bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Features of Bilambdoid and Sagittal Synostosis (BLSS): A Retrospective Multicenter Study in Japan
Authors: Tamada Ikkei , Hikosaka Makoto , Sakamoto Yoshiaki , Tsuda Kyoji , Ihara Satoshi , Kaneko Tsuyoshi , Kishi Kazuo
Published: February 2021

Bilambdoid and sagittal synostosis (BLSS), a rare form of multisutural craniosynostosis, is sometimes known as the Mercedes-Benz syndrome due to the appearance of the fused sagittal and bilateral lambdoid sutures. Although previous studies have described some of its clinical features, the pathology of this disease is not yet fully understood. Moreover, it has been pointed out that BLSS is more common among individuals of Hispanic ethnicity, but its incidence in Asia remains unclear. In the present study, BLSS cases in Japan were analyzed to determine the characteristics of the condition in Japan. Three hospitals in Tokyo participated in the present study. Patients with BLSS who underwent cranial remodeling were included. Data on patient demographics, clinical symptoms, status of the cranial sutures, morphological subclassification, surgical procedures, developmental status, and genetic mutations were analyzed. In total, 22 patients met the enrollment criteria and were included, indicating a higher incidence of BLSS in Japan than in other nations reported in previous studies. In terms of morphological subclassification, there were 15 brachycephalic, 4 dolichocephalic, and 3 normocephalic. For the initial cranial procedure, 7 patients underwent a single-stage cranioplasty, 13 underwent a posterior distraction, and 2 underwent lateral expansion. Patients with a normocephalic cranial morphology tended to undergo surgery at an older age than patients with the other two types. Appropriate timing for surgery is important for healthy development; hence, surgeons should remember that BLSS can lead to “balanced dysmorphism” that may have led to a delay in diagnosis due to its normal-looking morphology.
Evaluation of the Effectiveness of Using Platelet Rich Fibrin (PRF) With Bone Graft in the Reconstruction of Alveolar Cleft, A Prospective Study
Authors: Al-Mahdi Akmam H. , Abdulrahman Mustafa Salim , Al-Jumaily Hassanien Ahmed Hadi
Published: February 2021

Clefts of the lip, alveolus, and palate are the most common congenital malformation of the orofacial region. Bone grafting of the alveolar cleft is necessary for rehabilitation of oral function. Platelet rich fibrin (PRF), an autologous fibrin matrix is a second-generation platelet concentrate that has a positive effect on bone healing.

Aim of the Study:

The aim of this prospective study is to investigate and evaluate the quality and quantity of the bone graft that mixed with PRF when used in reconstruction of alveolar cleft in terms of bone density and resorption rate of the bone graft.

Materials and Methods:

Sixteen patients with unilateral alveolar clefts were treated. The control group received bone grafts without PRF, while the remaining patients comprised the PRF group and received grafts with PRF. Postoperative bone graft density and rate of bone resorption were assessed by CBCT at 1 month and 6 months after surgery

Results:

Satisfactory bone bridging formation was observed in all patients and the mean of bone resorption in PRF group within 6 months after surgery lower than control group. The bone density of the PRF group was lower than that of the control group at 1st month, which later after 6 months increased to be more than the control group.

Conclusions:

Platelet rich fibrin that mixed with autogenous bone graft was significantly reduce postoperative bone resorption. PRF may provide a higher bone density in the long postoperative course.
Endoscopic Intranasal Marsupialization of the Isolated Mucocele in the Inferior Orbit
Authors: Lee Dong Hoo , Park Sung Yool , Jang JunHyuk , Park Seong Kook
Published: February 2021

Isolated intraorbital mucocele without anatomical communication between the sinus and orbital cavity, and all orbital walls are intact is rare. It may lead to many orbital symptoms including proptosis, diplopia, orbital pain. Traditionally, many cases of typical paranasal sinus mucocele are successfully treated with endoscopic marsupialization. Most of the isolated intraorbital mucoceles were treated with complete removal of the mucocele via an external approach. However, there are many disadvantages of the external approach, and a case of isolated intraorbital mucocele in medial orbit treated by endoscopic intranasal marsupialization was reported. Here, the authors report a case of isolated orbital mucocele in inferior orbit treated by endoscopic intranasal marsupialization.
A Case of Atypical Skull Base Osteomyelitis Secondary to Otitis Media Due to Delayed Diagnosis
Authors: Fu Ze-Ming , Zhang De-Jun , Guan Guo-Fang
Published: February 2021

Skull base osteomyelitis that is secondary to otitis media is extremely rare in the modern antibiotic era. The authors present an 84-year-old male with atypical skull base osteomyelitis that developed from otitis media during the COVID-19 pandemic due to delayed diagnosis and partial treatment which is blamed for development of skull base osteomyelitis. The atypical presentations of skull base osteomyelitis pose a diagnostic challenge. This case highlights that even otitis media is a potentially fatal infection in older patients with diabetes. Early diagnosis and aggressive management of skull base osteomyelitis are of upmost importance and will ensure a more favorable prognosis.
Serum Mitochondrial Quality Control Related Biomarker Levels are Associated with Organ Dysfunction in Septic Patients
Authors: Huang Wei , Wang Xiaoting , Zhang Hongmin , Wang Guangjian , Xie Fang , Liu Dawei
Published: February 2021

Background:

To investigate the feasibility and the value of using mitochondrial quality control (MQC)-related proteins as biomarkers in septic patients.

Methods:

The enrolled subjects were divided into four groups: healthy control group (n = 30), intensive care unit (ICU) control group (n = 62), septic nonshock group (n = 40), and septic shock group (n = 94). Serum levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fission protein 1 (Fis1), mitofusin2 (Mfn2), and Parkin were measured by enzyme-linked immunosorbent assay at the time of enrollment for all groups. Clinical parameters and laboratory test results were also collected.

Results:

The levels of MQC-related biomarkers between any two of the four groups were significantly different (P < 0.001 for all). The serum levels of PGC-1α, Mfn2, and Parkin were lowest in healthy individuals; the levels were dramatically higher in the ICU control group compared with the others, and they decreased progressively from the septic nonshock group to the septic shock group. However, the pattern for Fis1 was inverse; the more severe the condition was, the higher the level of Fis1. Moreover, there was moderate correlation between MQC-related biomarkers and the SOFA score (PGC-1α, r = −0.662; Fis1, r = 0.609; Mfn2, r = −0.677; Parkin, r = 0.−0.674, P < 0.001 for all).

Conclusions:

The serum levels of PGC-1α, Fis1, Mfn2, and Parkin were significantly correlated with organ dysfunction and reflected the disease progression and severity. The dynamic surveillance of these four biomarkers could be beneficial to predict outcome and guide treatment.
Association of Postoperative Opioid Prescription Size and Patient Satisfaction
Authors: Fry Brian T. , Howard Ryan A. , Gunaseelan Vidhya , Lee Jay S. , Waljee Jennifer F. , Englesbe Michael J. , Vu Joceline V.
Published: February 2021

Objective:

To evaluate the association between postoperative opioid prescription size and patient-reported satisfaction among surgical patients.

Summary background data:

Opioids are overprescribed after surgery, which negatively impacts patient outcomes. The assumption that larger prescriptions increase patient satisfaction has been suggested as an important driver of excessive prescribing.

Methods:

This prospective cohort study evaluated opioid-naive adult patients undergoing laparoscopic cholecystectomy, laparoscopic appendectomy, and minor hernia repair between January 1 and May 31, 2018. The primary outcome was patient satisfaction, collected via a 30-day postoperative survey. Satisfaction was measured on a scale of 0 to 10 and dichotomized into “highly satisfied” (9–10) and “not highly satisfied” (0–8). The explanatory variable of interest was size of opioid prescription at discharge from surgery, converted into milligrams of oral morphine equivalents (OME). Hierarchical logistic regression was performed to evaluate the association between prescription size and satisfaction while adjusting for clinical covariates.

Results:

One thousand five hundred twenty patients met the inclusion criteria. Mean age was 53 years and 43% of patients were female. One thousand two hundred seventy-nine (84.1%) patients were highly satisfied and 241 (15.9%) were not highly satisfied. After multivariable adjustment, there was no significant association between opioid prescription size and satisfaction (OR 1.00, 95% CI 0.99–1.00). The predicted probability of being highly satisfied ranged from 83% for the smallest prescription (25 mg OME) to 85% for the largest prescription (750 mg OME).

Conclusions:

In a large cohort of patients undergoing common surgical procedures, there was no association between opioid prescription size at discharge after surgery and patient satisfaction. This implies that surgeons can provide significantly smaller opioid prescriptions after surgery without negatively affecting patient satisfaction.
Thoracic Epidural Analgesia for Postoperative Pain Management in Liver Transplantation: A 10-year Study on 685 Liver Transplant Recipients
Authors: Hausken John , Haugaa Håkon , Hagness Morten , Line Pål-Dag , Melum Espen , Tønnessen Tor Inge
Published: February 2021

Background.

Thoracic epidural analgesia (TEA) is not widely used for postoperative pain management in liver transplantation due to hepatic coagulopathy-related increased risk of inducing an epidural hematoma. However, an increasing number of patients are transplanted for other indications than the end-stage liver disease and without coagulopathy allowing insertion of an epidural catheter.

Methods.

This study is a retrospective observational single-center study of all adult patients undergoing first-time liver transplantation at Oslo University Hospital between January 1, 2008, and December 31, 2017. Data regarding patient characteristics were obtained from the Nordic liver transplant registry, medical records, and pain registration forms. Patients without coagulopathy (international normalized ratio <1.5 and platelets >100 × 109/L) were eligible for TEA.

Results.

Out of 685 first-time liver transplantations in a 10-year period, 327 received TEA, and 358 did not. The median Model of End-stage Liver Disease score was lower in the TEA group than in the non-TEA-group (9 versus 17, P < 0.001), and fewer patients were hospitalized preoperatively (16 versus 127, P < 0.001). The median international normalized ratio (1.1 versus 1.6, P < 0.001) and platelet count (190 versus 78, P < 0.001) were different between the TEA and non-TEA groups. There were no serious complications related to insertion or removal of the TEA catheters. Patients in the TEA group had less pain with a mean numeric rating scale at postoperative days 0–5 of 1.4 versus 1.8 (P = 0.008). Nearly 50% of the patients were prescribed opioids when discharged from hospital (non-TEA 154 versus TEA 158, P = 0.23), and there was no difference after 1 year (P = 0.718).

Conclusions.

Our report revealed very good pain control with both TEA and the non-TEA modality. TEA was without any serious complications like epidural hematoma or infection/abscess in selected liver transplant recipients without severe coagulopathy. Opioid prescription at hospital discharge and by 1-year follow-up did not differ between the groups.
Estimation of infection rate and the population size potentially exposed to SARS-CoV-2 in Japan during 2020
Authors: Naito Motohiko
Published: February 2021

Background

The infectious respiratory disease COVID-19, caused novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reached pandemic status during 2020. The primary statistic data are important to survey the actual circumstances of COVID-19. Here, we report the analysis of the primary data of COVID-19 in Japan during 2020.

Methods

Data were collected and released systematically under Japan domestic law. Machine learning was conducted to estimate the positive rate in Japan and four prefectures (Tokyo, Osaka, Chiba, and Fukuoka).

Results

Primary data analysis revealed there were at least two peaks of infection in Japan; the first one was during April 2020 and the second one started from November 1, 2020. Estimating the positive rate in Japan as well as in the four prefectures reinforced the above observations. The positive rate in Japan during 2020 was estimated to be around 6% to 8%. We also estimated that 1.95 million people were possibly exposed to the novel virus on October 31, 2020. The numbers of related deaths were over 3,000 people at the end of 2020.

Conclusion

We estimated the infection rate of SARS-CoV-2 in Japan to be 6–8% in 2020. We also concluded that Japan had at least two infection-spreading periods, the first one being from Jan 19, 2020 until May 2020, and the second one beginning from November 1, 2020. Importantly, our analysis supports the need for clear definition of the criteria for conducting confirmation tests before embarking on data analysis.
The effect of Alzheimer’s disease-associated genetic variants on longevity
Authors: Tesi Niccolò , Hulsman Marc , van der Lee Sven J. , Jansen Iris E. , Stringa Najada , van Schoor Natasja M. , Scheltens Philip , van der Flier Wiesje M. , Huisman Martijn , Reinders Marcel J. T. , Holstege Henne
Published: February 2021

The genetics underlying human longevity is influenced by the genetic risk to develop -or escape- age-related diseases. As Alzheimer’s disease (AD) represents one of the most common conditions at old age, an interplay between genetic factors for AD and longevity is expected.

We explored this interplay by studying the prevalence of 38 AD-associated single-nucleotide-polymorphisms (SNPs) identified in AD-GWAS, in self-reported cognitively healthy centenarians, and we replicated findings in the largest GWAS on parental-longevity.

We found that 28/38 SNPs identified to associate with increased AD-risk also associated with decreased odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. When grouping the SNPs based on these distributions, we found three groups: 17 variants increased AD-risk more than they decreased the risk of longevity (AD-group): these variants were functionally enriched for β-amyloid metabolism and immune signaling, and they were enriched in microglia. 11 variants reported a larger effect on longevity as compared to their AD-effect (Longevity-group): these variants were enriched for endocytosis/immune signaling, and at the cell-type level were enriched in microglia and endothelial cells. Next to AD, these variants were previously associated with other aging-related diseases, including cardiovascular and autoimmune diseases, and cancer. Unexpectedly, 10 variants associated with an increased risk of both AD and longevity (Unexpected-group). The effect of the SNPs in AD- and Longevity-groups replicated in the largest GWAS on parental-longevity, while the effects on longevity of the SNPs in the Unexpected-group could not be replicated, suggesting that these effects may not be robust across different studies.

Our study shows that some AD-associated variants negatively affect longevity primarily by their increased risk of AD, while other variants negatively affect longevity through an increased risk of multiple age-related diseases, including AD.
Ensovibep, a novel trispecific DARPin candidate that protects against SARS-CoV-2 variants
Authors: Rothenberger Sylvia , Hurdiss Daniel L. , Walser Marcel , Malvezzi Francesca , Mayor Jennifer , Ryter Sarah , Moreno Hector , Liechti Nicole , Bosshart Andreas , Iss Chloe , Calabro Valérie , Cornelius Andreas , Hospodarsch Tanja , Neculcea Alexandra , Looser Thamar , Schlegel Anja , Fontaine Simon , Villemagne Denis , Paladino Maria , Kaufmann Yvonne , Schaible Doris , Schlegel Iris , Schiegg Dieter , Zitt Christof , Sigrist Gabriel , Straumann Marcel , Sacarcelik Feyza , Wolter Julia , Comby Marco , Adler Julia M. , Eschke Kathrin , Nascimento Mariana , Abdelgawad Azza , Gruber Achim D. , Bushe Judith , Kershaw Olivia , Lyoo Heyrhyoung , Wang Chunyan , Li Wentao , Drulyte Ieva , Du Wenjuan , Binz H. Kaspar , Herrup Rachel , Lusvarghi Sabrina , Neerukonda Sabari Nath , Vassell Russell , Wang Wei , Mangold Susanne , Reichen Christian , Radom Filip , Knutson Charles G. , Balavenkatraman Kamal K. , Ramanathan Krishnan , Lewis Seth , Watson Randall , Haeuptle Micha A. , Zürcher Alexander , Dawson Keith M. , Steiner Daniel , Weiss Carol D. , Amstutz Patrick , van Kuppeveld Frank J.M. , Stumpp Michael T. , Bosch Berend-Jan , Engler Olivier , Trimpert Jakob
Published: February 2021

SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced immunity and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron BA.1 and BA.2, as of February 2022. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.
Automatic Identification and Avoidance of Axon Bundle Activation for Epiretinal Prosthesis
Authors: Tandon Pulkit , Bhaskhar Nandita , Shah Nishal , Madugula Sasi , Grosberg Lauren , Fan Victoria H. , Hottowy Pawel , Sher Alexander , Litke Alan M. , Chichilnisky E.J. , Mitra Subhasish
Published: February 2021

Retinal prostheses must be able to activate cells in a selective way in order to restore high-fidelity vision. However, inadvertent activation of far-away retinal ganglion cells (RGCs) through electrical stimulation of axon bundles can produce irregular and poorly controlled percepts, limiting artificial vision. Therefore, the problem ofaxon bundle activationcan be defined as the axonal stimulation of RGCs with unknown soma and receptive field locations, typically outside the electrode array. Here, a new algorithm is presented that utilizes electrical recordings to determine the stimulation current amplitudes above which bundle activation occurs. The method exploits several spatiotemporal characteristics of electrically-evoked spikes to overcome the challenge of detecting small axonal spikes in extracellular recordings. The algorithm was validated using large-scaleex vivostimulation and recording experiments in macaque retina, by comparing algorithmically and manually identified bundle activation thresholds. The algorithm could be used in a closed-loop manner by a future epiretinal prosthesis to reduce poorly controlled visual percepts associated with bundle activation. The method may also be applicable to other types of retinal implants and to cortical implants.

Contributions

PT developed the algorithm and analyzed the data, with input from SMi and EJC. NB and NS helped with the analysis. SMa and LG performed dissections and collected the data. PT and VFH performed manual identification. PH, AS and AML developed and supported recording hardware and software. PT, EJC and SMi wrote the manuscript. NS and SMa edited it. EJC and SMi supervised the project.
Who infects Whom? - Reconstructing infection chains of Mycobacterium avium ssp. paratuberculosis in an endemically infected dairy herd by use of genomic data
Authors: Nigsch Annette , Robbe-Austerman Suelee , Stuber Tod P. , Bitar Paulina D. Pavinski , Gröhn Yrjö , Schukken Ynte H.
Published: February 2021

Recent evidence of circulation of multiple strains within herds and mixed infections of cows marks the beginning of a rethink of our knowledge on Mycobacterium avium ssp. paratuberculosis (MAP) epidemiology. Strain typing opens new ways to investigate MAP transmission. This work presents a method for reconstructing infection chains in a setting of endemic Johne’s disease on a well-managed dairy farm. By linking genomic data with demographic field data, strain-specific differences in spreading patterns could be quantified for a densely sampled dairy herd. Mixed infections of dairy cows with MAP are common, and some strains spread more successfully. Infected cows remain susceptible for co-infections with other MAP genotypes. The model suggested that cows acquired infection from 1–4 other cows and spread infection to 0–17 individuals. Reconstructed infection chains supported the hypothesis that high shedding animals that started to shed at an early age and showed a progressive infection pattern represented a greater risk for spreading MAP. Transmission of more than one genotype between animals was recorded. In this farm with a good MAP control management program, adult-to-adult contact was proposed as the most important transmission route to explain the reconstructed networks. For each isolate, at least one more likely ancestor could be inferred. Our study results help to capture underlying transmission processes and to understand the challenges of tracing MAP spread within a herd. Only the combination of precise longitudinal field data and bacterial strain type information made it possible to trace infection in such detail.
Ground cover presence in organic olive orchards affects the interaction of natural enemies againstPrays oleae, promoting an effective egg predation
Authors: Álvarez Hugo Alejandro , Jiménez-Muñoz Raquel , Morente Marina , Campos Mercedes , Ruano Francisca
Published: February 2021

The olive moth,Prays oleae, is one of the most common insects that damages olives in the Mediterranean region. The establishment of ground cover within olive orchards has been promoted in this region in recent years to avoid erosion and soil degradation. Nevertheless, its role as a shelter for natural enemies of pests has been controversial. In this study, we have investigated the effectiveness of the biological control ofP. oleaein organic olive orchards with ground cover (mowed) and without ground cover (tilled). For this, (1) we assessed the relationship between predated eggs and the abundance of natural enemies in both types of orchards; (2) we compared both the potential damage of the pest and the egg hatching in the two types of orchards; and (3) we examined the interaction amongst families of natural enemies andP. oleae(as adults and as predated eggs). The results showed that there is a high rate of predation in the studied olive orchards, 81% of the eggs were predated, 12.2% hatched, and 6.9% were live eggs. However, mowed orchards were more effective for controllingP. oleaeby means of egg predation rather than tilled orchards, i.e., in mowed orchards, whilst the potential damage of the pest was higher, egg hatching was rather low. The structure of the adult arthropod community, i.e., the composition and abundance of families of natural enemies did not differ between the orchards, but the abundance of the families Anthocoridae, Miridae and Scelionidae was significantly higher in the mowed orchards. Finally, the interaction amongst natural enemies andP. oleaeshowed that the families that better explained the effects on egg predation were Aeolothripidae, Anthocoridae, Miridae, Chrysopidae (predators), and Formicidae (omnivore). We discuss the results in terms of ecological interactions of trophic guilds and we conclude that the establishment and maintenance of ground cover in organic olive orchards, at least in June and July, is of great significance because it positively affects the egg predation ofP. oleae. This effect is especially significant when there is a low abundance of natural enemies in the olive orchards.
Alien chromatin other than the GST-encodingFhb7candidate confers Fusarium head blight resistance in wheat breeding
Authors: Guo Xianrui , Shi Qinghua , Yuan Jing , Zhang Jing , Wang Mian , Wang Jing , Wang Chunhui , Fu Shulan , Su Handong , Liu Yang , Huang Yuhong , Liu Chang , Liu Qian , Sun Yishuang , Wang Long , Wang Ke , Jing Donglin , Zhang Pingzhi , Li Jinbang , Kang Houyang , Zhou Yonghong , Ye Xingguo , Han Fangpu
Published: February 2021

The lack of resistance resources is a major bottleneck for wheat Fusarium head blight (FHB) resistance breeding. Three wheat-Th. elongatumFHB resistant translocation lines have been developed and used for wheat breeding without yield penalty. Transcriptomic analysis identified a derivative glutathione S-transferase transcript T26102, which was homologous toFhb7and induced dramatically byFusarium graminearum. Unlike other studies,Fhb7homologs were detected not only inThinopyrumbut also inElymus,Leymus,PseudoroegeriaandRoegeria. We also found that several wheat-Th. ponticumderivatives carryingFhb7and its homologs were highly susceptible to FHB. Moreover, the transgenic plants expressingFhb7and its homolog on different backgrounds did not improve the FHB resistance.

One Sentence Summary

The GST-encodingFhb7candidate cannot improve Fusarium head blight resistance in wheat breeding.
Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis
Authors: Cid Elena , Marquez-Galera Angel , Valero Manuel , Gal Beatriz , Medeiros Daniel C. , Navarron Carmen M. , Ballesteros-Esteban Luis , Reig-Viader Rita , Morales Aixa V. , Fernandez-Lamo Ivan , Gomez-Dominguez Daniel , Sato Masaaki , Hayashi Yasunori , Bayes Alex , Barco Angel , Lopez-Atalaya Jose P , de la Prida Liset M
Published: February 2021

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type specific vulnerability, their progression and histopathological classification remain controversial. Here using single-cell electrophysiology in vivo and immediate early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rats and micein vivo. Bulk tissue and single-nucleus expression profiling disclosed sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage-channels, synaptic signalling and cell adhesion molecules were deregulated by epilepsy differently across sublayers, while neurodegenerative signatures primarily involved superficial cells. Pseudotime analysis of gene expression in single-nuclei andin situvalidation revealed separated trajectories from health to epilepsy across cell types, and identified a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate sublayer- and cell type-specific changes associated with selective CA1 neuronal damage contributing to progression of hippocampal sclerosis.
Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner
Authors: White Matthew A. , Massenzio Francesca , Li Xingli , Coleman Michael P. , Barmada Sami J. , Sreedharan Jemeen
Published: February 2021

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a progressive and ultimately fatal disease spectrum characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration inDrosophila.Here, we investigated the potential of GSK3 inhibition to ameliorate TDP43-mediated toxicity in mammalian neurons. Expression of TDP-43 was found to both activate GSK3 and promote caspase mediated cleavage of TDP-43. Inhibition of GSK3 reduced the abundance of full-length and cleaved TDP-43 in rodent neurons expressing wild-type or disease-associated mutant TDP-43 and also ameliorated neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity could have therapeutic value.
Usingde novoassembly to identify structural variation of complex immune system gene regions
Authors: Zhang Jia-Yuan , Roberts Hannah , Flores David S. C. , Cutler Antony J. , Brown Andrew C. , Whalley Justin P. , Mielczarek Olga , Buck David , Lockstone Helen , Xella Barbara , Oliver Karen , Corton Craig , Betteridge Emma , Bashford-Rogers Rachael , Knight Julian C. , Todd John A. , Band Gavin
Published: February 2021

Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build ade novoassembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data; application of these methods to larger samples would provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.
Multi-modal artificial dura for simultaneous large-scale optical access and large-scale electrophysiology in non-human primate cortex
Authors: Griggs Devon J. , Khateeb Karam , Zhou Jasmine , Liu Teng , Wang Ruikang , Yazdan-Shahmorad Azadeh
Published: February 2021

Objective

Non-human primates (NHPs) are critical for development of translational neural technologies because of their neurological and neuroanatomical similarities to humans. Large-scale neural interfaces in NHPs with multiple modalities for stimulation and data collection poise us to unveil network-scale dynamics of both healthy and unhealthy neural systems. We aim to develop a large-scale multi-modal interface for NHPs for the purpose of studying large-scale neural phenomena including neural disease, damage, and recovery.

Approach

We present a multi-modal artificial dura (MMAD) composed of flexible conductive traces printed into transparent medical grade polymer. Our MMAD provides simultaneous neurophysiological recordings and optical access to large areas of the cortex (~3 cm2) and is designed to mitigate photo-induced electrical artifacts. The MMAD is the centerpiece of the interfaces we have designed to support electrocorticographic recording and stimulation, cortical imaging, and optogenetic experiments, all at the large-scales afforded by the brains of NHPs. We performed electrical and optical experiments bench-side andin vivowith macaques to validate the utility of our MMAD.

Main results

Using our MMAD we present large-scale electrocorticography from sensorimotor cortex of three macaques. Furthermore, we validated surface electrical stimulation in one of our animals. Our bench-side testing showed up to 90% reduction of photo-induced artifacts with our MMAD. The transparency of our MMAD was confirmed both via bench-side testing (87% transmittance) and viain vivoimaging of blood flow from the underlying microvasculature using optical coherence tomography angiography.

Significance

Our results indicate that our MMAD supports large-scale electrocorticography, large-scale cortical imaging, and, by extension, large-scale optical stimulation. The MMAD prepares the way for both acute and long-term chronic experiments with complimentary data collection and stimulation modalities. When paired with the complex behaviors and cognitive abilities of NHPs, these assets prepare us to study large-scale neural phenomena including neural disease, damage, and recovery.
How much does habitat isolation drive forest bird morphology?
Authors: Desrochers André , Noreau Flavie
Published: February 2021

Rapid environmental change caused by humans has become a major concern for wildlife conservationists. But phenotypic and evolutionary responses of species to such change may often be swift enough to prevent their collapse. Several North American bird species living in boreal forests now have more pointed wings (a proxy for sustained ight efficiency), than they had a century ago. This remarkable pattern has been hypothesized as resulting from selective pressures favoring colonization of isolated habitat. Additionally, aerodynamics predict that heavier birds can achieve faster ight, a further advantage for exploring isolated habitats. We tested whether birds establishing territories in isolated areas have more pointed wings and are heavier than con-specifics found in more densely populated areas. Wing shapes of wild-caught adults from 21 passerine bird species did not generally support this prediction. However individuals with large body mass relative to their species were found more frequently in isolated habitats. Our results offer partial support for the isolation hypothesis at the landscape scale. We encourage further work at coarser, regional, scales to further examine whether wing shape and body mass evolutionarily respond to habitat isolation.
Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration
Authors: Fitzgerald Allison A. , Maynard Rachael E. , Marcisak Emily F. , Nasir Apsra , Glasgow Eric , Jablonski Sandra A. , Van Der Veken Pieter , Pearson Gray , Eisman Shira E. , Mace Emily M. , Fertig Elana J. , Weiner Louis M.
Published: February 2021

Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novelin vivozebrafish andin vitro3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors.

Graphical Abstract
Discovery of a first-in-class inhibitor of the PRMT5-substrate adaptor interaction
Authors: McKinney David C , McMillan Brian J , Ranaghan Matthew , Moroco Jamie A , Brousseau Merissa , Mullin-Bernstein Zachary , O’Keefe Meghan , McCarren Patrick , Mesleh Michael F. , Mulvaney Kathleen M. , Singh Ritu , Bajrami Besnik , Skepner Adam , Timm David E. , Porter Dale , Kaushik Virendar K. , Sellers William R. , Ianari Alessandra
Published: February 2021

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action and structure determination studies revealed that these compounds form a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts the PRMT5-RIOK1 complex, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive small molecule that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.
Cryptic microgeographic variation in responses of larval Atlantic cod to warmer temperatures
Authors: Oomen Rebekah A. , Juliussen Elisabeth , Olsen Esben M. , Knutsen Halvor , Jentoft Sissel , Hutchings Jeffrey A.
Published: February 2021

Although temperature is known to drive species dynamics and distributions, our understanding of the extent to which thermal plasticity varies within species is poor. Differences in plasticity can arise through local adaptation to heterogeneous environments, hybridization, and the release of cryptic genetic variation in novel environments. Here, wild Atlantic cod (Gadus morhua) from contrasting environments inside and outside of a fjord system in southern Norway spawned freely in a semi-natural laboratory environment, generating pure crosses and reciprocal hybrids. A common-garden rearing experiment of the larvae at 6°C, 9.5°C, and 13°C revealed cryptic genetic variation in thermal responses of growth and survival at warmer temperatures. Variation in growth plasticity was greatest from 9.5°C to 13°C, the latter of which exceeds temperatures currently typical of larvae in their native environments. In contrast to our prediction of intermediate hybrid responses consistent with additive genetic effects, one reciprocal hybrid cross showed a 4% increase in size at the highest temperature, whereas most crosses exhibited 4-12% reductions in size. All crosses experienced severe (76-93%) reductions in survival from 9.5°C to 13°C. Variation in survival plasticity suggests a genetically variable basis for the severity with which survival declines with increasing temperature and the potential for an adaptive response to warming. Notably, we demonstrate the potential for hybridization between coexisting ‘fjord’ and ‘North Sea’ ecotypes that naturally inhabit the inner and outer fjord environments at contrasting frequencies. Yet, ecotype explained a minor (3-10%) component of growth reaction norm variation, suggesting it is insufficient for describing important biological variation. Current broad-scale management and lack of coastal monitoring impede the development of strategies to maintain the potential for adaptation to warming temperatures in systems with such phenotypic complexity resulting from cryptic genetic variation, coexisting ecotypes, and gene flow.
Assessing knowledge, concerns, and risk perceptions among Italian medical students during the SARS-CoV-2 pandemic
Authors: Greco Manfredi , Maietti Elisa , Rallo Flavia , Reno Chiara , Trerè Davide , Savoia Elena , Fantini Maria Pia , Gori Davide
Published: February 2021

INTRODUCTION

During the first phase of COVID-19 pandemic, Italian medical students transitioned from in-person to remote learning. This study was carried out to early assess students’ sources of information, perceived risk of infection, knowledge and preventive practices in order to resume academic activity. The impact of training and volunteer work was also assessed.

METHODS

A cross-sectional online survey was conducted in May 2020 among medical students enrolled in the School of Medicine and Surgery, Bologna University.

RESULTS

The analysis included 537 responses. On average students used seven sources of information on COVID-19. Scientific journals were considered the most trustworthy but they ranked only 6th in the frequency of use. Perceived risk of infection was higher for academic activities, especially in the hospital than daily living activities. Less than 50% of students reported being trained on biological risk and use of PPE. Training received was significantly associated with both perceived risk of infection and confidence in the use of PPE. Students engaged in volunteer work had higher confidence in PPE usage.

DISCUSSION

Accessible scientific information and students’ engagement in spreading correct knowledge play an important role in challenging misinformation during the pandemic crisis. Students showed suboptimal knowledge about PPE use, calling for additional training. We found a moderate-high perceived risk of infection that could be mitigated with specific educational programs and by promoting voluntary work. Students’ engagement in public health emergencies (PHE) could potentially be beneficial for their training and as well as for the healthcare system.
Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determineMycobacterium tuberculosisbacterial burden
Authors: Brandenburg Julius , Heyckendorf Jan , Waldow Franziska , Zehethofer Nicole , Linnemann Lara , Gisch Nicolas , Karaköse Hande , Reimann Maja , Kranzer Katharina , Kalsdorf Barbara , Sanchez-Carballo Patricia , Weinkauf Michael , Scholz Verena , Malm Sven , Homolka Susanne , Gaede Karoline I. , Herzmann Christian , Schaible Ulrich E. , Hölscher Christoph , Reiling Norbert , Schwudke Dominik
Published: February 2021

It is estimated that approximately one-fourth of the world's population is infected with strains of theMycobacterium tuberculosiscomplex (MTBC), the causative agents of tuberculosis (TB). In this study, we present rationally developed molecular markers for bacterial burden, which are derived from mycobacterial phospholipids. Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PI) are present in all clinically relevant MTBC lineages investigated. For the major abundant lipid PI 16:0_19:0 (TSA), a detection limit equivalent to 102colony forming units (CFU) was determined for bacterial cultures and approximately 103for cell culture systems. We further developed a mass spectrometry based targeted lipid assay, which – in contrast to bacterial quantification on solid medium – can be performed within several hours including sample preparation. Translation of this indirect and culture-free detection approach allowed the determination of pathogen loads in infected murine macrophages, human neutrophils and murine lung tissue. We show that marker lipids inferred from the mycobacterial PIs are increased in peripheral blood mononuclear cells (PBMCs) of TB patients beyond the lipid metabolic background in comparison to healthy controls. In a small cohort of drug-susceptible TB patients elevated levels of these marker molecules were detected at therapy start and declined following successful anti-tuberculosis treatment. The concentration of TSA-containing PIs can be used as correlate for reliable and rapid quantification ofMycobacterium tuberculosis (Mtb)burden in experimentalin vitromodel systems and may also provide a clinically relevant tool for monitoring TB therapy.

One Sentence Summary

Tuberculostearic acid containing phosphatidylinositols represent a novel, fast to measure, reliable correlate ofMycobacterium tuberculosisbacterial burden in experimental model systems, which makes a future clinical application conceivable.
Different computations over the same inputs produce selective behavior in algorithmic brain networks
Authors: Jaworska Katarzyna , van Rijsbergen Nicola J. , Ince Robin A.A. , Schyns Philippe G.
Published: February 2021

A key challenge in systems neuroscience remains to understand where, when and now particularlyhowbrain networks compute over sensory inputs to achieve behavior. We used XOR, OR and AND functions as behavioral tasks, because each requires a different computation over the same inputs to produce correct outputs. In each task, source-localized magnetoencephalographic activity progresses through four systems-level computations identified within individual participants (N = 10/task): (1) linear discrimination of each visual input, first contra-laterally in occipital cortex then (2) jointly in midline occipital cortex and right fusiform gyrus, followed by (3) nonlinear task-dependent input integration in temporal-parietal cortex and finally (4) behavioral response representation in post-central gyrus. Our results show how network algorithms differently compute over the same inputs to produce different behaviors.

One sentence summary

Four stages of task-specific computations over the same visual inputs achieve different behaviors in dynamic brain networks