but directly to the scotopic center. In contrast to the stationary fovea, the scotopic center can relocate over the scotopic band. The scotopic center relocates to match changing visual conditions and contextual needs. Ambient light intensity is mapped monotonically onto the scotopic band, with mesopic vision at one end. The dimmer the light is, the more dorsal the scotopic center relocates on the scotopic band. Importantly, the scotopic center relocates (or ‘set’) not only in passive response to ambient light but also actively, driven by internal factors. In near-threshold conditions the scotopic center relocates to a more dorsal band location than in salient conditions. That the same relocation of the scotopic center can be instigated both by dimming the ambient light and by reducing the detectability of targets indicates that, at the core, the longitudinal axis of the scotopic band encodes the level of perceptual uncertainty.
Inference and Uncertainty Quantification of Stochastic Gene Expression via Synthetic Models
Authors: Öcal Kaan , Gutmann Michael U. , Sanguinetti Guido , Grima Ramon 
Published: January 2022

AbstractEstimating uncertainty in model predictions is a central task in quantitative biology. Biological models at the single-cell level are intrinsically stochastic and nonlinear, creating formidable challenges for their statistical estimation which inevitably has to rely on approximations that trade accuracy for tractability. Despite intensive interest, a sweet spot in this trade off has not been found yet. We propose a flexible procedure for uncertainty quantification in a wide class of reaction networks describing stochastic gene expression including those with feedback. The method is based on creating a tractable coarse-graining of the model that is learned from simulations, asynthetic model, to approximate the likelihood function. We demonstrate that synthetic models can substantially outperform state-of-the-art approaches on a number of nontrivial systems and datasets, yielding an accurate and computationally viable solution to uncertainty quantification in stochastic models of gene expression.
Prior exposure to speech rapidly modulates cortical processing of high-level linguistic structure
Authors: Meng Qingqing , Li Hegner Yiwen , Giblin Iain , McMahon Catherine , Johnson Blake W 
Published: January 2022

AbstractNeural activity has been shown to track hierarchical linguistic units in connected speech and these responses can be directly modulated by changes in speech intelligibility caused by spectral degradation. In the current study, we manipulate prior knowledge to increase the intelligibility of physically identical speech sentences and test the hypothesis that the tracking responses can be enhanced by this intelligibility improvement. Cortical magnetoencephalography (MEG) responses to intelligible speech followed by either the same (matched) or different (unmatched) unintelligible speech were measured in twenty-three normal hearing participants. Driven by prior knowledge, cortical coherence to “abstract” linguistic units with no accompanying acoustic cues (phrases and sentences) was enhanced relative to the unmatched condition, and was lateralized to the left hemisphere. In contrast, cortical responses coherent to word units, aligned with acoustic onsets, were bilateral and insensitive to contextual information changes. No such coherence changes were observed when prior experience was not available (unintelligible speech before intelligible speech). This dissociation suggests that cerebral responses to linguistic information are directly affected by intelligibility, which in turn are powerfully shaped by physical cues in speech. These results provide an objective and sensitive neural index of speech intelligibility, and explain why previous studies have reported no effect of prior knowledge on cortical entrainment.
PPMO-mediated exon skipping induces uniform sarcolemmal dystrophin rescue with dose-dependent restoration of circulating microRNA biomarkers and muscle biophysical properties
Authors: Chwalenia Katarzyna , Oieni Jacopo , Zemła Joanna , Lekka Małgorzata , Ahlskog Nina , Coenen-Stass Anna M.L. , McClorey Graham , Wood Matthew J.A. , Lomonosova Yulia , Roberts Thomas C. 
Published: January 2022

AbstractDuchenne muscular dystrophy (DMD) is a paediatric muscle-wasting disorder caused by genetic loss of the gene encoding the dystrophin protein. Therapies that restore dystrophin expression are presumed to correct the disease, with antisense-mediated exon skipping being the leading approach. In this study, we aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform dystrophin localization, together with correction of putative DMD serum and muscle biomarkers. To this end, dystrophin-deficient mdx mice were treated with a PPMO (Pip9b2-PMO) designed to induce Dmd exon 23 skipping and dystrophin rescue at single, ascending intravenous doses (3, 6, or 12 mg/kg) and sacrificed two weeks later. Dose-dependent exon skipping and dystrophin protein restoration were observed. Importantly, dystrophin expression was uniformly distributed at the sarcolemma of corrected myofibers at all doses. The abundance of serum microRNA biomarkers (i.e. miR-1a-3p, miR-133a-3p, miR-206-3p, miR-483-3p) and creatinine kinase were restored towards wild-type levels after treatment in a dose-dependent manner. All biomarkers were strongly anti-correlated with both exon skipping level and dystrophin expression. Dystrophin rescue was also strongly positively correlated with muscle stiffness (i.e. Young’s modulus) as determined by atomic force microscopy (AFM) nanoindentation assay. These data demonstrate that PPMO-mediated exon skipping generates myofibers with uniform dystrophin expression, and that both serum miRNA biomarkers and muscle AFM have potential utility as pharmacodynamic biomarkers of dystrophin restoration therapy in the context of DMD.
Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD
Authors: Hanson Britt , Stenler Sofia , Ahlskog Nina , Chwalenia Katarzyna , Svrzikapa Nenad , Coenen-Stass Anna M. L. , Weinberg Marc S. , Wood Matthew J. A. , Roberts Thomas C. 
Published: January 2022

AbstractDuchenne muscular dystrophy (DMD) is the most prevalent inherited myopathy affecting children, caused by genetic loss of the gene encoding the dystrophin protein. There are currently four FDA-approved drugs for DMD that aim to restore expression of dystrophin by exon skipping using splice switching oligonucleotides. While these therapies require lifelong repeat administration, recent advancements in gene editing technologies have raised the possibility of achieving ‘permanent exon skipping’, and thereby curing the disease with a single treatment. Here we have investigated the use of the Staphylococcus aureus CRISPR/Cas9 system and a double-cut strategy, delivered using a pair of AAV9 vectors, for dystrophin restoration in the severely-affected dystrophin/utrophin double knock-out (dKO) mouse. Single guide RNAs were designed to induce double-strand DNA breaks on either side of Dmd exon 23, such that the intervening exon 23 sequence is excised when the flanking intronic regions are joined via the non-homologous end joining repair pathway. Exon 23 deletion was confirmed at the DNA level by PCR and Sanger sequencing, and at the RNA level by RT-qPCR. Restoration of dystrophin protein expression was demonstrated by western blot and immunofluorescence staining in mice treated via either intraperitoneal or intravenous routes of delivery. Dystrophin restoration was most effective in the diaphragm, where a maximum of 5.7% of wild-type dystrophin expression was observed. CRISPR treatment was insufficient to extend lifespan in the dKO mouse, and dystrophin was expressed in a within-fiber patchy manner in skeletal muscle tissues. Further analysis revealed a plethora of non-productive DNA repair events, including AAV genome integration at the CRISPR cut sites. This study highlights potential challenges for the successful development of CRISPR therapies in the context of DMD.
Mouse Nuclear RNAi-defective 2 Promotes Splicing of Weak 5’ Splice Sites
Authors: Flemr Matyas , Schwaiger Michaela , Hess Daniel , Iesmantavicius Vytautas , Tuck Alex Charles , Mohn Fabio , Bühler Marc 
Published: January 2022

ABSTRACTRemoval of introns during pre-mRNA splicing, which is central to gene expression, initiates by base pairing of U1 snRNA with a 5’ splice site (5’SS). In mammals, many introns contain weak 5’SSs that are not efficiently recognized by the canonical U1 snRNP, suggesting alternative mechanisms exist. Here, we develop a cross-linking immunoprecipitation coupled to a high-throughput sequencing method, BCLIP-seq, to identify NRDE2 (Nuclear RNAi defective-2) and CCDC174 (Coiled-Coil Domain-Containing 174) as novel RNA-binding proteins in mouse ES cells that associate with U1 snRNA and unspliced 5’SSs. Both proteins bind directly to U1 snRNA independently of canonical U1 snRNP specific proteins, and they are required for the selection and effective processing of weak 5’SSs. Our results reveal that mammalian cells use non-canonical splicing factors bound directly to U1 snRNA to effectively select suboptimal 5’SS sequences in hundreds of genes, promoting proper splice site choice and accurate pre-mRNA splicing.
LET-dependence of radiation-induced makers of Immunogenic Cell Death in human cancer cell lines
Authors: Ponnaiya Brian , LoMastro Anthony , Grabham Peter W. , Garty Guy , Harken Andrew D. , Amundson Sally A. , Hillman Elizabeth M.C. , Brenner David J. 
Published: January 2022

ABSTRACTPurposeIt has been suggested that heavy-ion radiation therapy may contribute to the control of distal metastases. These distant responses may include immune cell activation. Immunostimulation resulting from radiation-induced immunogenic cell death (ICD) of cancer cells, leads to the recruitment of anti-tumor T cells. Specific markers of ICD include translocation of calreticulin (CRT) and extracellular release of high mobility group box 1 protein (HMGB1), and ATP. However, the LET dependence of these effects remains unknown.Materials and MethodsExpression of the molecular indicators described above were tested in a panel of human cancer cell lines, that included pancreatic cancer (Panc1 and Paca2), glioblastoma (U87 and LN18) and melanoma (HTB129 and SK-Mel5). Cells were irradiated with 5 Gy of particles spanning a range of LETs, from 10 KeV/μm to 150 KeV/μm and assayed for relocalization of calreticulin and release of HMGB1 and ATP were assayed 24 hours later.ResultsIn the pancreatic cancer cell lines (Panc1 and Paca2) there was a continued increase in the membrane relocalization of calreticulin as a function of increasing LET up to 150 KeV/μm. The melanoma cell lines, HTB129 and Sk-Mel5 showed similar patterns. In contrast, calreticulin levels were higher, but not LET-dependent, in irradiated U87 and LN18 (glioblastoma) lines. With the exception of the response in Paca2, increases in LET correlated with increases in HMGB1 that seemed to peak at 100 KeV/μm and then either remain unchanged or decrease at 150 KeV/μm. while the ATP levels were elevated in media from some of the irradiated groups, there were no clear patterns either by cell type or LET.ConclusionsOur results indicate that at equal doses, although there is an overall trend of increases in the responses to increasing LETs, there are significant cell line-specific differences in the patterns of expression of these key ICD markers.
Polymorphism, polytypism and modular aspect of compounds with the general formula A
2
M
3(TO4)4 (A = Na, Rb, Cs, Ca; M = Mg, Mn, Fe3+, Cu2+; T = S6+, P5+): order–disorder, topological description and DFT calculations
Authors: Aksenov Sergey , Antonov Andrey , Deyneko Dina , Krivovichev Sergey , Merlino Stefano 
Published: January 2022

The crystal structure of Na2Mn3(SO4)4 [unit-cell parameters a = 14.8307 (18), b = 9.9107 (18), c = 8.6845 (12) Å, space group Cmc21] displays order–disorder (OD) character and can be described using the OD groupoid family, more precisely a family of OD structures built up by two types of non-polar layers, with layer symmetry P(m)c21 (L
2n+1 type) and P(b)cm (L
2n
type) (category IV). A new hypothetical MDO2 polytype has been proposed and the geometry optimization demonstrates its reasonability as another possible stable polytype. Compounds Na2Mn3–x
Mg
x
(SO4)4 with the unit-cell parameters a ∼ 29.2–29.7 Å, b ∼ 9.5–9.9 Å, c ∼ 8.7 Å and space group Pbca can be described in terms of modularity as a sequence of A, S
1 and S
2 modules:…|AS
1
AS
2
AS
1
AS
2|… or (AS
1
AS
2), together with MDO1 (AS
1
AS
1) and MDO2 (AS
2
AS
2). The crystal structures of itelmenite, NaCaFe3+
3(PO4)4, and Ca2MgFe3+
2(PO4)4 are crystal-chemical isotypic to Na2Mn3–x
Mg
x
(SO4)4 and should be considered as (A*S
1
A*S
2) derivatives of the (AS
1
AS
2)-type structure.