bluuebunny/crossref_metadata_2025 huggingface dataset:
LB-14. CovidIQ- a Text Message-Based Symptom Surveillance Tracker that Predicts New Areas of Increased Incidence of Covid-19 Disease
Authors: Reza Mohammed , Magen Eran , Vora Naheed , Rogers Katherine , Moll Debbie , Warren Elaine , Suryaprasad Anil , Armas-Kolostroubis Laura , Cheung Alice
Published: January 2021

Background

Testing for SARS-CoV-2 is limited, making it difficult to estimate the true prevalence of disease and control the spread of new cases. Therefore, finding other ways to diagnose new cases of Covid-19 early is essential for preventing further spread of SARS-CoV-2 to other people in the community and prevent further outbreaks from occurring.

Methods

CovidIQ is a confidential and secure text messaging platform that works by collecting participants’ self-reported symptoms. Upon agreeing to participate, users are asked some basic demographic questions including gender, age range, ethnic background, and zip code. Participants are then queried via text message on a weekly or biweekly basis as to what symptoms they are experiencing: none, temperature >99.6F, cough, shortness of breath, headache, fatigue, loss of appetite, loss of sense of smell or taste, diarrhea, body ache, sore throat, and/or chills. The symptoms are further broken down into major and minor criteria, allowing presumptive cases to be identified with more accuracy. The major criteria include elevated body temperature, cough, and shortness of breath. If a participant has any 2 major criteria, 1 major or 2 minor, or 3 minor criteria, they are considered a presumptive positive case.

While CovidIQ cannot be used to diagnose individuals, the combined results from many individuals show real-time changes in rates of infection for entire counties. Not all people who develop Covid-19 will need hospitalization. They may remain out in the community unaware of the risk they pose to others. And, because the official count of confirmed cases is delayed by 2–4 weeks from the time of actual infection, CovidIQ can sound the alarm much earlier when rates of infection begin to spike. Advanced warning can help communities and individuals make informed decisions about how they should conduct themselves.

Results

CovidIQ identified the spike in COVID-19 cases in Jacksonville/Duval County, Florida a full two weeks before it was reported by the Florida Department of Health and Johns Hopkins University.

Prevalence of Suspected COVID-19 Cases Through the Use of the CovidIQ Platform in Relation to Dates of OfficiallyReported Cases, Duval County, FL

Conclusion

CovidIQ is a novel tool developed to augment the public health response to this ongoing crisis by informing the public sector of potential new hot spots before areas experience a surge as compared to the current reporting structure.

Disclosures

All Authors: No reported disclosures
LB-16. Association Between Universal Face Shield in a Quaternary Care Center and Reduction of SARS-COV2 Infections Among Healthcare Personnel and Hospitalized Patients
Authors: Hemmige Vagesh , Winterer Becky , Lasco Todd , Lembcke Bradley
Published: January 2021

Background

SARS-COV2 transmission to healthcare personnel (HCP) and hospitalized patients is a significant challenge. Our hospital is a quaternary healthcare system with more than 500 beds and 8,000 HCP. Between April 1 and April 17, 2020, we instituted several infection prevention strategies to limit transmission of SARS-COV2 including universal masking of HCP and patients, surveillance testing every two weeks for high-risk HCP and every week for cluster units, and surveillance testing for all patients on admission and prior to invasive procedures. On July 6, 2020, we implemented universal face shield for all healthcare personnel upon entry to facility. The aim of this study is to assess the impact of face shield policy on SARS-COV2 infection among HCP and hospitalized patients.

Figure 1- Interrupted time series

Methods

The preintervention period (April 17, 2020-July 5, 2020) included implementation of universal face masks and surveillance testing of HCP and patients. The intervention period (July 6, 2020-July 26, 2020) included the addition of face shield to all HCP (for patient encounters and staff-to-staff encounters). We used interrupted time series analysis with segmented regression to examine the effect of our intervention on the difference in proportion of HCP positive for SARS-COV2 (using logistic regression) and HAI (using Poisson regression). We defined significance as p values < 0.05.

Results

Of 4731 HCP tested, 192 tested positive for SARS-COV2 (4.1%). In the preintervention period, the weekly positivity rate among HCP increased from 0% to 12.9%. During the intervention period, the weekly positivity rate among HCP decreased to 2.3%, with segmented regression showing a change in predicted proportion positive in week 13 (18.0% to 3.7%, p< 0.001) and change in the post-intervention slope on the log odds scale (p< 0.001). A total of 14 HAI cases were identified. In the preintervention period, HAI cases increased from 0 to 5. During the intervention period, HAI cases decreased to 0. There was a change between pre-intervention and post-intervention slope on the log scale was significant (p< 0.01).

Conclusion

Our study showed that the universal use of face shield was associated with significant reduction in SARS-COV2 infection among HCP and hospitalized patients.

Disclosures

All Authors: No reported disclosures
Impact of isolating COVID-19 patients in a supervised community facility on transmission reduction among household members
Authors: López Mercé , Gallego Claudia , Abós-Herrándiz Rafael , Tobella Ana , Turmo Nuria , Monclús Alba , Martinez Alba , Rami Artur , Navas Elena , Muñoz Miguel-Angel
Published: January 2021

Background

Isolation of COVID-19 patients has been universally implemented to control transmission of the outbreak. Hotels and other facilities have been adapted to help appropriate isolation be achieved. Our study tested the efficacy of isolating patients in a reconditioned hotel versus isolation in their domiciles to reduce infection transmission.

Methods

Observational cohort study based on a survey to COVID-19 patients between April and June 2020. One cohort had been isolated in a hotel and the other in their domiciles. Multivariate regression models analyzed the factors related to the occurrence of COVID-19 infection among the household members.

Results

A total of 229 household members of COVID-19 patients were analyzed, 139 of them belonging to the group of hotel-isolated patients and 90 in the group of domicile-isolated ones. More than half of the household members became infected (53.7%). Higher risk of infection was found in the household members of domicile-isolated patients isolated and in those reporting overcrowding at home, (odds ratio [OR] 1.67, 95% confidence interval [CI] 0.89–3.12) and (OR 1.44, 95% CI 0.81; 2.56), respectively.

Conclusions

The isolation of COVID-19 patients in community-supervised facilities may protect their household members from transmission of the disease. Overcrowded homes may contribute to the transmission of the infection.
Black pepper and piperine induce anticancer effects on leukemia cell line
Authors: Banerjee Somesh , Katiyar Parul , Kumar Vijay , Saini Shashank Sagar , Varshney Ritu , Krishnan Vengadesan , Sircar Debabrata , Roy Partha
Published: January 2021

The black pepper, most commonly used in Indian cuisines for ages, is considered as “king of spices.” The present study evaluates the anticancer potential of black pepper and its main constituent, i.e. alkaloid piperine, against human leukemia cell line, K-562 cells. Gas chromatography–mass spectrometry (GC–MS) analysis confirmed the presence of piperine in black pepper extract. The methanolic extract of black pepper (BP-M) and pure piperine (PIP) showed a strong cytotoxic effect against this cell line. Both BP-M and PIP generated apoptotic bodies in K-562 cells and caused nuclear condensation as visualized by fluorescent microscopy, which was further confirmed by flow cytometry analysis. BP-M and PIP also generated reactive oxygen species in K-562 cells as established by flow cytometry. The translation of Bax, caspase-3 and caspase-9 genes was found to be upregulated with subsequent downregulation of Bcl-2 gene. The anti-proliferative effect of both BP-M and PIP was also observed by trypan blue staining and was further confirmed by the downregulated expression of proliferating cell nuclear antigen (PCNA). The molecular docking studies showed the binding of PIP with PCNA and Bcl-2 and supported the in vitro findings. The docking studies also proposed the binding of PIP to ADP binding pocket of Apaf-1 protein. Taken together, these findings signify the anticancer potential of both black pepper and PIP, thus proposing black pepper as a potent nutraceutical for preventing the progression of chronic myeloid leukemia.
Structure of African Populations of Pyricularia oryzae from Rice
Authors: Odjo Théophile , Diagne Diariatou , Adreit Henri , Milazzo Joëlle , Raveloson Harinjaka , Andriantsimialona Dodelys , Kassankogno Abalo Itolou , Ravel Sébastien , Gumedzoé Yawovi Mawuéna Dieudonné , Ouedraogo Ibrahima , Koita Ousmane , Silué Drissa , Tharreau Didier
Published: January 2021

Rice blast, caused by the filamentous ascomycete Pyricularia oryzae, is one of the most devastating diseases of rice. Four genetic clusters were previously identified, and three have a large geographic distribution. Asia is the center of diversity and the origin of most migrations to other continents, and sexual reproduction persisted only in the South China–Laos–North Thailand region, which was identified as the putative center of origin of all P. oryzae populations on rice. Despite the importance of rice blast disease, little is known about the diversity and the population structure of the pathogen in Africa (including Madagascar). The present study was intended to describe the structure of African populations of P. oryzae and identify the relationship between African and worldwide genetic clusters. A set of 2,057 strains (937 African and 1,120 Madagascan strains) were genotyped with 12 simple sequence repeat markers to assess the diversity and the population structure of P. oryzae. Four genetic clusters were identified in Africa and Madagascar. All four clusters previously identified are present in Africa. Populations from West Africa, East Africa, and Madagascar are highly differentiated. The geographic structure is consistent with limited dispersion and with some migration events between neighboring countries. The two mating types are present in Africa with a dominance of Mat1.2, but no female-fertile strain was detected, supporting the absence of sexual reproduction on this continent. This study showed an unsuspected high level of genetic diversity of P. oryzae in Africa and suggested several independent introductions.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Lignin Composition and Timing of Cell Wall Lignification Are Involved in Brassica napus Resistance to Stem Rot Caused by Sclerotinia sclerotiorum
Authors: Höch Kerstin , Koopmann Birger , von Tiedemann Andreas
Published: January 2021

Sclerotinia stem rot (SSR) is an economically and globally significant disease in oilseed rape (Brassica napus) caused by the necrotrophic ascomycete Sclerotinia sclerotiorum. This study explored the role of cell wall reinforcement by lignin as a relevant factor for effective plant defense against attack by this pathogen. Expression of key genes in the phenylpropanoid pathway and the induced synthesis of lignin in infected stem tissues were investigated in a study comparing a susceptible (‘Loras’) and a moderately resistant cultivar (‘Zhongyou 821’ [ZY821]). Data revealed an earlier and more rapid defense activation in ZY821 through upregulation of transcript levels of genes related to key steps in the phenylpropanoid pathway associated with increased lignin deposition in the resistant B. napus genotype. Expression level of BnCAD5, encoding a cinnamyl alcohol dehydrogenase, responsible for conversion of monolignol to lignin, was more rapidly upregulated in ZY821 than ‘Loras’. The similar expression pattern of BnCAD5 and the gene BnF5H, encoding for ferulate-5-hydroxylase, which catalyzes the synthesis of syringyl (S) lignin precursors, suggests that BnCAD5 is involved in S lignin formation. Histological observations confirmed these results, showing an earlier increase of S lignin deposition in the infected resistant genotype. Deposition of guaiacyl lignin was detected in both genotypes and is thus considered a component of basal, cultivar-independent defense response of B. napus to stem rot. The results indicate the importance of cell wall modification for quantitative stem rot resistance by responses in the phenylpropanoid metabolism generating distinct lignin types on different temporal scales.
Identifying Acute Lumbar Spondylolysis in Young Athletes with Low Back Pain
Authors: Aoyagi Masashi , Naito Kei , Sato Yuichi , Kobayashi Atsushi , Sakamoto Masaaki , Tumilty Steve
Published: January 2021

Study Design.

Case–control study.

Objective.

The aim of this study was to establish an algorithm to distinguish acute lumbar spondylolysis (LS) from nonspecific low back pain (NSLBP) among patients in junior high school by classification and regression tree (CART) analysis.

Summary of Background Data.

Rapid identification of acute LS is important because delayed diagnosis may result in pseudarthrosis in the pars interarticularis. To diagnose acute LS, magnetic resonance imaging (MRI) or computed tomography is necessary. However, not all adolescent patients with low back pain (LBP) can access these technologies. Therefore, a clinical algorithm that can detect acute LS is needed.

Methods.

The medical records of 223 junior high school-aged patients with diagnosed acute NSLBP or LS verified by MRI were reviewed. A total of 200 patients were examined for establishing the algorithm and 23 were employed for testing the performance of the algorithm. CART analysis was applied to establish the algorithm using the following data; age, sex, school grades, days after symptom onset, history of LBP, days of past LBP, height, passive straight leg raising test results, hours per week spent in sports activities, existence of spina bifida, lumbar lordosis angle, and lumbosacral joint angle. Sensitivity and specificity of the algorithm and the area under the ROC curve were calculated to assess algorithm performance.

Results.

The algorithm revealed that sex, days after symptom onset, days of past LBP, hours per week spent in sports activities, and existence of spina bifida were key predictors for identifying acute LS versus NSLBP. Algorithm sensitivity was 0.64, specificity was 0.92, and the area under the ROC curve was 0.79.

Conclusion.

The algorithm can be used in clinical practice to distinguish acute LS from NSLBP in junior high school athletes, although referral to MRI may be necessary for definitive diagnosis considering the algorithm's sensitivity.

Level of Evidence: 4
Characteristic Clinicopathological Features of Secondary Extramammary Paget Disease With Underlying Anorectal Adenocarcinoma: Evenly Circumferential Perianal Distribution, Fibroepithelioma of Pinkus-like Changes, and Subepidermal Mucin Deposits Without Invasive Tumor Cells
Authors: Sasaki Yosuke , Goto Keisuke , Sugino Takashi , Satake Kosuke , Yoshikawa Shusuke , Kiyohara Yoshio
Published: January 2021

This study aimed to identify the clinical and histopathological characteristics of secondary extramammary Paget disease (EMPD) with underlying anorectal adenocarcinoma so as to differentiate it from primary cutaneous EMPD. Seventeen and 8 cases of primary and secondary EMPD with anorectal adenocarcinoma, respectively, were retrieved from the pathology archive and the clinical and histopathological features reviewed. The tumor samples from 21 cases were totally resected specimens, whereas 3 and 1 of secondary and primary cases were punch biopsied, respectively. All 8 (100%) cases of secondary EMPD presented evenly distributed perianal lesions. By contrast, 4 of 17 (23.5%) primary EMPD cases had perianal skin lesions and displayed an uneven, asymmetrical distribution around the anus. Fibroepithelioma of Pinkus-like changes and subepidermal mucin deposits with no or few invasive tumor cells were observed in 6 (75%) and 3 (37.5%) of the 8 secondary EMPD cases, respectively, although 3 secondary case samples were small biopsy specimens. Both the histopathological changes were not observed in any of the 17 primary EMPD cases. Evenly circumferential perianal distribution, fibroepithelioma of Pinkus-like changes, and subepidermal mucin deposits without invasive tumor cells were characteristic to cases of secondary EMPD with anorectal adenocarcinoma. These clinicopathological features could be used to differentiate between secondary and primary EMPD.
Safety of Ventricular Reservoir Sampling in Pediatric Posthemorrhagic Hydrocephalus Patients: Institutional Experience and Review of the Literature
Authors: Li Daphne , Romanski Kathy , Kilgallon Maureen , Speck Stacy , Bowman Robin , DiPatri Arthur , Alden Tord , Tomita Tadanori , Lam Sandi , Saratsis Amanda M.
Published: January 2021

INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) is a common disease process encountered in neonates. Management often includes cerebrospinal fluid (CSF) aspiration through ventricular access devices (VADs). However, a common concern surrounding serial access of implanted subcutaneous reservoirs includes introduction of infection. In addition, there is great variability in aseptic technique. Therefore, the authors sought to evaluate the incidence of VAD access-associated infections in the literature and compare them with the rate of infection found at our institution. We also highlight the use of a preassembled VAD access kit and standardized access protocol, as well as the role of provider education, in maintaining safety and sterility during serial VAD access. METHODS: A single-institution retrospective review was performed for PHH patients younger than 1 year old undergoing serial CSF aspirations via implanted VADs (2009–2019). Patients were excluded if they had a ventriculoperitoneal shunt placed as primary intervention. MEDLINE search for reports of serial VAD access in PHH was also performed. Reports were excluded if they did not include full-text articles in the English literature. RESULTS: At our institution, subcutaneous reservoirs were placed in 37 neonates with PHH for serial CSF aspiration. No infections occurred after a total of 630 taps (average, 17 taps per reservoir; range, 0–83) and 10 420 collective reservoir days (average, 282 per patient; range, 6–3700). Only 2 reservoirs required revision for malfunction. Serial VAD taps for PHH were described in 14 articles in the medical literature, with 7.9% (n = 47/592) of patients reported with tap-related infectious complications. CONCLUSION: A standardized VAD access kit, along with stringent adherence to access protocol, can significantly minimize risk of infection associated with serial VAD access. These principles can be generalized to percutaneous aspiration of CSF from subcutaneous reservoirs placed for other indications to promote safety and sterility of this common procedure.
Preserving and enhancing social health in neurocognitive disorders
Authors: Samtani Suraj , Stevens Ashley , Brodaty Henry
Published: January 2021

Purpose of review

The WHO updated concept of health includes social health alongside physical and mental health. No existing reviews have examined the evidence for preserving or enhancing social health in people living with neurocognitive disorders, such as mild cognitive impairment and dementia. The present review examines recent epidemiological studies and interventions with social health outcome measures, including interventions across multiple modalities and settings, from communities to assisted living facilities.

Recent findings

Epidemiological evidence shows that neurocognitive disorders are associated with poorer social support, and greater social isolation and loneliness. This highlights the importance of maintaining and enhancing social health in people living with neurocognitive disorders. Group activities involving dance or music have emerging evidence indicating improvements in social health in communities and assisted living facilities. More quantitative research is required on the social health benefits of cognitive/multicomponent interventions, community social groups, exercise groups and other interventions. Several socially assistive robots are being developed to help foster social participation and require further research.

There is evidence that group music or dance interventions can improve social health for people living with neurocognitive disorders. Larger trials with multiple social health outcome measures are required to investigate the social health benefits of exercise, cognitive/multicomponent and community social group interventions.
Identifiability of infection model parameters early in an epidemic
Authors: Sauer Timothy , Berry Tyrus , Ebeigbe Donald , Norton Michael M. , Whalen Andrew , Schiff Steven J.
Published: January 2021

It is known that the parameters in the deterministic and stochastic SEIR epidemic models are structurally identifiable. For example, from knowledge of the infected population time series I(t) during the entire epidemic, the parameters can be successfully estimated. In this article we observe that estimation will fail in practice if only infected case data during the early part of the epidemic (pre-peak) is available. This fact can be explained using a long-known phenomenon called dynamical compensation. We use this concept to derive an unidentifiability manifold in the parameter space of SEIR that consists of parameters indistin-guishable to I(t) early in the epidemic. Thus, identifiability depends on the extent of the system trajectory that is available for observation. Although the existence of the unidentifiability manifold obstructs the ability to exactly determine the parameters, we suggest that it may be useful for uncertainty quantification purposes. A variant of SEIR recently proposed for COVID-19 modeling is also analyzed, and an analogous unidentifiability surface is derived.
SARS-CoV-2 positivity in asymptomatic-screened dental patients
Authors: Conway DI , Culshaw S , Edwards M , Clark C , Watling C , Robertson C , Braid R , O’Keefe E , McGoldrick N , Burns J , Provan S , VanSteenhouse H , Hay J , Gunson R ,   Dental COVID-19 Surveillance Survey Group
Published: January 2021

Enhanced community surveillance is a key pillar of the public health response to COVID-19. Asymptomatic carriage of SARS-CoV-2 is a potentially significant source of transmission, yet remains relatively poorly understood. Disruption of dental services continues with significantly reduced capacity. Ongoing precautions include pre- and/or at appointment COVID-19 symptom screening and use of enhanced personal protective equipment (PPE). This study aimed to investigate SARS-CoV-2 infection in dental patients to inform community surveillance and improve understanding of risks in the dental setting. Thirty-one dental care centres across Scotland invited asymptomatic screened patients over 5-years-old to participate. Following verbal consent and completion of sociodemographic and symptom history questionnaire, trained dental teams took a combined oropharyngeal and nasal swab sample using standardised VTM-containing testkits. Samples were processed by the Lighthouse Lab and patients informed of their results by SMS/e-mail with appropriate self-isolation guidance in the event of a positive test. Over a 13-week period (from 3August to 31October2020) n=4,032 patients, largely representative of the population, were tested. Of these n=22 (0.5%; 95%CI 0.5%, 0.8%) tested positive for SARS-CoV-2. The positivity rate increased over the period, commensurate with uptick in community prevalence identified across all national testing monitoring data streams. All positive cases were successfully followed up by the national contact tracing program. To the best of our knowledge this is the first report of a COVID-19 testing survey in asymptomatic-screened patients presenting in a dental setting. The positivity rate in this patient group reflects the underlying prevalence in community at the time. These data are a salient reminder, particularly when community infection levels are rising, of the importance of appropriate ongoing Infection Prevention Control and PPE vigilance, which is relevant as healthcare team fatigue increases as the pandemic continues. Dental settings are a valuable location for public health surveillance.
Synaptopodin is required for stress fiber and contractomere assembly at the epithelial junction
Authors: Morris Timothy , Sue Eva , Geniesse Caleb , Brieher William M , Tang Vivian W
Published: January 2021

The apical junction of epithelial cells can generate force to control cell geometry and perform contractile processes while maintaining barrier function and adhesion. Yet, the structural basis for force generation at the apical junction is not fully understood. Here, we describe 2 synaptopodin-dependent actomyosin structures that are spatially, temporally, and structurally distinct. The first structure is formed by retrograde flow of synaptopodin initiated at the apical junction, creating sarcomeric stress fibers that lie parallel to the junction and insert into junctional complexes on the apical plane. Retrograde flow of synaptopodin is also seen at vinculin-decorated basal junctions on the basal plane. Contractions of apical stress fibers is associated with clustering of membrane complexes via side-on synaptopodin linkers whereas contractions of stress fibers inserted at the apical junction via head-on synaptopodin linkers results in junction shortening. Upon junction maturation, apical stress fibers are disassembled. In mature epithelial monolayer, a motorized “contractomere” complex capable of “walking the junction” is formed at junction vertices. Contractomere motility results in changes in junctional length, altering the overall shape of the cell and packing geometry within the monolayer. We propose a model of epithelial homeostasis that utilizes contractomere motility to preserve the permeability barrier during intercellular movement and junctional processes.

Summary Statement

Synaptopodin retrograde flows initiate the assembly of apical and basal stress fibers from the apical and basal junctions. In mature apical junction, a motorized junctional complex, we termed the contractomere, allows the apical junction to change length and organize cell geometry within a confluent monolayer.
Cell type resolved co-expression networks of core clock genes in brain development
Authors: Sharma Surbhi , Ansari Asgar Hussain , Ramasamy Soundhar
Published: January 2021

The circadian clock regulates vital cellular processes by adjusting the physiology of the organism to daily changes in the environment. Rhythmic transcription of core Clock Genes (CGs) and their targets regulate these processes at the cellular level. Circadian clock disruption has been observed in people with neurodegenerative disorders like Alzheimer’s and Parkinson’s. Also, ablation of CGs during development has been shown to affect neurogenesis in both in vivo and in vitro models. Previous studies on the function of CGs in the brain have used knock-out models of a few CGs. However, a complete catalog of CGs in different cell types of the developing brain is not available and it is also tedious to obtain. Recent advancements in single-cell RNA sequencing (scRNA-seq) has revealed novel cell types and elusive dynamic cell states of the developing brain. In this study by using publicly available single-cell transcriptome datasets we systematically explored CGs-coexpressing networks (CGs-CNs) during embryonic and adult neurogenesis. Our meta-analysis reveals CGs-CNs in human embryonic radial glia, neurons and also in lesser studied non-neuronal cell types of the developing brain.
Simultaneous inhibition of human CD4 and 4-1BB biogenesis suppresses cytotoxic T lymphocyte proliferation
Authors: Claeys Elisa , Pauwels Eva , Humblet-Baron Stephanie , Schols Dominique , Waer Mark , Sprangers Ben , Vermeire Kurt
Published: January 2021

The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA usingin vitroactivation models. CADA inhibited lymphocyte proliferation in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads or phytohemagglutinin. The immunosuppressive effect of CADA involved both CD4+and CD8+T cells but was, surprisingly, most prominent in the CD8+T cell subpopulation where it inhibited cell-mediated lympholysis. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8+T cells. More specifically, CADA blocked 4-1BB protein biosynthesis by inhibition of its co-translational translocation across the ER membrane in a signal peptide-dependent way. This study demonstrates that CADA, as potent down-modulator of human CD4 and 4-1BB, has promisingin vitroimmunomodulatory characteristics for futurein vivoexploration as immunosuppressive drug.
Fluctuations in population densities inform stability mechanisms in host-parasitoid interactions
Authors: Singh Abhyudai
Published: January 2021

Population dynamics of host-parasitoid interactions has been traditionally studied using a discrete-time formalism starting from the classical work of Nicholson and Bailey. It is well known that differences in parasitism risk among individual hosts can stabilize the otherwise unstable equilibrium of the Nicholson-Bailey model. Here, we consider a stochastic formulation of these discrete-time models, where the host reproduction is a random variable that varies from year to year and drives fluctuations in population densities. Interestingly, our analysis reveals that there exists an optimal level of heterogeneity in parasitism risk that minimizes the extent of fluctuations in the host population density. Intuitively, low variation in parasitism risk drives large fluctuations in the host population density as the system is on the edge of stability. In contrast, high variation in parasitism risk makes the host equilibrium sensitive to the host reproduction rate, also leading to large fluctuations in the population density. Further results show that the correlation between the adult host and parasitoid densities is high for the same year, and gradually decays to zero as one considers cross-species correlations across different years. We next consider an alternative mechanism of stabilizing host-parasitoid population dynamics based on a Type III functional response, where the parasitoid attack rate accelerates with increasing host density. Intriguingly, this nonlinear functional response makes qualitatively different correlation signatures than those seen with heterogeneity in parasitism risk. In particular, a Type III functional response leads to uncorrelated adult and parasitoid densities in the same year, but high cross-species correlation across successive years. In summary, these results argue that the cross-correlation function between population densities contains signatures for uncovering mechanisms that stabilize consumer-resource population dynamics.
The structural basis for Ulp2 recruitment to the kinetochore
Authors: Quan Yun , Hinshaw Stephen M. , Wang Pang-Che , Harrison Stephen C. , Zhou Huilin
Published: January 2021

The step-by-step process of chromosome segregation defines the stages of the cell division cycle. In eukaryotes, signaling pathways that control these steps converge upon the kinetochore, a multiprotein assembly that connects spindle microtubules to the centromere of each chromosome. Kinetochores control and adapt to major chromosomal transactions, including replication of centromeric DNA, biorientation of sister centromeres on the metaphase spindle, and transit of sister chromatids into daughter cells during anaphase. Although the mechanisms that ensure tight microtubule coupling at anaphase are at least partly understood, kinetochore adaptations that support other cell cycle transitions are not. We report here a mechanism that enables regulated control of kinetochore sumoylation. A conserved surface of the Ctf3/CENP-I kinetochore protein provides a binding site for the SUMO protease, Ulp2. Ctf3 mutations that disable Ulp2 recruitment cause elevated inner kinetochore sumoylation and defective chromosome segregation. The location of the site within the assembled kinetochore suggests coordination between sumoylation and other cell cycle-regulated processes.
Impact ofCymbopogon flexuosus(Poaceae) essential oil and primary components on the eclosion and larval development ofAedes aegypti(Diptera: Culicidae)
Authors: Castillo-Morales Ruth Mariela , Serrano Sugey Ortiz , Villamizar Adriana Lisseth Rodríguez , Mendez-Sanchez Stelia Carolina , Duque Jonny E.
Published: January 2021

The current study describes the effects of sub-lethal concentrations and constituent compounds (citral and geranyl acetate) ofCymbopogon flexuosusessential oil (EO) on the development ofAedes aegypti(L.) eggs and larvae. To demonstrate the ovicidal activity of EO, we treated embryonated eggs with 6, 18, and 30 mg.L-1and larvae with 3 and 6 mg.L-1EO concentrations. Citral and geranyl acetate were evaluated at 18, 30, and 42 mg.L-1and compared with commercial growth inhibitors (diflubenzuron and methoprene) at 3 and 6 mg.L-1concentrations. For each treatment, we measured larval head diameter, siphon length, and body length. To complement the morphological analysis, we examined concentrations of moult hormone (MH) and juvenile hormone III (JH III) using high-performance liquid chromatography (HPLC) coupled to mass spectrometry. The EO decreased egg hatching at all concentrations: 6 mg.L-1in 45.3%; 18 mg.L-1in 23.3%, and 30 mg.L-1in 34.6%. EO also altered molting among larval instars and between larvae and pupae, with an increase in the length (3 mg.L-1: 6 ± 0.0 mm; 6 mg.L-1: 6 ± 0.7 mm) and head width (3 mg.L-1: 0.8 ± 0 mm; 6 mg.L-1: 0.8 ± 0.0 mm) compared with the control group (length: 5.3 ± 0 mm; head width: 0.7 ± 0.0 mm). We did not detect chromatographic signals of MH and JH III in larvae treated withC. flexuosusEO or their major compounds. The sub-lethal concentrationsC. flexuosusEO caused a similar effect to diflubenzuron, decreasing hormone concentration, extending the larval period, and death.
Hippocampal representations of distance, space, and direction and their plasticity predict navigational performance
Authors: Moore Jason J , Cushman Jesse D , Acharya Lavanya , Mehta Mayank R
Published: January 2021

The hippocampus is implicated in episodic memory and allocentric spatial navigation. However, spatial selectivity is insufficient to navigate; one needs information about the distance and direction to the reward on a specific journey. The nature of these representations, whether they are expressed in an episodic-like sequence, and their relationship with navigational performance are unknown. We recorded single units from dorsal CA1 of the hippocampus while rats navigated to an unmarked reward zone defined solely by distal visual cues, similar to the classic water maze. The allocentric spatial selectivity was substantially weaker than in typical real world tasks, despite excellent navigational performance. Instead, the majority of cells encoded path distance from the start of trials. Cells also encoded the rat’s allocentric position and head angle. Often the same cells multiplexed and encoded path distance, head direction and allocentric position in a sequence, thus encoding a journey-specific episode. The strength of neural activity and tuning strongly correlated with performance, with a temporal relationship indicating neural responses influencing behavior and vice versa. Consistent with computational models of associative Hebbian learning, neural responses showed increasing clustering and became better predictors of behaviorally relevant variables, with neurometric curves exceeding and converging to psychometric curves. These findings demonstrate that hippocampal neurons multiplex and exhibit highly plastic, task- and experience-dependent tuning to path-centric and allocentric variables to form an episode, which could mediate navigation.
The characteristics of intracellular Ca2+signalsin vivonecessitate a new model for salivary fluid secretion
Authors: Takano Takahiro , Wahl Amanda M. , Huang Kai-Ting , Rugis John , Sneyd James , Yule David I.
Published: January 2021

Salivary fluid secretion involves an intricate choreography to result in the trans-epithelial movement of NaCl and water into the acinus lumen. Current models are based on experimental observations in enzymatically isolated cells where the Ca2+signal invariably propagates globally and thus appears ideally suited to activate spatially separated Cl and K channels. We monitored Ca2+signals and salivary secretion in live mice expressing GCamp6F, following stimulation of the nerves innervating the submandibular gland. Consistent within vitrostudies, Ca2+signals were initiated in the apical endoplasmic reticulum. In marked contrast toin vitrodata, highly localized trains of Ca2+transients that failed to propagate from the apical region were observed. Following stimuli optimum for secretion, large apical-basal gradients were elicited. Given this incompatibility to the previous model, a new mathematical model was constructed to explain how salivary secretion can be efficiently stimulated by apically localized Ca2+signals.
Pan-cancer analysis of mRNA stability for decoding tumour post-transcriptional programs
Authors: Perron Gabrielle , Jandaghi Pouria , Rajaee Maryam , Alkallas Rached , Riazalhosseini Yasser , Najafabadi Hamed S.
Published: January 2021

RNA stability is a crucial and often overlooked determinant of gene expression. Some of the regulators of mRNA stability are long known as key oncogenic or tumour suppressor factors. Nonetheless, the extent to which mRNA stability contributes to transcriptome remodeling in cancer is unknown, and the factors that modulate mRNA stability during cancer development and progression are largely uncharacterized. Here, by decoupling transcriptional and post-transcriptional effects in RNA-seq data of 7760 samples from 18 cancer types, we present a pan-cancer view of the mRNA stability changes that accompany tumour development and progression. We show that thousands of genes are dysregulated at the mRNA stability level, and identify the potential factors that drive these changes, including >80 RNA-binding proteins (RBPs) and microRNAs (miRNAs). Most RBPs and miRNAs have cancer type-specific activities, but a few show recurrent inactivation across multiple cancers, including the RBFOX family of RBPs and miR-29. Analysis of cell lines with phenotypic activation or inhibition of RBFOX1 and miR-29 confirms their role in modulation of genes that are dysregulated across multiple cancers, with functions in calcium signaling, extracellular matrix organization, and stemness. Overall, our study highlights the critical role of mRNA stability in shaping the tumour transcriptome, with recurrent post-transcriptional changes that are ~30% as frequent as transcriptional events. These results provide a resource for systematic interrogation of cancer-associated stability drivers and pathways.
Allosteric communication in Class A β-lactamases occurs via Cooperative Coupling of Loop Dynamics
Authors: Galdadas Ioannis , Qu Shen , F Oliveria Ana Sofia , Olehnovics Edgar , Mack Andrew R , Mojica Maria F , Agarwal Pratul K , Tooke Catherine L , Gervasio Francesco L , Spencer James , Bonomo Robert A , Mulholland Adrian J , Haider Shozeb
Published: January 2021

Allosteric effects control protein (e.g. enzyme) activity in ways that are not fully understood. Better understanding of allosteric effects, and tools to identify them, would offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways from two distant ligand binding sites to important active site structural elements that control enzymatic activity in two prototypical class A β-lactamases, TEM-1 and KPC-2. Both of these enzymes are important determinants of antibiotic resistance in widespread bacterial pathogens. The simulations show that the allosteric sites are connected to the active site in both enzymes, (e.g. affecting the conformation of the Ω-loop) highlighting how allosteric inhibitors may exert their effects. Nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. In these identified signaling pathways, the propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more clinically relevant amino acid substitutions in each enzyme map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.
Integrative analysis reveals unique features of the Smc5/6 complex
Authors: Yu You , Li Shibai , Ser Zheng , Sanyal Tanmoy , Choi Koyi , Wan Bingbing , Sali Andrej , Kentsis Alex , Patel Dinshaw J. , Zhao Xiaolan
Published: January 2021

Structural maintenance of chromosomes (SMC) complexes are critical chromatin modulators. In eukaryotes, the cohesin and condensin SMC complexes organize chromatin, while the Smc5/6 complex directly regulates DNA replication and repair. The molecular basis for Smc5/6’s distinct functions is currently poorly understood. Here, we report an integrative structural study of the budding yeast Smc5/6 complex using electron microscopy, cross-linking mass spectrometry, and computational modeling. We show that while the complex shares a similar overall organization with other SMC complexes, it possesses several unique features. In contrast to the reported folded-arm structures of cohesin and condensin, our data suggest that Smc5 and Smc6 arm regions do not fold back on themselves. Instead, these long filamentous regions interact with subunits uniquely acquired by the Smc5/6 complex, namely the Nse2 SUMO ligase and the Nse5-Nse6 subcomplex. Further, we show that Nse5-Nse6 subcomplex adopts a novel structure with an extensive dimerization interface and multiple domains contacting other subunits of the Smc5/6 complex. We also provide evidence that the Nse5-Nse6 module uses its SUMO-binding motifs to contribute to Nse2-mediated sumoylation. Collectively, our integrative multi-scale study identifies distinct structural features of the Smc5/6 complex and functional cooperation amongst its co-evolved unique subunits.
Olfactory coding in the bumble bee antennal lobe
Authors: Mertes Marcel , Carcaud Julie , Sandoz Jean-Christophe
Published: January 2021

Sociality is classified as one of the major transitions in evolution, with the largest number of eusocial species found in the insect order Hymenoptera, including the Apini (honey bees) and the Bombini (bumble bees). Bumble bees and honey bees not only differ in their social organization and foraging strategies, but comparative analyses of their genomes demonstrated that bumble bees have a slightly less diverse family of olfactory receptors than honeybees, suggesting that their olfactory abilities have adapted to different social and/or ecological conditions. However, unfortunately, no precise comparison of olfactory coding has been performed so far between honey bees and bumble bees, and little is known about the rules underlying olfactory coding in the bumble bee brain. In this study, we usedin vivocalcium imaging to study olfactory coding of a panel of floral odorants in the antennal lobe (AL) of the bumble beeBombus terrestris. Our results show that odorants evoke consistent neuronal activity in the bumble bee antennal lobe. Each odorant evokes a different glomerular activity pattern revealing this molecule’s chemical structure, i.e. its carbon chain length and functional group. Response intensity as well as odor-similarity relationships were highly correlated to those measured in honey bees. This study thus suggests that bumble bees, like honey bees, are equipped to respond to odorants according to their chemical features.
Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses
Authors: Banchenko Sofia , Krupp Ferdinand , Gotthold Christine , Bürger Jörg , Graziadei Andrea , O’Reilly Francis , Sinn Ludwig , Ruda Olga , Rappsilber Juri , Spahn Christian M. T. , Mielke Thorsten , Taylor Ian A. , Schwefel David
Published: January 2021

Viruses have evolved means to manipulate the host’s ubiquitin-proteasome system, in order to down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp the substrate receptor DCAF1 of host Cullin4-RING ligases (CRL4), a family of modular ubiquitin ligases involved in DNA replication, DNA repair and cell cycle regulation. CRL4DCAF1specificity modulation by Vpx and Vpr from certain simian immunodeficiency viruses (SIV) leads to recruitment, poly-ubiquitylation and subsequent proteasomal degradation of the host restriction factor SAMHD1, resulting in enhanced virus replication in differentiated cells. To unravel the mechanism of SIV Vpr-induced SAMHD1 ubiquitylation, we conducted integrative biochemical and structural analyses of the Vpr protein from SIVs infectingCercopithecus cephus(SIVmus). X-ray crystallography reveals commonalities between SIVmusVpr and other members of the Vpx/Vpr family with regard to DCAF1 interaction, while cryo-electron microscopy and cross-linking mass spectrometry highlight a divergent molecular mechanism of SAMHD1 recruitment. In addition, these studies demonstrate how SIVmusVpr exploits the dynamic architecture of the multi-subunit CRL4DCAF1assembly to optimise SAMHD1 ubiquitylation. Together, the present work provides detailed molecular insight into variability and species-specificity of the evolutionary arms race between host SAMHD1 restriction and lentiviral counteraction through Vpx/Vpr proteins.

Author summary

Due to the limited size of virus genomes, virus replication critically relies on host cell components. In addition to the host cell’s energy metabolism and its DNA replication and protein synthesis apparatus, the protein degradation machinery is an attractive target for viral re-appropriation. Certain viral factors divert the specificity of host ubiquitin ligases to antiviral host factors, in order to mark them for destruction by the proteasome, to lift intracellular barriers to virus replication. Here, we present molecular details of how the simian immunodeficiency virus accessory protein Vpr interacts with a substrate receptor of host Cullin4-RING ubiquitin ligases, and how this interaction redirects the specificity of Cullin4-RING to the antiviral host factor SAMHD1. The studies uncover the mechanism of Vpr-induced SAMHD1 recruitment and subsequent ubiquitylation. Moreover, by comparison to related accessory proteins from other immunodeficiency virus species, we illustrate the surprising variability in the molecular strategies of SAMHD1 counteraction, which these viruses adopted during evolutionary adaptation to their hosts. Lastly, our work also provides deeper insight into the inner workings of the host’s Cullin4-RING ubiquitylation machinery.