bluuebunny/crossref_metadata_2025 huggingface dataset:
Retention Time of Endoscopic Nasobiliary Drainage and Symptomatic Choledocholithiasis Recurrence After Endoscopic Retrograde Cholangiopancreatography: A Single-center, Retrospective Study in Fuyang, China
Authors: Wu Jinqing , Wang Guizhou
Published: May 2022

Background and Objectives:

Endoscopic nasobiliary drainage (ENBD) is usually retained for several days after choledocholithiasis is removed by endoscopic retrograde cholangiopancreatography (ERCP). ENBD placement provides reliable biliary drainage and perfusion, prevents pancreatitis, and allows for cholangiography. However, it has not been established whether retention time of ENBD is associated with symptomatic choledocholithiasis recurrence after ERCP. For this reason, we estimated the effect of ENBD retention time on symptomatic choledocholithiasis recurrence after ERCP.

Patients and Methods:

A total of 1016 patients in whom choledocholithiasis had been diagnosed and ERCP had been performed to remove choledocholithiasis were retrospectively reviewed. Their ENBD retention time was 4.01±1.53 days. They were divided into group 1 (n=570) and group 2 (n=446) according to the mean value. Cumulative recurrence rates of symptomatic choledocholithiasis after ERCP were compared between the 2 groups. To identify independent factors associated with symptomatic choledocholithiasis recurrence, various likely predictors associated with the intergroup differences were also recorded.

Results:

There were 570 patients with ENBD retention time ≤4.01 days (group 1) and 446 patients with ENBD retention time >4.01 days (group 2). No statistically significant differences between the 2 groups were evident in terms of demographic factors and laboratory results, except for amylase (AMY) and opening diet time after ERCP. The median (interquartile range) follow-up was 23.7 (14.6, 32.13) months (range: 4.3 to 70 mo) in group 1 and 23.7 (14.6, 31.2) months (range: 4.2 to 69.4 mo) in group 2 (P=0.762). The cumulative recurrence rates of symptomatic choledocholithiasis were 3.1% (2.5% vs. 3.8%) at month 20, 6.7% (5.1% vs. 8.7%) at month 40, and 8.2% (6.7% vs. 10.1%) at month 60 for groups 1 and 2, respectively (P=0.048). By multivariate analysis, being in group 1 reduced symptomatic choledocholithiasis recurrence, with a hazard ratio of 0.641 (95% confidence interval: 0.416-0.987, P=0.044).

Conclusions:

This preliminary study showed that symptomatic choledocholithiasis recurrence may be associated with ENBD retention time after ERCP, particularly for duration of ENBD more than 4.01 days.
The Omental Plug: A Novel Management Approach of Concomitant Ventral Hernias During Bariatric Surgery
Authors: Portela Ray , Mehta Kabir , Vahibe Ahmet , McKenzie Travis , Kendrick Michael , Ghanem Omar M.
Published: May 2022

Background:

Severe obesity leads to a higher incidence of ventral hernias, thus complicating up to 8% of bariatric procedures. The optimal management of these hernias continues to be a controversial topic. We present our novel approach of utilizing an omental plug for concomitant ventral hernia management during metabolic surgery.

Methods:

To prevent early bowel incarceration and obstruction during bariatric surgery, we sutured the omentum circumferentially to the edges of the hernia defect and to the hernia sac itself with absorbable suture.

Results:

Four patients were managed with this novel omental plug technique. All patients were female. The mean age was 53 years (range 39 to 68 y), the mean body-mass index was 54.75 kg/m2 (range 49 to 59 kg/m2), and the mean follow-up was 4.6 months (range 1.5 to 6.5 mo). There were no hernia-related complications through the follow-up period.

Conclusion:

The omental plug technique is a feasible, inexpensive, and safe alternative for ventral hernias with the potential prevention of bowel incarceration during bariatric surgery. This approach allows deferring the definitive hernia repair for a later stage.
Evidence-based principles of time, triage and treatment: Refining the initial medical response to massive casualty incidents
Authors: Shackelford Stacy A. , Remley Michael A. , Keenan Sean , Kotwal Russ S. , Baker Jay B. , Gurney Jennifer , Rush Stephen , Friedrichs Paul
Published: May 2022

BACKGROUND

The overall approach to massive casualty triage has changed little in the past 200 years. As the military and civilian organizations prepare for the possibility of future large-scale combat operations, terrorist attacks and natural disasters, potentially involving hundreds or even thousands of casualties, a modified approach is needed to conduct effective triage, initiate treatment, and save as many lives as possible.

METHODS

Military experience and review of analyses from the Department of Defense Trauma Registry are combined to introduce new concepts in triage and initial casualty management.

RESULTS

The classification of the scale of massive casualty (MASCAL) incidents, timeline of life-saving interventions, immediate first pass actions prior to formal triage decisions during the first hour after injury, simplification of triage decisions, and the understanding that ultra-MASCAL will primarily require casualty movement and survival needs with few prehospital life-saving medical interventions are discussed.

CONCLUSION

Self aid, bystander, and first responder interventions are paramount and should be trained and planned extensively. Military and disaster planning should not only train these concepts, but should seek innovations to extend the timelines of effectiveness and to deliver novel capabilities within the timelines to the greatest extent possible.
The new face of war: Craniofacial injuries from Operation Inherent Resolve
Authors: Neubauer Daniel C. , Camacho Macario , O’Reilly Eamon B. , Brice Matthew , Gurney Jennifer M. , Martin Matthew J.
Published: May 2022

BACKGROUND

During the last 20 years of conflict in the Middle East, improvements in body armor and the use of improvised explosive devices have resulted in an increased incidence of complex craniofacial trauma (CFT). Currently, CFT comprises up to 40% of all casualties. We present new data from the recent conflict in Iraq and Syria during Operation Inherent Resolve.

METHODS

Data were collected for patients treated at role 1, role 2, and role 3 facilities in Iraq and Syria over a 1-year period. During this time, a specialized head & neck surgical augmentation team was deployed and colocated with the central role 3 facility. Data included for this cross-sectional study are as follows: injury type and mechanism, triage category, initial managing facility and subsequent levels of care, and procedures performed.

RESULTS

Ninety-six patients sustained CFT over the study period. The most common injuries were soft tissue (57%), followed by cranial (44%) and orbital/facial (31%). Associated truncal and/or extremity injuries were seen in 46 patients (48%). There were marked differences in incidence and pattern of injuries between mechanisms (all p < 0.05). While improvised explosive devices had the highest rate of cranial and truncal injuries, gunshot wounds and blunt mechanisms had higher incidences of orbital/facial and neck injuries. Overall, 45% required operative interventions including complex facial reconstruction, craniotomy, and open globe repair. Mortality was 6% with 83% due to associated severe brain injury. Most patients were local nationals (70%) who required discharge or transfer to the local health care system.

CONCLUSION

Complex craniofacial trauma is increasingly seen by deployed surgeons, regardless of subspecialty training or location. Deployment of a centrally located head and neck team greatly enhances the capabilities for forward deployed management of CFT, with excellent outcomes for both US and local national patients.

LEVEL OF EVIDENCE

Therapeutic/care management; Level V.
Military-civilian partnerships and the clinical readiness mission: A preliminary study from the Military Health System and the American College of Surgeons
Authors: Grabo Daniel J. , Gurney Jennifer M. , Parascandola Lowell , Knudson M. Margaret
Published: May 2022

BACKGROUND

The Blue Book, published in conjunction with the Military Health System Strategic Partnership with the American College of Surgeons, serves as a reference manual for institutions wishing to establish a military-civilian partnership (MCP). To evaluate the applicability of the criteria contained in the Blue Book, we created a survey to be distributed to MCP military surgeons and their civilian host champions.

METHODS

E-mail surveys were sent to MCP military surgeons and civilian host champions. Military surgeons were queried about basic demographic information and aspects of the MCP including type, duration of assignment, onboarding, malpractice coverage, and billing for services. We gathered information on the role of military surgeons at the MCP, workload information, and trauma cases. The civilian host champions survey focused on institutional activities including trauma surgical volume, clinical and educational opportunities for the military surgeons, and exposure to research. Military-civilian partnership military surgeons and civilian host champions were questioned on program attributes: administrative support, budget, and profile of the program within the institution.

RESULTS

Ten MCP military surgeons and 7 host champions completed surveys. The majority of military surgeons were assigned to the MCP for a 3-year instructor role (90%), and most were trauma surgeons (80%). Clinical activities for the military surgeon were where 60% spent ≥13 weeks annually on trauma. Military surgeons identified host program support in academic growth, deployment preparation, and sense of value at the MCP as positive attributes. Civilian host champions unanimously reported that exposure to research, opportunities to lead trauma teams, dedicated intensive care unit time, and patient volume were positive program attributes.

CONCLUSION

This preliminary survey demonstrates that the criteria put forth in the Blue Book align with experiences of MCP military surgeons and host champions. Continued development of this survey and others like it may be useful in the MCP program selection and evaluation process.

LEVEL OF EVIDENCE

Therapeutic/care management; Level V.
The efficacy of weight-based enoxaparin dosing for venous thromboembolism prophylaxis in trauma patients: A systematic review and meta-analysis
Authors: Ebeid Annelize , Cole Elaine , Stallwood-Hall Catrin
Published: May 2022

BACKGROUND

Trauma patients are at high risk of developing venous thromboembolism (VTE), and standard dosing enoxaparin regimens may be inadequate for prophylaxis. This meta-analysis was performed to clarify the efficacy of alternative dosing regimens for VTE prophylaxis in this high-risk group. The objective of this systematic review was to review the evidence regarding weight-based dosing of enoxaparin for VTE prophylaxis in trauma patients.

METHODS

A systematic database search was undertaken for studies comparing standard versus weight-based dosing of enoxaparin for VTE prophylaxis in adult trauma patients, 18 years or older. The primary outcome was the achievement of anti–factor Xa (AFXa) levels within the prophylactic range. Secondary outcomes included subprophylactic AFXa levels, supraprophylactic AFXa levels, VTE incidence, and bleeding events. Meta-analysis was conducted using both fixed- and random-effects models, and presented as odds ratios, risk ratios (RRs), and risk differences (RDs) with 95% confidence intervals (CIs).

RESULTS

Four cohort studies were eligible for inclusion. Compared with standard dosing, weight-based enoxaparin prophylaxis dosing was associated with increased odds of prophylactic AFXa levels (odds ratio, 5.85; 95% CI, 3.02–11.30; p < 0.00001) and reduced risk of subprophylactic AFXa levels (RR, 3.97; 95% CI, 3.02–5.22; p < 0.00001). Standard dosing was associated with a reduced risk of supratherapeutic AFXa levels (RR, 0.23; 95% CI, 0.11–0.50; p = 0.0002), but this was not associated with a difference in risk of bleeding events (RD, −0.00; 95% CI, −0.02 to 0.01; p = 0.55). There was no statistical difference in incidence VTE between the two groups (RD, 0.01; 95% CI, −0.02 to 0.03; p = 0.64).

CONCLUSION

Compared with standard dosing, weight-based enoxaparin dosing regimens are associated with increased odds of prophylactic range AFXa levels. Further investigation is required to determine if this translates into improved VTE prophylaxis and reduced VTE incidence.

LEVEL OF EVIDENCE

Systematic Review and Meta-Analysis; Level III.
The impact of environment on genetic and epigenetic variation inTrifolium pratensepopulations from two contrasting semi-natural grasslands
Authors: Lehmair Theresa Anna , Poschlod Peter , Reisch Christoph
Published: May 2022

Central European grasslands, such as calcareous grasslands and oat-grass meadows, are characterized by diverse environmental conditions and management regimes. Therefore, we aimed to determine potential differences in genetic and epigenetic variation patterns between the contrasting habitats and to identify the drivers of genetic and epigenetic variation. We investigated the genetic and epigenetic variation of the ecologically variable plant speciesTrifolium pratenseL. applying amplified fragment length polymorphism and methylation-sensitive amplification polymorphism analyses. We observed low levels of genetic and epigenetic differentiation among populations and between habitat types. Genetic and epigenetic variations were not interdependent. Thus, genetic variation was significantly isolated by habitat dissimilarity, whereas epigenetic variation was affected by environment. More specifically, we observed a significant correlation of epigenetic diversity with soil moisture and soil pH (the latter potentially resulting in phosphorus limitation). Genetic variation was, therefore, affected more strongly by habitat-specific environmental conditions induced by land use-related disturbance and gene flow patterns, while epigenetic variation was driven by challenging environmental conditions.
The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study
Authors: Borges Maria Carolina , Haycock Phillip , Zheng Jie , Hemani Gibran , Howe Laurence J , Schmidt A Floriaan , Staley James R , Thomas Lumbers R , Henry Albert , Lemaitre Rozenn N , Gaunt Tom R , Holmes Michael V , Smith George Davey , Hingorani Aroon D , Lawlor Deborah A
Published: May 2022

Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.
Making Biomedical Research Software FAIR: Actionable Step-by-step Guidelines with a User-support Tool
Authors: Patel Bhavesh , Soundarajan Sanjay , Ménager Hervé , Hu Zicheng
Published: May 2022

Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles tailored for research software have been proposed by the FAIR for Research Software (FAIR4RS) Working Group. They provide a foundation for optimizing the reuse of research software. The FAIR4RS principles are, however, aspirational and do not provide practical instructions to the researchers. To fill this gap, we propose in this work the first actionable step-by-step guidelines for biomedical researchers to make their research software compliant with the FAIR4RS principles. We designate them as the FAIR Biomedical Research Software (FAIR-BioRS) guidelines. Our process for developing these guidelines, presented here, is based on an in-depth study of the FAIR4RS principles and a thorough review of current practices in the field. To support researchers, we have also developed a workflow that streamlines the process of implementing these guidelines. This workflow is incorporated in FAIRshare, a free and open-source software application aimed at simplifying the curation and sharing of FAIR biomedical data and software through user-friendly interfaces and automation. Details about this tool are also presented.
A Platform for Data-centric, Continuous Epidemiological Analyses
Authors: Coelho Flávio Codeço , Câmara Daniel , Araújo Eduardo , Bianchi Lucas , Ogasawara Ivan , Dalal Jyoti , James Ananthu , Abbate Jessica Lee , Merzouki Aziza , Reis Izabel , Nwosu Kenechukwu , Keiser Olivia
Published: May 2022

Guaranteeing durability, provenance, accessibility, and trust in open datasets can be challenging for researchers and organizations that rely on public repositories of data critical to epidemiology and other health analytics. Not only are the required repositories sometimes difficult to locate, and nearly always require conversion into a compatible format, they may move or change unpredictably. Any single change of the rules in one repository can hinder updating of a public dashboard reliant on pulling data from external sources. These concerns are particularly challenging at the international level, because systems aimed at harmonizing health and related data are typically dictated by national governments to serve their individual needs. In this paper, we introduce a comprehensive public health data platform, the EpiGraphHub, that aims to provide a single interoperable repository for open health and related data, curated by the international research community, which allows secure local integration of sensitive databases whilst facilitating the development of data-driven applications and reports for decision-makers. The platform development is co-funded by the World Health Organization and is fully open-source to maximize its value for large-scale public health studies.
SARS-CoV-2 testing of aircraft wastewater shows that mandatory tests and vaccination pass before boarding did not prevent massive importation of Omicron variant in Europe
Authors: Targa Lorlane Le , Wurtz Nathalie , Lacoste Alexandre , Penant Gwilherm , Jardot Priscilla , Annessi Alexandre , Colson Philippe , Scola Bernard La , Aherfi Sarah
Published: May 2022

Background

Most new SARS-CoV-2 epidemics in France occurred following importation from abroad of emerging viral variants. Currently, the control of such risk of new variant importation is based on the negativity of a screening test (PCR or antigenic) and on an up-to-date vaccine status, such as International Air Transport Association travel pass.

Methods

Wastewater of 2 planes arriving in Marseille (France) from Addis-Ababa (Ethiopia) on December 2021 were i) tested by RT-PCR for SARS-CoV2 detection, and variants screening; these tests were carried out between landing and custom clearance, ii)sequenced by MiSeq Illumina.

Antigenic tests and sequencing by NovaSeq were carried out on respiratory samples collected from the 56 passengers of the second flight.

Results

SARS-CoV-2 RNA suspected of being from the Omicron BA.1 variant was detected on the aircraft’s wastewater.,

SARS-CoV2 RNA was detected for 11 (20%) passengers and the Omicron BA.1 variant was identified.

Conclusion

Our work shows the efficiency of aircraft wastewater testing to detect SARS-CoV-2 cases among travelers and identify the viral genotype. It also highlights the low performance for incoming flights from outside Europe to France of the current filter strategy that combines requirement for a vaccine pass and a negative testing before boarding.
Slowing of Frontocentral Beta Oscillations in Atypical Parkinsonism
Authors: Krösche Marius , Kannenberg Silja , Butz Markus , Hartmann Christian J. , Florin Esther , Schnitzler Alfons , Hirschmann Jan
Published: May 2022

Diagnosis of atypical parkinsonian syndromes mostly relies on clinical presentation as well as structural and molecular brain imaging. It has not been investigated whether cortical oscillatory activity exhibits features distinguishing these syndromes. Therefore, we measured resting-state magnetoencephalography in 13 patients with corticobasal syndrome, 10 patients with progressive supranuclear palsy, 23 patients with idiopathic Parkinson’s disease and 23 healthy controls. We compared spectral power as well as amplitude and frequency of power peaks between the groups.

Atypical Parkinsonism was associated with spectral slowing, distinguishing both corticobasal syndrome and progressive supranuclear palsy from age-matched healthy controls and Parkinson’s disease. Patients with atypical Parkinsonism showed a shift of beta peaks (13-30 Hz) towards lower frequencies in frontal and central areas bilaterally. A concomitant increase in theta/alpha power relative to controls was observed in both atypical parkinsonian syndromes and in Parkinson’s disease.

Our results demonstrate that slowing of frontocentral beta oscillations is characteristic of atypical Parkinsonism. Spectral slowing with a different topography has previously been observed in other neurodegenerative disorders, such as Alzheimer’s disease, suggesting that spectral slowing might be an electrophysiological marker of cortical neurodegeneration. As such, it might support differential diagnosis of parkinsonian syndromes in the future.

Highlights

Slowing of beta oscillations distinguishes atypical parkinsonian syndromes from healthy controls and idiopathic Parkinson’s disease

Spectral slowing is most pronounced in frontocentral areas

Beta oscillations are shifted towards lower frequencies independent of their amplitude
A new in vitro checkerboard-parasite reduction ratio interaction assay for early de-risk of clinical development of antimalarial combinations
Authors: Wicha Sebastian G. , Walz Annabelle , Cherkaoui-Rbati Mohammed H. , Bundgaard Nils , Kuritz Karsten , Gumpp Christin , Gobeau Nathalie , Möhrle Jörg , Rottmann Matthias , Demarta-Gatsi Claudia
Published: May 2022

The development and spread of drug resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapies parasitological data to predict the parasitological endpoints of the combination. This allows to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel - piperaquine and artefenomel - ferroquine drug combinations. Besides, the predictive performance of our novel in vitro model was equivalent to the humanized mouse model outcome. Lastly, our more granular in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g. a concentration-dependent change in the Emax and the EC50 values of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations in malaria and potentially also in other therapeutic areas.
Low-dose bivalent mRNA vaccine is highly effective against different SARS-CoV-2 variants in a transgenic mouse model
Authors: Corleis Björn , Hoffmann Donata , Rauch Susanne , Fricke Charlie , Roth Nicole , Gergen Janina , Kovacikova Kristina , Schlottau Kore , Halwe Nico Joel , Ulrich Lorenz , Schön Jacob , Wernike Kerstin , Widera Marek , Ciesek Sandra , Mueller Stefan O. , Mettenleiter Thomas C. , Petsch Benjamin , Beer Martin , Dorhoi Anca
Published: May 2022

Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve COVID-19 control. We compared monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein, primarily in a transgenic mouse model and a Wistar rat model. The low-dose bivalent mRNA vaccine contained half the mRNA of each respective monovalent vaccine, but induced comparable neutralizing antibody titres, enrichment of lung-resident memory CD8+ T cells, specific CD4+ and CD8+ responses, and fully protected transgenic mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduced viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized Wistar rats also contained neutralizing antibodies against the B.1.1.529 (Omicron BA.1) variant. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins is a feasible approach for increasing the potency of vaccines against emerging and co-circulating SARS-CoV-2 variants.
An Efficient Approach for SARS-CoV-2 Monoclonal Antibody Production via Modified mRNA-LNP Immunization
Authors: Hsu Fu-Fei , Liang Kang-Hao , Kumari Monika , Chen Wan-Yu , Lin Hsiu-Ting , Cheng Chao-Min , Tao Mi-Hua , Wu Han-Chung
Published: May 2022

Throughout the COVID-19 pandemic, many prophylactic and therapeutic drugs have been evaluated and introduced. Among these treatments, monoclonal antibodies (mAbs) that bind to and neutralize SARS-CoV-2 virus have been applied as complementary and alternative treatments to vaccines. Although different methodologies have been utilized to produce mAbs, traditional hybridoma fusion technology is still commonly used for this purpose due to its unmatched performance record. In this study, we coupled the hybridoma fusion strategy with mRNA-lipid nanoparticle (LNP) immunization. This time-saving approach can circumvent biological and technical hurdles, such as difficult to express membrane proteins, antigen instability, and the lack of posttranslational modifications on recombinant antigens. We used mRNA-LNP immunization and hybridoma fusion technology to generate mAbs against the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein. Compared with traditional protein-based immunization approaches, inoculation of mice with RBD mRNA-LNP induced higher titers of serum antibodies. In addition, the mAbs we obtained can bind to SARS-CoV-2 RBDs from several variants. Notably, RBD-mAb-3 displayed particularly high binding affinities and neutralizing potencies against both Alpha and Delta variants. In addition to introducing specific mAbs against SARS-CoV-2, our data generally demonstrate that mRNA-LNP immunization may be useful to quickly generate highly functional mAbs against emerging infectious diseases.
Rapid learning of predictive maps with STDP and theta phase precession
Authors: George Tom M , de Cothi William , Stachenfeld Kimberly , Barry Caswell
Published: May 2022

The predictive map hypothesis is a promising candidate principle for hippocampal function. A favoured formalisation of this hypothesis, called the successor representation, proposes that each place cell encodes the expected state occupancy of its target location in the near future. This predictive framework is supported by behavioural as well as electrophysiological evidence and has desirable consequences for both the generalisability and efficiency of reinforcement learning algorithms. However, it is unclear how the successor representation might be learnt in the brain. Error-driven temporal difference learning, commonly used to learn successor representations in artificial agents, is not known to be implemented in hippocampal networks. Instead, we demonstrate that spike-timing dependent plasticity (STDP), a form of Hebbian learning, acting on temporally compressed trajectories known as “theta sweeps”, is sufficient to rapidly learn a close approximation to the successor representation. The model is biologically plausible – it uses spiking neurons modulated by theta-band oscillations, diffuse and overlapping place cell-like state representations, and experimentally matched parameters. We show how this model maps onto known aspects of hippocampal circuitry and explains substantial variance in the temporal difference successor matrix, consequently giving rise to place cells that demonstrate experimentally observed successor representation-related phenomena including backwards expansion on a 1D track and elongation near walls in 2D. Finally, our model provides insight into the observed topographical ordering of place field sizes along the dorsal-ventral axis by showing this is necessary to prevent the detrimental mixing of larger place fields, which encode longer timescale successor representations, with more fine-grained predictions of spatial location.
Matrix stiffness regulates Notch signaling activity in endothelial cells
Authors: Kretschmer Maibritt , Mamistvalov Rose , Sprinzak David , Vollmar Angelika M. , Zahler Stefan
Published: May 2022

The Notch signaling pathway plays a critical role in many developmental and disease related processes. It is widely accepted that Notch has a mechano-transduction module that regulates cleavage of the receptor. However, the role of biomechanical properties of the cellular environment on this module and on Notch signaling in general is still poorly understood. During angiogenesis, differentiation into tip and stalk cells is regulated by Notch. The endothelial cells in this process respond to biochemical and mechanical cues triggered by local stiffening of the ECM. Here, we investigated the influence of substrate stiffness on the Notch signaling pathway in endothelial cells. Using stiffness tuned PDMS substrates we show that Notch signaling pathway activity inversely correlates with the physiologically relevant substrate stiffness, with increased Notch activity on softer substrates. We show that trans-endocytosis of the Notch extracellular domain, but not the overall endocytosis, is regulated by substrate stiffness. Furthermore, we could show that integrin cell-matrix connections are both stiffness-dependent and influenced by Notch. Cadherin mediated cell-cell adhesion and Notch, however, influence each other in that basal Notch signaling is cell-cell contact dependent, but inhibition of the Notch signaling pathway also results in a reduction of VE-cadherin levels. We conclude that mechano-transduction of Notch activation depends on substrate stiffness highlighting the role of substrate rigidity as a modulator of Notch signaling. This may have important implications in pathological situations, such as tumor growth, associated with stiffening of the extracellular matrix.
Multistage and transmission-blocking tubulin targeting potent antimalarial discovered from the open access MMV Pathogen Box
Authors: Kumari Geeta , Jain Ravi , Sah Raj Kumar , Kalia Inderjeet , Vashistha Manu , Singh Pooja , Singh Agam Prasad , Samby Kirandeep , Burrows Jeremy , Singh Shailja
Published: May 2022

Development of resistance to current antimalarial therapies remains a significant source of concern. To address this risk, new drugs with novel targets in distinct developmental stages of Plasmodium parasites are required. In our current work, we have targeted P. falciparum Tubulin (PfTubulin) proteins which represent some of the potential drug targets for malaria chemotherapy. Plasmodial Microtubules play a crucial role during parasite proliferation, growth, and transmission, which render them highly desirable targets for the development of next-generation chemotherapeutics. Towards this, we have evaluated the antimalarial activity of Tubulin targeting compounds received from the Medicines for Malaria Venture (MMV) “Pathogen Box” against the human malaria parasite, P. falciparum (including 3D7, RKL-9 (Chloroquine resistant) and R539T (Artemisinin resistant) strains). At nanomolar concentrations, filtered out compounds exhibited pronounced multistage antimalarial effects across the parasite life cycle, including intra-erythrocytic blood stages, liver stage parasites, gametocytes and ookinetes. Concomitantly, these compounds were found to impede male gamete ex-flagellation, thus showing transmission-blocking potential of these compounds. Target mining of these potent compounds, by combining in silico, biochemical and biophysical assays, implicated PfTubulin as their molecular target, which may possibly act by disrupting microtubule assembly dynamics by binding at the interface of α-βTubulin-dimer. Further, promising ADME profile of the parent scaffold supported its consideration as a lead compound for further development. Thus, our work highlights the potential of targeting PfTubulin proteins in discovering and developing next-generation, multistage antimalarial agents for treating Multi-Drug Resistant (MDR) malaria parasites.

GRAPHICAL ABSTRACT
G6PD Inhibition Sensitizes Ovarian Cancer Cells to Oxidative Stress in the Metastatic Omental Microenvironment
Authors: Bose Shree , Huang Qiang , Ma Yunhan , Wang Lihua , Rivera Grecia O. , Ouyang Yunxin , Whitaker Regina , Gibson Rebecca A. , Kontos Christopher D. , Berchuck Andrew , Previs Rebecca , Shen Xiling
Published: May 2022

Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of ovarian cancer related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we show metastatic OC cells experience increased oxidative stress in the omental microenvironment. Metabolic reprogramming, including upregulation of the pentose phosphate pathway (PPP), a key cellular redox homeostasis mechanism, allows OC cells to compensate for this challenge. Inhibition of G6PD, the rate-limiting enzyme of the PPP, reduces tumor burden in pre-clinical models of OC, suggesting this adaptive metabolic dependency is important for OC omental metastasis.

Highlights

The omental microenvironment poses a high oxidative stress metastatic niche for ovarian cancer cells.

G6PD, a key enzyme involved in redox homeostasis and the rate-limiting enzyme of the pentose phosphate pathway (PPP) is upregulated in omental metastasis.

Inhibition of G6PD increases oxidative stress and cytotoxicity in the omental microenvironment.

Pharmacological G6PD inhibition reduces omental metastases in vivo.
Persistent Memory as an Effective Alternative to Random Access Memory in Metagenome Assembly
Authors: Sun Jingchao , Egan Rob , Ho Harrison , Li Yue , Wang Zhong
Published: May 2022

The assembly of metagenomes decomposes members of complex microbe communities and allows the characterization of these genomes without laborious cultivation or single-cell metagenomics. Metagenome assembly is a process that is memory intensive and time consuming. Multi-terabyte sequences can become too large to be assembled on a single computer node, and there is no reliable method to predict the memory requirement due to data-specific memory consumption pattern. Currently, out-ofmemory (OOM) is one of the most prevalent factors that accounts for metagenome assembly failures. In this study, we explored the possibility of using Persistent Memory (PMem) as a less expensive substitute for dynamic random access memory (DRAM) to reduce OOM and increase the scalability of metagenome assemblers. We evaluated the execution time and memory usage of three popular metagenome assemblers (MetaSPAdes, MEGAHIT, and MetaHipMer2) in datasets up to one terabase. We found that PMem can enable metagenome assemblers on terabyte-sized datasets by partially or fully substituting DRAM at a cost of longer running times. In addition, different assemblers displayed distinct memory/speed trade-offs in the same hardware/software environment. Because PMem was provided directly without any application-specific code modification, these findings are likely to be generalized to other memory-intensive bioinformatics applications.
Strategies for enriching and characterizing proteins with inhibitory properties on the yeast surface
Authors: Rezhdo Arlinda , Lessard Catherine T. , Islam Mariha , Van Deventer James A.
Published: May 2022

Display technologies are powerful tools for discovering antibodies and other binding proteins against a broad range of biological targets. However, it remains challenging to adapt display technologies for the discovery of proteins that inhibit the enzymatic activities of such targets because the phenotypic readout during display screens is binding. The goal of this work is to investigate approaches for discovering inhibitory antibodies in yeast display format using a well-defined series of constructs and the target matrix metalloproteinase-9 (MMP-9). Three previously reported antibodies (DX-2802, M0076 and FAPB2.3.6) were used to create model libraries that are representative of protein libraries consisting of inhibitory binders, non-inhibitory binders, and non-binding constructs. Conditions that preferentially enrich for inhibitory clones were identified for both magnetic bead-based enrichments and fluorescence-activated cell sorting (FACS). Finally, we used direct titration of yeast to estimate inhibitor IC50 values with yeast-displayed and soluble constructs and found that the IC50 obtained for DX-2802 in yeast display format (20.01 ± 9.01 nM) falls within the confidence interval of IC50 the soluble scFv-Fc form of DX-2802 (17.56 ± 6.16 nM). Thus, it is possible to obtain IC50 values on the yeast surface, which greatly streamlines initial characterizations of inhibitory properties. Overall, we used these well-defined constructs to identify strategies for the discovery and characterization of inhibitory clones directly in surface display format.
Genome-wide identification and expression analysis of bHLH transcription factors reveal their putative regulatory effects on petal nectar spur development in Aquilegia
Authors: Li Xueyan , Huang Hui , Zhang Zhi-Qiang
Published: May 2022

The basic helix-loop-helix (bHLH) transcription factors (TFs) control a diversity of organ morphogenesis involved in cell division and cell expansion processes. The development of petal nectar spur, which plays important roles in plant-pollinator interaction and adaptive radiation, comprised cell division and cell expansion phases in Aquilegia. Here, we conducted a genome-wide identification of the bHLH gene family in Aquilegia to determine the characteristics and the expression profiles of this gene family during the development of petal nectar spur. A total of 120 AqbHLH proteins were identified from the Aquilegia coerulea genome. The phylogenetic tree showed that AqbHLH members were divided into 15 subfamilies, among which S7 and S8 subfamilies occurred marked expansion. Nineteen residues with conservation of more than 50% were found in the four conserved regions. The publicly RNA-Seq data and qRT-PCR results showed that AqbHLH027, AqbHLH083, AqbHLH046, and AqbHLH092 would be associated with the development of petal nectar spur by regulating cell division and cell cycle in phase I. While AqbHLH036 might participate the spur cell elongation and cell expansion in phase Ⅱ. This study provides useful insights for further probing on the function of AqbHLH TFs in the regulation of petal nectar spur development.
The AraC/XylS protein MxiE and its co-regulator IpgC control a negative feedback loop in the transcription cascade that regulates type III secretion in Shigella flexneri
Authors: McKenna Joy A. , Karney Monika MA. , Chan Daniel K. , Weatherspoon-Griffin Natasha , Larios Brianda Becerra , Pilonieta Maria Carolina , Munson George P. , Wing Helen J.
Published: May 2022

Members of the AraC Family of Transcriptional Regulators (AFTRs) control the expression of many genes important to cellular processes, including virulence. In Shigella species, the type III secretion system (T3SS), a key determinant for host cell invasion, is regulated by the three-tiered VirF/VirB/MxiE transcription cascade. Both VirF and MxiE belong to the AFTRs and are characterized as positive transcriptional regulators. Here, we identify a novel regulatory activity for MxiE and its co-regulator IpgC, which manifests as a negative feedback loop in the VirF/VirB/MxiE transcription cascade. Our findings show that MxiE and IpgC down-regulate the virB promoter and hence VirB protein production, thus, decreasing VirB-dependent promoter activity at ospD1, one of the nearly 50 VirB-dependent genes. At the virB promoter, regions required for negative MxiE- and IpgC-dependent regulation were mapped and found to be coincident with regions required for positive VirF-dependent regulation. In tandem, negative MxiE- and IpgC-dependent regulation of the virB promoter only occurred in the presence of VirF suggesting that MxiE and IpgC can function to counter VirF activation of the virB promoter. Lastly, MxiE and IpgC do not down-regulate another VirF-activated promoter, icsA, demonstrating that this negative feedback loop targets the virB promoter. Our study provides insight into a mechanism that may reprogram Shigella virulence gene expression following type III secretion and provides the impetus to examine if MxiE and IpgC homologs in other important bacterial pathogens such as Burkholderia pseudomallei and Salmonella enterica serovars Typhimurium and Typhi coordinate similar negative feedback loops.

IMPORTANCE

The large AraC Family of Transcriptional Regulators (AFTRs) control virulence gene expression in many bacterial pathogens. In Shigella species, the AraC/XylS protein MxiE and its co-regulator IpgC positively regulate the expression of type III secretion system genes within the three-tiered VirF/VirB/MxiE transcription cascade. Our findings suggest a negative feedback loop in the VirF/VirB/MxiE cascade in which MxiE and IpgC counter VirF-dependent activation of the virB promoter, thus, making this the first characterization of negative MxiE- and IpgC-dependent regulation. Our study provides insight into a mechanism that likely reprograms Shigella virulence gene expression following type III secretion, which has implications for other important bacterial pathogens with functional homologs of MxiE and IpgC.
McaA and McaB control the dynamic positioning of a bacterial magnetic organelle
Authors: Wan Juan , Monteil Caroline L , Taoka Azuma , Ernie Gabriel , Park Kieop , Amor Matthieu , Taylor-Cornejo Elias , Lefevre Christopher T , Komeili Arash
Published: May 2022

Magnetotactic bacteria (MTB) are a diverse group of microorganisms that use intracellular chains of ferrimagnetic nanocrystals, produced within their magnetosome organelles, to align and navigate along the geomagnetic field. The cell biological and biochemical properties of magnetosomes make them a powerful model for studying the molecular mechanisms of biomineralization and compartmentalization in bacteria. While several conserved magnetosome formation genes have been described, the evolutionary strategies for their species-specific diversification remain unknown. Here, we demonstrate that the fragmented nature of magnetosome chains in Magnetospirillum magneticum AMB-1 is controlled by two genes named mcaA and mcaB. McaA recognizes the positive curvature of the inner cell membrane while McaB localises to magnetosomes. Along with the MamK actin-like cytoskeleton, they create space for addition of new magnetosomes in between pre-existing magnetosomes. Phylogenetic analyses suggest that McaAB homologs are widespread and may represent an ancient strategy for organelle positioning in MTB.
Concert: Genome-wide prediction of sequence elements that modulate DNA replication timing
Authors: Yang Yang , Wang Yuchuan , Zhang Yang , Ma Jian
Published: May 2022

Proper control of replication timing (RT) is of vital importance to maintain genome and epigenome integrity. However, the genome-wide sequence determinants regulating RT remain unclear. Here, we develop a new machine learning method, named Concert, to simultaneously predict RT from sequence features and identify RT-modulating sequence elements in a genome-wide manner. Concert integrates two functionally cooperative modules, a selector, which performs importance estimationbased sampling to detect predictive sequence elements, and a predictor, which incorporates bidirectional recurrent neural networks and self-attention mechanism to achieve selective learning of longrange spatial dependencies across genomic loci. We apply Concert to predict RT in mouse embryonic stem cells and multiple human cell types with high accuracy. The identified RT-modulating sequence elements show novel connections with genomic and epigenomic features such as 3D chromatin interactions. In particular, Concert reveals a class of RT-modulating elements that are not transcriptional regulatory elements but are enriched with specific repetitive sequences. As a generic interpretable machine learning framework for predicting large-scale functional genomic profiles based on sequence features, Concert provides new insights into the potential sequence determinants of RT.
Cholesterol binds the amphipathic helix of IFITM3 and regulates antiviral activity
Authors: Rahman Kazi , Datta Siddhartha A.K. , Beaven Andrew H. , Jolley Abigail A. , Sodt Alexander J. , Compton Alex A.
Published: May 2022

The interferon-induced transmembrane (IFITM) proteins broadly inhibit the entry of diverse pathogenic viruses, including Influenza A virus (IAV), Zika virus, HIV-1, and SARS coronaviruses by inhibiting virus-cell membrane fusion. IFITM3 was previously shown to disrupt cholesterol trafficking, but the functional relationship between IFITM3 and cholesterol remains unclear. We previously showed that inhibition of IAV entry by IFITM3 is associated with its ability to promote cellular membrane rigidity, and these activities are functionally linked by a shared requirement for the amphipathic helix (AH) found in the intramembrane domain (IMD) of IFITM3. Furthermore, it has been shown that the AH of IFITM3 alters lipid membranes in vitro in a cholesterol-dependent manner. Therefore, we aimed to elucidate the relationship between IFITM3 and cholesterol in more detail. Using a fluorescence-based in vitro binding assay, we found that a peptide derived from the AH of IFITM3 directly interacted with the cholesterol analog, NBD-cholesterol, while other regions of the IFITM3 IMD did not, and native cholesterol competed with this interaction. In addition, recombinant full-length IFITM3 protein also exhibited NBD-cholesterol binding activity. Importantly, previously characterized mutations within the AH of IFITM3 that strongly inhibit antiviral function (F63Q and F67Q) disrupted AH structure in solution, inhibited cholesterol binding in vitro, and restricted bilayer insertion in silico. Our data suggest that direct interactions with cholesterol may contribute to the inhibition of membrane fusion pore formation by IFITM3. These findings may facilitate the design of therapeutic peptides for use in broad-spectrum antiviral therapy.