bluuebunny/crossref_metadata_2025 huggingface dataset:
Ameliorative impact of herbal formulation —Majoon-Dabeed-ul-ward and Sharbat-e-Deenar against CCl4 induced liver toxicity via regulation of antioxidant enzymes and oxidative stress
Authors: Shakya Arvind Kumar , Sharma Neetu , Bhadauria Monika , Nirala Satendra Kumar , Shrivastava Sadhana , Shukla Sangeeta
Published: August 2022

Polyherbal Unani formulations have been used in the treatment of liver diseases for a long time. (Ibrahim M, Khaja MN, Aara A, Khan AA, Habeeb MA, Devi YP, Narasu ML, Habibullah CM. Hepatoprotective activity of Sapindus mukorossi and Rheum emodi extracts: in vitro and in vivo studies. World J Gastroenterol. 2008:14:2566–2571.) The aim of the present study was to investigate comparative hepatoprotective potential of Majoon-e-Dabeed-ul-ward (MD) and Sharbat-e-Deenar (SD) against CCl4 induced subchronic hepatic toxicity. In vivo study, albino rats were divided into 5 groups. Group I was control; Group II was experimental control treated with CCl4 (0.15 mL/kg, i.p. for 21 days); Groups III–IV treated with SD (2 mL/kg, p.o.) and MD (1,000 mg/kg, p.o.) for 5 days following CCl4 intoxication as in group 2 respectively; and Group V was positive control treated with silymarin (50 mg/kg, p.o.). In vitro hepatoprotective activity of SD and MD (25, 50, and 100 μg/mL) was assessed by SRB assay and flow cytometry analysis. CCl4 exposure significantly elevated the release of hepatic enzymes i.e. AST, ALT, LDH, and SALP in serum and lipid peroxidation in liver tissue which all these parameters were reversed after SD and MD administration. Therapy for 5 days also normalized the levels of antioxidant enzymes i.e. catalase, SOD, GPx, GR, tissue GSH, and aniline hydroxylase in CCl4 treated group. DNA damage and histological alterations caused by CCl4 were restored towards normal group. In vitro study showed protective effect of SD and MD against CCl4 treated HepG2 cell lines and rat hepatocytes. The results suggested that MD has a significant hepatoprotective potential and regulatory effect on oxidative stress than SD against CCl4 induced hepatotoxicity, and that this effect may be related to its antioxidant activity.
Silica exposure activates non-canonical inflammasome complex in intratracheal instilled rat model
Authors: Niu Yingmei , Yang Shuangli , Hu Xiumei
Published: August 2022

Background

Inhalation of silica crystals in occupational settings is a main cause of silicosis, a chronic irreversible pulmonary disorder. Our prior studies demonstrated the activation of inflammasome sensors AIM2 and NLRP3, effector protein caspase-1, and significant increase in IL-1β in silica exposed rats, suggesting that the canonical inflammasome activation may be associated with silica-induced tissue damage and inflammation.

Aims and Methods

In our current study using the same animal model system, we further evaluated the components of non-canonical inflammasome, including NEK7, caspase-11, and GSDMD following silica exposure.

Results

We demonstrated sustained NEK7 elevation in the rat lung epithelial cells and macrophages following 1- and 3-day exposure. Enhanced NEK7 expression was also detected in lung homogenate by western blot. Similarly, caspase-11 expression was induced by silica exposure in lung sections and homogenate. Elevated GSDMD was observed both in lung sections by immunohistochemical staining and in lung tissue homogenate by western blot.

Conclusion

In summary, our current study demonstrated increase in NEK7, caspase-11, and GSDMD in silica exposed rats, indicating activation of non-canonical inflammasome complex, thereby providing a broad inflammasome activation pathway caused by silica exposure.
Technical Trick: Supplemental Medial Column Screw Fixation of Distal Femur Fractures Treated With a Laterally Based Locked Plate
Authors: Chen Stephen R. , Shaikh Humza , Turvey Blake R. , Moloney Gele B.
Published: August 2022

Given known failure rates after lateral plating of distal femur fractures, there is an increasing interest in augmenting fixation to improve outcomes. The addition of medial plates or intramedullary nails have been described with promising results, decreasing nonunion and varus collapse rates. However, the use of dual implants increases implant costs, adds surgical complexity, and requires a second surgical approach that may increase morbidity. A supplemental, percutaneously placed, medial column screw may provide a less invasive means of improving stability and achieving fracture union compared with lateral plating alone.
Feeding challenges in the newborn with congenital heart disease
Authors: Ravishankar Chitra
Published: August 2022

Purpose of review

Feeding challenges and growth failure are lifelong issues for infants with congenital heart disease. The purpose of this review is to summarize the literature on the topic from North America.

Recent findings

Despite recognition of feeding challenges and ongoing national collaboration, >50% of infants with univentricular physiology continue to require supplemental tube feeds at the time of discharge from neonatal surgery. Preoperative feeding is now commonly used in prostaglandin dependent neonates with congenital heart disease. The value of a structured nutritional program with establishment of best practices in nutrition is well recognized in the current era. Despite implementation of these best practices, neonates undergoing cardiac surgery continue to struggle with weight gain prior to discharge. This suggests that there is more to growth than provision of adequate nutrition alone.

The National Pediatric Cardiology Quality Improvement Collaborative continues to play a major role in optimizing nutrition in infants with congenital heart disease. This among other registries underscores the importance of collaboration in improving overall outcomes for children with congenital heart disease. Nurses should be encouraged to lead both clinical and research efforts to overcome feeding challenges encountered by these children.
Plasmacytoid Dendritic Cell Dermatosis Associated to Myeloproliferative/Myelodysplastic Neoplasms
Authors: Machan Salma , Alonso-Dominguez Juan M. , Sánchez García F. Javier , Nieves Salgado Rocío , Soto Carlos , Castro Yolanda , Pajares Raquel , Manso Rebeca , Santonja Carlos , Serrano del Castillo Cristina , Piris Miguel A. , Requena Luis , Rodríguez Pinilla Socorro M.
Published: August 2022

Cutaneous lesions in the setting of myeloproliferative neoplasms and myelodysplastic syndromes are poorly understood. We report 6 patients with pruritic papular eruptions composed of mature T-lymphocytes with large clusters of CD123-positive cells. Double immunohistochemical studies demonstrated a lack of myeloid cell nuclear differentiation antigen in the CD123-positive cells, which expressed SPIB, confirming that they were mature plasmacytoid dendritic cells. Four patients were diagnosed with chronic myelomonocytic leukemia and 2 with myelodysplastic syndromes (AREB-I and myelodysplastic syndromes with 5q deletion, respectively). All patients had a long history of hematological alterations, mainly thrombocytopenia, preceding the cutaneous disorder. Nevertheless, the skin lesions developed in all cases coincidentally with either progression or full-establishment of their hematological disease. Most cutaneous lesions disappeared spontaneously or after corticosteroid treatment. Molecular studies performed in both bone marrow and cutaneous lesions in 2 patients demonstrated the same mutational profile, confirming the specific, neoplastic nature of these mature plasmacytoid dendritic cells-composed cutaneous lesions.
Identification of early-induced broadly neutralizing activities against transmitted founder HIV strains
Authors: Lucas Julie , Lin Li-Yun , Paul Nicodème , Laumond Géraldine , Klingler Jéromine , Schmidt Sylvie , Frappier Julia , Essat Asma , Meyer Laurence , Gordon Alicia Castro , Goujard C.é.cile , Bahram Seiamak , Moog Christiane
Published: August 2022

Objectives:

Broadly neutralizing antibodies have been proposed as key actors for HIV vaccine development. However, they display features of highly matured antibodies, hampering their induction by vaccination. As protective broadly neutralizing antibodies should be induced rapidly after vaccination and should neutralize the early-transmitted founder (T/F) viruses, we searched whether such antibodies may be induced following HIV infection.

Design:

Sera were collected during acute infection (Day 0) and at viral set point (Month 6/12) and the neutralizing activity against T/F strains was investigated. Neutralizing activity in sera collected from chronic progressor was analyzed in parallel.

Methods:

We compared neutralizing activity against T/F strains with neutralizing activity against non-T/F strains using the conventional TZM-bL neutralizing assay.

Results:

We found neutralizing antibodies (nAbs) preferentially directed against T/F viruses in sera collected shortly after infection. This humoral response evolved by shifting to nAbs directed against non-T/F strains.

Conclusion:

Although features associated with nAbs directed against T/F viruses need further investigations, these early-induced nAbs may display lesser maturation characteristics; therefore, this might increase their interest for future vaccine designs.
Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV
Authors: Jaschinski Nadine , Greenberg Lauren , Neesgaard Bastian , Miró Jose M. , Grabmeier-Pfistershammer Katharina , Wandeler Gilles , Smith Colette , De Wit Stéphane , Wit Ferdinand , Pelchen-Matthews Annegret , Mussini Cristina , Castagna Antonella , Pradier Christian , d’Arminio Monforte Antonella , Vehreschild Jörg , Sönnerborg Anders , Anne Alain V. , Carr Andrew , Bansi-Matharu Loveleen , Lundgren Jens , Garges Harmony , Rogatto Felipe , Zangerle Robert , Günthard Huldrych F. , Rasmussen Line D. , Nescoi Coca , Van Der Valk Marc , Menozzi Marianna , Muccini Camilla , Mocroft Amanda , Peters Lars , Ryom Lene
Published: August 2022

Objective:

Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people with HIV.

Design:

Multinational cohort collaboration.

Methods:

RESPOND participants were followed from the latest of 1 January 2012 or cohort enrolment until the first of a CVD event (myocardial infarction, stroke, invasive cardiovascular procedure), last follow-up or 31 December 2019. Logistic regression examined the odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within the past 6 months) and risk of CVD with negative binomial regression models, adjusted for potential confounders.

Results:

Of 29 340 individuals, 34% recently used ABC. Compared with those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk [odds ratio 1.12 (95% confidence interval = 1.04–1.21)] and significantly lower for individuals at moderate, high or very high CVD risk [0.80 (0.72–0.88), 0.75 (0.64–0.87), 0.71 (0.56–0.90), respectively]. During 6.2 years of median follow-up (interquartile range; 3.87–7.52), there were 748 CVD events (incidence rate 4.7 of 1000 persons-years of follow up (4.3–5.0)]. The adjusted CVD incidence rate ratio was higher for individuals with recent ABC use [1.40 (1.20–1.64)] compared with individuals without, consistent across sensitivity analyses. The association did not differ according to estimated CVD (interaction P = 0.56) or CKD (P = 0.98) risk strata.

Conclusion:

Within RESPOND's contemporarily treated population, a significant association between CVD incidence and recent ABC use was confirmed and not explained by preferential ABC use in individuals at increased CVD or CKD risk.
Speech Symptoms of Velopharyngeal Insufficiency and the Incidence of Secondary Speech Surgery in 10-Year-Old Children With Unilateral Cleft Lip and Palate: Comparison of 2 Randomized Surgical Methods for Primary Palatal Surgery
Authors: Alaluusua Suvi , Hölttä Elina , Saarikko Anne , Geneid Ahmed , Leikola Junnu , Heliövaara Arja
Published: August 2022

Objective:

To compare speech symptoms of velopharyngeal insufficiency (VPI) and incidence of secondary speech surgery in 10-year-old Finnish children with unilateral cleft lip and palate (UCLP) following primary palatal surgery using 2 surgical methods.

Design:

Single center analysis within the Scandcleft multicenter randomized controlled trial of primary surgery for UCLP.

Materials and Methods:

Patients comprised 79 nonsyndromic 10-year-old children with UCLP. Two randomized surgical methods were used in the primary palatal surgery: soft palate closure at 4 months and hard palate closure at 12 months (Arm A) and closure of both the soft and hard palate at 12 months (Arm C). Speech symptoms of VPI were analyzed from standardized video recordings by 2 experienced speech pathologists. The incidences of surgery for correcting VPI, fistula closure, and speech therapy were evaluated retrospectively from patient records.

Results:

No differences in speech symptoms of VPI, need for VPI surgery or speech therapy were found between the surgical methods. Of all 79 children, 33% had had VPI surgery and 61% had speech therapy. The number of fistulas was significantly higher in Arm A (25%) than in Arm C (2%). Moderate to severe speech symptoms of VPI (hypernasality, continuous nasal air leakage, weak pressure consonants, and/or compensatory articulation) were found in 11% of the children.

Conclusion:

No differences were present between groups in speech symptoms of VPI or need for VPI surgery or speech therapy between the 2 surgical methods. One third of the children had undergone VPI surgery. Most of the children (89%) had good or relatively good speech.
Effect of Orthognathic Surgery on Movement of the Cheilion
Authors: Sağlam Reyhan , Çukurova Yilmaz Zeynep , Ozel Abdullah , Uckan Sina
Published: August 2022

The cheilion (Ch), corner of the mouth, is the soft-tissue landmark where the upper and lower lips intersect. Orthognathic surgery can modify Ch position, which can affect facial esthetics. The aims were to evaluate Ch movements resulting from Le Fort I maxillary advancement with maxillary impaction or downgrafting, and with mandibular advancement or setback, and to investigate relationships between surgical movements and Ch movements. The 45 patients had undergone bilateral sagittal split ramus osteotomy with Le Fort I advancement surgery. They were divided into 4 groups according to surgical movement direction. Preoperative and postoperative photographs were calibrated. Standardized methods were used to identify and measure preoperative and postoperative Ch positions. Significant correlations were detected between extent of maxillary downgrafting and inferior movement of the Ch in group 1 (r=0.988, P=0.001) and group 3 (r=0.915, P=0.001). Also, significant correlations were detected between extent of mandibular advancement and anterior movement of the Ch in group 3 (r=0.561, P=0.046) and group 4 (r=0.661, P=0.005). The findings indicate that, in patients who undergo bilateral sagittal split ramus osteotomy/Le Fort I surgeries, mandibular advancement moves Ch anteriorly and maxillary downgrafting moves Ch inferiorly.
Insect decline in Brazil: an appraisal of current evidence
Authors: Lewinsohn Thomas M. , Agostini Kayna , Lucci Freitas André Victor , Melo Adriano S.
Published: August 2022

Recent reviews of data on worldwide insect decline include almost no information on Brazil. We gathered evidence from literature searches and a survey sent to researchers, to which 96 replied and 56 provided information and publications. We present 75 instances of trends recorded over an average span of 11 years for aquatic and 22 years for terrestrial insects. These include time-replicated samples and expert opinion based on long-term local collections. Most terrestrial data are for butterflies, bees and scarab beetles. Aquatic studies include several insect orders, usually sorted to genus or family. Terrestrial insects showed significantly more cases of declines than increases, both in abundance (17 : 3) and in diversity (11 : 1). In aquatic cases, no tendency was detected in abundance (2 : 2) or diversity (3 : 4), not counting cases with no trend. Differences in these results among habitats may be due to the shorter span and less change in environmental conditions in the aquatic surveys, which included sites already degraded before sampling. We offer guidelines for future long-term assessments, including resampling of legacy collection sites.
Preliminary evidence for one-trial social learning of vervet monkey alarm calling
Authors: Deshpande Adwait , Van Boekholt Bas , Zuberbuhler Klaus
Published: August 2022

How do non-human primates learn to use their alarm calls? Social learning is a promising candidate, but its role in the acquisition of meaning and call usage has not been studied systematically, neither during ontogeny nor in adulthood. To investigate the role of social learning in alarm call comprehension and use, we exposed groups of wild vervet monkeys to two unfamiliar animal models in the presence or absence of conspecific alarm calls. To assess the learning outcome of these experiences, we then presented the models for a second time to the same monkeys, but now without additional alarm call information. In subjects previously exposed in conjunction with alarm calls, we found heightened predator inspection compared to control subjects exposed without alarm calls, indicating one-trial social learning of ‘meaning’. Moreover, some juveniles (but not adults) produced the same alarm calls they heard during the initial exposure whereas the authenticity of the models had an additional effect. Our experiment provides preliminary evidence that, in non-human primates, call meaning can be acquired by one-trail social learning but that subject age and core knowledge about predators additionally moderate the acquisition of novel call-referent associations.
Behaviour is more important than thermal performance for an Arctic host–parasite system under climate change
Authors: Peacock Stephanie J. , Kutz Susan J. , Hoar Bryanne M. , Molnár Péter K.
Published: August 2022

Climate change is affecting Arctic ecosystems, including parasites. Predicting outcomes for host–parasite systems is challenging due to the complexity of multi-species interactions and the numerous, interacting pathways by which climate change can alter dynamics. Increasing temperatures may lead to faster development of free-living parasite stages but also higher mortality. Interactions between behavioural plasticity of hosts and parasites will also influence transmission processes. We combined laboratory experiments and population modelling to understand the impacts of changing temperatures on barren-ground caribou (Rangifer tarandus) and their common helminth (Ostertagia gruehneri). We experimentally determined the thermal performance curves for mortality and development of free-living parasite stages and applied them in a spatial host–parasite model that also included behaviour of the parasite (propensity for arrested development in the host) and host (long-distance migration). Sensitivity analyses showed that thermal responses had less of an impact on simulated parasite burdens than expected, and the effect differed depending on parasite behaviour. The propensity for arrested development and host migration led to distinct spatio-temporal patterns in infection. These results emphasize the importance of considering behaviour—and behavioural plasticity—when projecting climate-change impacts on host–parasite systems.
Post-publication critique at top-ranked journals across scientific disciplines: a cross-sectional assessment of policies and practice
Authors: Hardwicke Tom E. , Thibault Robert T. , Kosie Jessica E. , Tzavella Loukia , Bendixen Theiss , Handcock Sarah A. , Köneke Vivian E. , Ioannidis John P. A.
Published: August 2022

Journals exert considerable control over letters, commentaries and online comments that criticize prior research (post-publication critique). We assessed policies (Study One) and practice (Study Two) related to post-publication critique at 15 top-ranked journals in each of 22 scientific disciplines (
N
= 330 journals). Two-hundred and seven (63%) journals accepted post-publication critique and often imposed limits on length (median 1000, interquartile range (IQR) 500–1200 words) and time-to-submit (median 12, IQR 4–26 weeks). The most restrictive limits were 175 words and two weeks; some policies imposed no limits. Of 2066 randomly sampled research articles published in 2018 by journals accepting post-publication critique, 39 (1.9%, 95% confidence interval [1.4, 2.6]) were linked to at least one post-publication critique (there were 58 post-publication critiques in total). Of the 58 post-publication critiques, 44 received an author reply, of which 41 asserted that original conclusions were unchanged. Clinical Medicine had the most active culture of post-publication critique: all journals accepted post-publication critique and published the most post-publication critique overall, but also imposed the strictest limits on length (median 400, IQR 400–550 words) and time-to-submit (median 4, IQR 4–6 weeks). Our findings suggest that top-ranked academic journals often pose serious barriers to the cultivation, documentation and dissemination of post-publication critique.
Improving the thermal resistance of fluorescent CsPb(Br,I)
3
perovskite quantum dots by surface modification with perfluorodecanoic acid
Authors: Iso Yoshiki , Eri Momoko , Hiroyoshi Risako , Kano Kensho , Isobe Tetsuhiko
Published: August 2022

CsPb(Br,I)
3
quantum dots (QDs) show application potential for optoelectronic devices. However, their thermal degradation is a significant problem. In this work, the effects of perfluorodecanoic acid (PFDA) modification on the photoluminescence (PL) and thermal resistance of CsPb(Br,I)
3
QDs were evaluated. The PL intensity of oleic-acid-modified quantum dots (OA-QDs) in toluene decreased drastically upon heating at 100°C. The PL quantum yield of the QDs increased from 69.6% to 77.4% upon modification with PFDA. Furthermore, the PL intensity of the QDs modified with PFDA (PFDA-QDs) increased to 140.6% upon heating, because of the reduction of surface defects upon adsorption of PFDA and its optimized adsorption state. A solid-film PFDA-QDs sample heated at 80°C for 4 h showed temporary PL enhancements for the OA-QDs and PFDA-QDs films to 445% and 557% of their initial values, respectively, upon heating for 0.25 h. This was attributed to the optimized adsorption states of the surface ligands. PFDA-QDs film maintained 354% after 4 h of heating, whereas that of OA-QDs film was 104%. Thus, PFDA modification enhances PL intensity and suppresses PL degradation under heating, which is important for wavelength converters for optoelectronic device applications.
Actinomadura spongiicola sp. nov., isolated from the marine sponge Leucetta chagosensis
Authors: Qin Qi , Jiang Lin , Zhang Die , Li Lei , Lin Hou-wen
Published: August 2022

A novel actinomycete strain, named LHW52907T, was isolated from a marine sponge (Leucetta chagosensis) collected in the South China Sea. The strain developed branched mycelia without fragmentation and short spore chains in hook-and- spiral form with wrinkled surfaces, bearing no more 10 spores. The cell-wall hydrolysates contained meso-diaminopimelic acid as the diagnostic diamino acid. The sugars in whole-cell hydrolysates consisted of mannose, ribose, glucose, galactose and madurose. The major fatty acids of the strain were C16 : 0, C17 : 0 and C18 : 1
 ω9c. The predominant menaquinone was MK-9(H6). The strain had the highest 16S rRNA gene sequence similarity of 99.72 % to

Actinomadura pelletieri

DSM 43383T. However, the average nucleotide identity and in silico DNA–DNA hybridization values between them were 93.6 and 52.6 %, respectively, readily distinguishing them as two different species. The results indicate that strain LHW52907T represents a novel species of the genus

Actinomadura

, for which we propose the name Actinomadura spongiicola sp. nov, with the type strain LHW52907T (=DSM 106571T=CGMCC 4.7596T).
Dynamic Control of Eye-Head Gaze Shifts by a Spiking Neural Network Model of the Superior Colliculus
Authors: Alizadeh Arezoo , Van Opstal A. John
Published: August 2022

To reorient gaze (the eye in space) towards a target can be achieved by infinitely many combinations of eye- and head movements. However, behavioral measurements show that the primate gaze-control system selects specific contributions of eye- and head to the saccade, which depend on the initial eye-in-head orientation. Single-unit recordings in the primate superior colliculus (SC) during head-unrestrained gaze shifts have further suggested that cells may encode the instantaneous trajectory of a desired straight gaze path in a feedforward way by the total cumulative number of spikes in the neural population, and that the instantaneous gaze kinematics are determined by the neural firing rates. The recordings also indicated that the latter depended strongly on the initial eye position as well. We recently proposed a conceptual model that accounts for many of the observed properties of eye-head gaze shifts and on the potential role of the SC. Here, we extend and test the model by incorporating a spiking neural network of the SC motor map, the output of which drives the eye-head motor control circuitry by linear cumulative summation of individual spike effects of each recruited SC neuron. We propose a simple neural mechanism on SC cells that explains the modulatory influence of feedback from an initial eye-in-head position signal on their spiking activity. The same signal also determines the onset delay of the head movement with respect to the eye. The downstream eye- and head burst generators were taken to be linear, as our earlier work had suggested that much of the nonlinear kinematics of saccadic eye movements may be due to neural encoding at the collicular level, rather than at the brainstem. We show that the spiking activity of the SC population drives gaze to the intended target location within a dynamic local gaze-velocity feedback circuit that yields realistic eye- and head-movement kinematics and dynamic SC gaze-movement fields.
Normalized LST is an efficient biomarker for homologous recombination deficiency and Olaparib response in ovarian carcinoma
Authors: Christinat Yann , Ho Liza , Clément Sophie , Genestie Catherine , Sehouli Jalid , Martin Antonio Gonzalez , Denison Ursula , Fujiwara Keiichi , Vergote Ignace , Tognon Germana , Hietanen Sakari , Ray-Coquard Isabelle , Pujade-Lauraine Eric , McKee Thomas A.
Published: August 2022

BACKGROUND

The efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors has been demonstrated in several phase III trials. However its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test.

PATIENTS AND METHODS

A novel biomarker to identify HRD was developed using TCGA data and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 phase 3 trial using the OncoScan™ CNV Assay. Results were compared to the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the Olaparib+Bevacizumab and placebo+Bevacizumab arms.

RESULTS

Analysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions (nLST) by the number of whole genome doubling events allows a better separation and classification of HRD samples than the GIS. The Oncoscan+nLST test yielded a lower failure rate on the 469 PAOLA-1 samples (10/469 vs 59/469 inconclusive results) and positive and negative agreement values of 96% (204/213) and, 81% (159/197) respectively. In nLST-positive samples, the hazard ratio (HR) was 0.40 (95% CI: 0.28-0.57) compared with 0.35 for Myriad GIS. In tumors that were BRCA wild-type and nLST-positive, the HR was 0.53 (Myriad: 0.41). In this subpopulation the nLST test and the Myriad myChoice test yielded a similar 1-year PFS (87% and 88%) but a different 2-year PFS (52% vs 60%) upon Olaparib+ Bevacizumab treatment.

CONCLUSION

The proposed test is a viable alternative to the Myriad myChoice HRD test and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the commercial test but its lower failure rate allows a 10% increase in the number of patients who will receive a conclusive laboratory result.

Highlights

-

A novel laboratory-developed test that increased HRD scoring accessibility for ovarian cancer patients

-

Clinically validated on 469 samples from the PAOLA-1 trial within the ENGOT HRD European Initiative

-

A similar performance as the Myriad myChoice Dx HRD test but at a lower failure rate
A35R and H3L are Serological and B Cell Markers for Monkeypox Infection
Authors: Yefet Ron , Friedel Nadav , Tamir Hadas , Polonsky Ksenia , Mor Michael , Hagin David , Sprecher Eli , Israely Tomer , Freund Natalia T
Published: August 2022

Monkeypox virus (MPXV) resides in two forms, mature and enveloped virions, and depending on it, distinct proteins are displayed on the viral surface. We expressed in mammalian cells two MPXV antigens from the mature form and two MPXV antigens from the enveloped form and tested their reactivity to sera of 11 MPXV convalescent donors diagnosed in Israel during May-June 2022 and collected 33-62 days post infection. While only 4 out of 11 donors neutralized the related Vaccinia Lister strain, all MPXV recoverees demonstrated a strong serological response to a 124-amino acid truncation of the A35R antigen, and to a 276-amino acid truncation of the H3L antigen. Moreover, A35R- and H3L-specific B cells ranging from 0.03-0.5% and 0.01-0.35% of IgG+CD19+ cells, respectively, were detected in all 11 MPXV donors (A35R), and in 8 out of 11 donors (H3L). Therefore, A35R and H3L represent MPXV immune targets, and can be used in a simple heat-inactivated serological enzyme-linked immunosorbent assay for the identification of recent MPXV infection.
The Impact of SARS-CoV-2 Vaccine Dose Separation and Dose Targeting on Hospital Admissions and Deaths from COVID-19 in England
Authors: Keeling Matt J. , Moore Samuel , Penman Bridget , Hill Edward M.
Published: August 2022

In late 2020, the JCVI (the Joint Committee on Vaccination and Immunisation, which provides advice to the Department of Health and Social Care, England) made two important recommendations for the initial roll-out of the COVID-19 vaccine. The first was that vaccines should be targeted to the elderly and vulnerable, with the aim of maximally preventing disease rather than infection. The second was to increase the interval between first and second doses from 3 to 12 weeks. Here, we re-examine these recommendations through a mathematical model of SARS-CoV-2 infection in England. We show that targeting the most vulnerable had the biggest immediate impact (compared to targeting younger individuals who may be more responsible for transmission). The 12-week delay was also highly beneficial, estimated to have averted between 32-72 thousand hospital admissions and 4-9 thousand deaths over the first ten months of the campaign (December 2020 - September 2021) depending on the assumed interaction between dose interval and efficacy.
Simulation of undiagnosed patients with novel genetic conditions
Authors: Alsentzer Emily , Finlayson Samuel G. , Li Michelle M. ,   Undiagnosed Diseases Network, Kobren Shilpa N. , Kohane Isaac S.
Published: August 2022

Rare Mendelian disorders pose a major diagnostic challenge and collectively affect 300-400 million patients worldwide. Many automated tools aim to uncover causal genes in patients with suspected genetic disorders, but evaluation of these tools is limited due to the lack of comprehensive benchmark datasets that include previously unpublished conditions. Here, we present a computational pipeline that simulates realistic clinical datasets to address this deficit. Our framework jointly simulates complex phenotypes and challenging candidate genes and produces patients with novel genetic conditions. We demonstrate the similarity of our simulated patients to real patients from the Undiagnosed Diseases Network and evaluate common gene prioritization methods on the simulated cohort. These prioritization methods recover known gene-disease associations but perform poorly on diagnosing patients with novel genetic disorders. Our publicly-available dataset and codebase can be utilized by medical genetics researchers to evaluate, compare, and improve tools that aid in the diagnostic process.
BNIP3 regulates Chikungunya virus infection independently of autophagy and cell death
Authors: Echavarria-Consuegra Liliana , Kumar Nilima Dinesh , Mauthe Mario , Van de Pol Denise , Reggiori Fulvio , Smit Jolanda M.
Published: August 2022

Chikungunya virus (CHIKV) is a human pathogen causing outbreaks of febrile illness for which vaccines and specific treatments remain unavailable. Autophagy-related (ATG) proteins and autophagy receptors are a set of host factors that participate in autophagy, but have also shown to function in other unrelated cellular pathways. Although autophagy is reported to both inhibit and enhance CHIKV replication, the specific role of individual ATG proteins remains largely unknown. Here, a siRNA screen was performed to evaluate the importance of the ATG proteome and autophagy receptors in controlling CHIKV infection. We observed that 7 out of 50 ATG proteins impact the replication of CHIKV. Among those, depletion of the mitochondrial protein and autophagy receptor BCL2 Interacting Protein 3 (BNIP3) increased CHIKV infection. Interestingly, BNIP3 controls CHIKV independently of autophagy and cell death. Detailed analysis of the CHIKV viral cycle revealed that BNIP3 interferes with the early stages of infection. Moreover, the antiviral role of BNIP3 was found conserved across two distinct CHIKV genotypes and the closely related Semliki Forest virus. Altogether, this study describes a novel and previously unknown function of the mitochondrial protein BNIP3 in the control of the early stages of the alphavirus viral cycle.
An outbreak of SARS-CoV-2 in big hairy armadillos (Chaetophractus villosus) associated with Gamma variant in Argentina three months after being undetectable in humans
Authors: Arteaga Franco Lucero , Jodar Mercedes Nabaes , Mondino Mariela , Portu Ana , Boeris Monica , Joly Ana , Jar Ana , Mundo Silvia , Castro Eliana , Alvarez Diego , Torres Carolina , Viegas Mariana , Bratanich Ana
Published: August 2022

The present pandemic produced by SARS-CoV-2 and its variants represents an example of the one health concept in which humans and animals are components of the same epidemiologic chain. Animal reservoirs of these viruses are thus the focus of surveillance programs to monitor their circulation and evolution in potentially new hosts and reservoirs. In this work, we report the detection of SARS-CoV-2 Gamma variant infection in four specimens of Chaetophractus villosus (big hairy armadillo/armadillo peludo) in Argentina. In addition to the finding of a new wildlife species susceptible to SARS-CoV-2 infection, the identification of the Gamma variant three months after its last detection in humans is a noteworthy result, raising the question of potential unidentified viral reservoirs.
A modular CRISPR screen identifies individual and combination pathways contributing to HIV-1 latency
Authors: Hsieh Emily , Janssens Derek H , Paddison Patrick J , Browne Edward P , Henikoff Steve , OhAinle Molly , Emerman Michael
Published: August 2022

Transcriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms that pose a major barrier toin vivoelimination of HIV-1. We developed a new latency CRISPR screening strategy, called Latency HIV-CRISPR, which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as a direct readout of factors involved in the maintenance of HIV-1 latency. We developed a custom guideRNA library targeting epigenetic regulatory genes and paired the screen with and without a latency reversal agent – AZD5582, an activator of the non-canonical NFκB pathway – to examine a combination of mechanisms controlling HIV-1 latency. A component of the Nucleosome Acetyltransferase of H4 histone acetylation (NuA4 HAT) complex, ING3, acts in concert with AZD5582 to activate proviruses in J-Lat cell lines and in a primary CD4+ T cell model of HIV-1 latency. We found that the knockout ofING3reduces acetylation of the H4 histone tail and BRD4 occupancy on the HIV-1 LTR, and only in the combination ofING3knockout with the activation of non-canonical NFκB via AZD5582 is there dramatic increase in initiation and elongation of RNA Polymerase II on the HIV-1 provirus in a manner that is nearly unique among all cellular promoters.
Engineering of NEMO as calcium indicators with large dynamics and high sensitivity
Authors: Li Jia , Shang Ziwei , Chen Jia-Hui , Gu Wenjia , Yao Li , Yang Xin , Sun Xiaowen , Wang Liuqing , Wang Tianlu , Liu Siyao , Li Jiajing , Hou Tingting , Xing Dajun , Gill Donald L. , Li Jiejie , Wang Shi-Qiang , Hou Lijuan , Zhou Yubin , Tang Ai-Hui , Zhang Xiaohui , Wang Youjun
Published: August 2022

Genetically-encoded calcium indicators (GECI) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of sub-optimal peak signal-to-baseline-ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+transients with peak SBRs ~20-fold larger than the top-of-the-range GCaMP series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared to GCaMPs, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times largerin vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.
Deep proteome profiling of white adipose tissue reveals marked conservation and distinct features between different anatomical depots
Authors: Madsen Søren , Nelson Marin E. , Deshpande Vinita , Humphrey Sean J. , Cooke Kristen C. , Howell Anna , Diaz-Vegas Alexis , Burchfield James G. , Stöckli Jacqueline , James David E.
Published: August 2022

White adipose tissue is deposited mainly as subcutaneous adipose tissue (SAT), often associated with metabolic protection, and abdominal/visceral adipose tissue (VAT), which contributes to metabolic disease. To investigate the molecular underpinnings of these differences, we conducted comprehensive proteomics profiling of whole tissue and isolated adipocytes from these two depots across two diets from C57Bl/6J mice. The adipocyte proteomes from lean mice were highly conserved between depots, with the major depot-specific differences encoded by just 3% of the proteome. Adipocytes from SAT (SAdi) were enriched in pathways related to mitochondrial complex I and beiging, whereas visceral adipocytes (VAdi) were enriched in structural proteins and positive regulators of mTOR presumably to promote nutrient storage and cellular expansion. This indicates that SAdi are geared toward higher catabolic activity, while VAdi are more suited for lipid storage.

By comparing adipocytes from mice fed chow or Western diet (WD), we define a core adaptive proteomics signature consisting of increased extracellular matrix proteins and decreased fatty acid metabolism and mitochondrial Coenzyme Q biosynthesis. Relative to SAdi, VAdi displayed greater changes with WD including a pronounced decrease in mitochondrial proteins concomitant with upregulation of apoptotic signaling and decreased mitophagy, indicating pervasive mitochondrial stress. Furthermore, WD caused reduction in lipid handling and glucose uptake pathways particularly in VAdi, consistent with adipocyte de-differentiation. By overlaying the proteomics changes with diet in whole adipose tissue and isolated adipocytes, we uncovered concordance between adipocytes and tissue only in the VAT, indicating a unique tissue-specific adaptation to sustained WD in SAT.

Finally, an in-depth comparison of isolated adipocytes and 3T3-L1 proteomes revealed a high degree of overlap, supporting the utility of the 3T3-L1 adipocyte model. These deep proteomes provide an invaluable resource highlighting differences between white adipose depots that may fine-tune their unique functions and adaptation to an obesogenic environment.
Data-Driven Design of Protein-Derived Peptide Multiplexes for Biomimetic Detection of Exhaled Breath VOC Profiles
Authors: Nakano-Baker Oliver , Fong Hanson , Shukla Shalabh , Lee Richard , Cai Le , Godin Dennis , Hennig Tatum , Rath Siddharth , Novosselov Igor , Dogan Sami , Sarikaya Mehmet , MacKenzie J. Devin
Published: August 2022

Exhaled human breath contains a rich mixture of volatile organic compounds (VOCs) whose concentration can vary in response to disease or other stressors. Using simulated odorant-binding proteins (OBPs) and machine learning methods, we designed a multiplex of short VOC- and carbon-binding peptide probes that detect the characteristic “VOC fingerprint”. Specifically, we target VOCs associated with COVID-19 in a compact, molecular sensor array that directly transduces vapor composition into multi-channel electrical signals. Rapidly synthesizable, chimeric VOC- and solid-binding peptides were derived from selected OBPs using multi-sequence alignment with protein database structures. Selective peptide binding to targeted VOCs and sensor surfaces was validated using surface plasmon resonance spectroscopy and quartz crystal microbalance. VOC sensing was demonstrated by peptide-sensitized, exposed-channel carbon nanotube transistors. The data-to-device pipeline enables the development of novel devices for non-invasive monitoring, diagnostics of diseases, and environmental exposures assessment.
Cryo-EM structure and functional landscape of an RNA polymerase ribozyme
Authors: McRae Ewan K.S. , Wan Christopher J.K. , Kristoffersen Emil L. , Hansen Kalinka , Gianni Edoardo , Gallego Isaac , Curran Joseph F. , Attwater James , Holliger Philipp , Andersen Ebbe S.
Published: August 2022

The emergence of an RNA replicase capable of self-replication is considered an important stage in the origin of life. RNA polymerase ribozymes (PR) including a variant that uses trinucleotide triphosphates (triplets) as substrates have been created byin vitroevolution and are the closest functional analogues of the replicase but the structural basis for their function is poorly understood. Here, we leverage single-particle cryo-EM and high-throughput mutation analysis to obtain the structure of a triplet polymerase ribozyme (TPR) apoenzyme and map its functional landscape. The TPR cryo-EM structure at 5-Å resolution reveals an RNA heterodimer comprising a catalytic and an inactive accessory subunit, where the complex resembles a left hand with thumb and fingers at a 70° angle. The two subunits are connected by two distinct kissing-loop (KL) interactions that are essential for polymerase function. Our combined structural and functional data suggest a model for templated RNA synthesis by the TPR holoenzyme whereby heterodimer formation and KL interactions preorganize the TPR for optimal template binding and templated RNA synthesis activity. These results provide a foundation for a better understanding RNA’s potential for self-replication.
New C3H KitN824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance
Authors: Klein-Rodewald Tanja , Micklich Kateryna , Sanz-Moreno Adrián , Calzada-Wack Julia , Tost Monica , Adler Thure , Klaften Matthias , Sabrautzki Sibylle , Aigner Bernhard , Kraiger Markus , Gailus-Durner Valerie , Fuchs Helmut ,   German Mouse Clinic Consortium, Gründer Albert , Pahl Heike , Wolf Eckhard , de Angelis Martin Hrabe , Rathkolb Birgit
Published: August 2022

Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT-mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT-variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous KIT-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.
Pathogen-specific structural features of two key players in Candida albicans morphogenetic switch
Authors: Manso José A , Carabias Arturo , Sárkány Zsuzsa , de Pereda José M , Pereira Pedro José Barbosa , Macedo-Ribeiro Sandra
Published: August 2022

Ras-like protein 1 (CaRas1) is a key regulator of the switch between the yeast and hyphal forms of Candida albicans, a feature associated with pathogenesis. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its highly conserved GTP-binding domain (G-domain). An important function in hyphal growth has also been proposed for the long hypervariable region downstream of the G-domain of CaRas1, whose unusual content of polyQ stretches and Q/N repeats make CaRas1 unique within Ras-family proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 displays an elongated shape and that its hypervariable region contains helical structural elements with intramolecular coiled-coil propensity and limited conformational flexibility. Functional assays revealed that CaRas1 activation by CaCdc25 is highly efficient, with 5-to 2000-fold higher activity levels than reported for human GEFs. In addition, the threedimensional structure of the catalytic region of CaCdc25, together with the structural characterization of CaRas1/CaCdc25 complexes, unveiled a specific region located in the α-helical hairpin of CaCdc25, critical for CaRas1 activation, where negatively charged substitutions reduce its activity. The unique structural features of the low complexity region of CaRas1 and the distinctive properties of CaRas1 activation by CaCdc25, common in the homologous proteins from CTG-clade species, uncover novel strategies to target key virulence factors in human-infecting fungal pathogens.