bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative Medicine and Health Therapy for Parkinson Disease
Authors: Hall Mary-Frances E. , Church Frank C.
Published: July 2020

Parkinson disease (PD) is the second most common neurodegenerative disorder with approximately 60 000 newly diagnosed patients yearly in the United States. PD is traditionally described as a motor system condition, although numerous nonmotor symptoms exist, and typically manifest within elderly patients. The hallmark pathogenesis of PD is the loss of dopaminergic neurons within the substantia nigra region. This leads to a traditional treatment goal of dopamine replacement. We outline an integrative medicine and health strategy for PD that utilizes not only traditional but also nontraditional therapeutic approaches. This strategy supports the neuronal microenvironment and restorative health of both the brain and the body.
Staging of Dementia Severity With the Hong Kong Version of the Montreal Cognitive Assessment (HK-MoCA)’s
Authors: Pan Ian Ming Yeung , Lau Mei Suen , Mak Shun Chi , Hariman Keith Wilfred , Hon Simon King Him , Ching Wing Ka , Cheng Koi Man , Chan Cheong Fai
Published: July 2020

Background:

The Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) has been used to screen for dementia, but it has not been validated to delineate the stages of Alzheimer disease (AD). This study aimed to determine the cut-off score ranges for mild, moderate, and severe AD.

Methods:

The HK-MoCA score was matched against the Clinical Dementia Rating on 155 patients with AD. Investigators performing the HK-MoCA and Clinical Dementia Rating were blinded to each other. Receiver-operating characteristic analysis was used to determine the cut-off scores between different stages of AD (mild, moderate, and severe stage). A secondary analysis with adjustments for age and education received were also performed.

Result:

The cut-off score in HK-MoCA was ≤4 for those with severe AD (sensitivity 84.4%, specificity 91.9%, area under curve=0.92, P<0.001) and 5 to 9 for those with moderate AD (sensitivity 86.3%, specificity of 93.3%, area under curve=0.953, P<0.001). With adjustments for age and education, the cut-off score for moderate AD was adjusted to 5 to 8, whereas the cut-off score for severe AD remained unchanged.

Conclusions:

The severity of AD could be delineated using the HK-MoCA for the Cantonese-speaking population in Hong Kong, and the effect of education on the cut-off score needs further investigation.
Nonepileptic Electroencephalographic Correlates of Episodic Increases in Intracranial Pressure
Authors: Sheikh Zubeda B. , Maciel Carolina B. , Dhakar Monica B. , Hirsch Lawrence J. , Gilmore Emily J.
Published: July 2020

Purpose:

Continuous EEG can potentially be used as real-time brain telemetry for the early detection of neurologic decline. Scant literature on EEG changes related to elevated intracranial pressure (ICP) limits its use in this context.

Methods:

Retrospective, observational case series of patients in whom we noted EEG changes correlating with a clinical concern for elevated ICP, measured or unmeasured.

Results:

We noted EEG changes of varying severity and duration correlating with either measured or unmeasured clinical concern for elevated ICP. In two patients with recurrent transient unresponsiveness (presumed from plateau waves), generalized rhythmic delta activity and attenuation of fast activity occurred 30 minutes before a clinical change. Elevated ICP in two patients, one related to progressive mass effect from infarctions, and the other to dialysis, correlated with generalized slowing and attenuation of fast activity up to 24 hours before clinical deterioration, leading to diffuse suppression. Two patients with intraventricular hemorrhage had cyclic patterns at ∼1 per minute and ∼6 per minute (similar frequency to described frequency of Lundberg B and C waves, respectively).

Conclusions:

Cyclic patterns and varying degrees of slowing and attenuation often preceded clinical deterioration associated with intracranial hypertension. Future systematic studies of EEG changes in this setting will facilitate early and noninvasive detection of elevated ICP.
Comparative Effectiveness Study of Home-Based Interventions to Prevent CA-MRSA Infection Recurrence
Authors: Tobin Jonathan N. , Hower Suzanne , D’Orazio Brianna M. , de la Gándara María Pardos , Evering Teresa H. , Khalida Chamanara , Kost Rhonda G. , Vasquez Kimberly S. , de Lencastre Hermínia , Tomasz Alexander , Coller Barry S. , Vaughan Roger
Published: July 2020

BACKGROUND

Recurrent skin and soft tissue infections (SSTI) caused by Community-Associated Methicillin-Resistant (CA-MRSA) or Methicillin-SensitiveStaphylococcus aureus(CA-MSSA) present treatment challenges.

OBJECTIVES

Can an evidence-based intervention (CDC Guidelines, topical decolonization, surface decontamination) reduce SSTI recurrence, mitigate household contamination and transmission, and improve patient-reported outcomes?

DESIGN

Randomized trial

SETTING

Community settings

PARTICIPANTS

Participants (n=186) with confirmed MRSA(+)/MSSA(+) SSTIs and household members.

INTERVENTION Community Health Workers/Promotoras conducted home visits and provided participants with instructions, a five-day supply of mupirocin for nasal application, chlorhexidine for body cleansing, and disinfecting wipes for household cleaning (EXP) versus Usual Care (UC).

MEASUREMENTS

Primary outcome was six-month SSTI recurrence recorded in electronic health records (EHR). Home visits (months 0/3) and telephone assessments (months 0/1/6) collected self-report data. Surveillance culture swabs (nares, axilla, groin) were obtained from index patients and participating household members. Secondary outcomes included household surface contamination, household member colonization and transmission, quality of life and satisfaction with care.

RESULTS

Among patients with SSTIs (n=421), 44.2% were MRSA(+)/MSSA(+); an intent-to-treat analyses (n=186) demonstrated no significant differences in SSTI recurrence (OR: 1.4, 95% CI: 0.51-3.5). Among the enrolled cohort (n=119), there were no significant SSTI recurrence effects (OR=1.14, 95% CI=0.35-3.6). EXP participants showed reduced but non-significant colonization rates. There were no differential reductions in household member transmission or in reductions in proportions of households with ≥1 contaminated surface. Mupirocin resistance did not increase. No significant improvements for patient-reported outcomes were seen.

LIMITATIONS

A lower-than-predicted six-month recurrence rate may have limited the ability to detect effects.

CONCLUSION

This intervention did not reduce clinician-reported MRSA/MSSA SSTI recurrence. No differences were observed for household members decolonization or household surfaces decontamination.
The architecture of the centriole cartwheel-containing region revealed by cryo-electron tomography
Authors: Klena Nikolai , Le Guennec Maeva , Tassin Anne-Marie , van den Hoek Hugo , Erdmann Philipp S. , Schaffer Miroslava , Geimer Stefan , Aeschlimann Gabriel , Kovacik Lubomir , Goldie Kenneth N. , Stahlberg Henning , Engel Benjamin D. , Hamel Virginie , Guichard Paul
Published: July 2020

Centrioles are evolutionarily conserved barrels of microtubule triplets that form the core of the centrosome and the base of the cilium. In the proximal region of the centriole, nine microtubule triplets attach to each other via A-C linkers and encircle a central cartwheel structure, which directs the early events of centriole assembly. While the crucial role of the proximal region in centriole biogenesis has been well documented in many species, its native architecture and evolutionary conservation remain relatively unexplored. Here, using cryo-electron tomography of centrioles from four evolutionarily distant species, including humans, we report on the architectural diversity of the centriolar proximal cartwheel-bearing region. Our work reveals that the cartwheel central hub, previously reported to have an 8.5 nm periodicity inTrichonympha, is constructed from a stack of paired rings with an average periodicity of ∼4 nm. In all four examined species, cartwheel inner densities are found inside the hub’s ring-pairs. In bothParameciumandChlamydomonas, the repeating structural unit of the cartwheel has a periodicity of 25 nm and consists of three ring-pairs with 6 radial spokes emanating and merging into a single bundle that connects to the triplet microtubule via the pinhead. Finally, we identified that the cartwheel is indirectly connected to the A-C linker through a flexible triplet-base structure extending from the pinhead. Together, our work provides unprecedented evolutionary insights into the architecture of the centriole proximal region, which underlies centriole biogenesis.
A novel predicted ADP-ribosyltransferase family conserved in eukaryotic evolution
Authors: Wyżewski Zbigniew , Gradowski Marcin , Krysińska Marianna , Dudkiewicz Małgorzata , Pawłowski Krzysztof
Published: July 2020

The presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers full understanding of the functioning of the living cells. ADP-ribosylation is a common post-translational modification of proteins; also nucleic acids and small molecules can be modified by the covalent attachment of ADP-ribose. This modification, important in cellular signalling and infection processes, is usually executed by enzymes from the large superfamily of ADP-ribosyltransferases (ARTs)

Here, using bioinformatics approaches, we identify a novel putative ADP-ribosyltransferase family, conserved in eukaryotic evolution, with a divergent active site. The hallmark of these proteins is the ART domain nestled between flanking leucine-rich repeat (LRR) domains. LRRs are involved in innate immune surveillance.

The novel family appears as likely novel ADP-ribosylation “writers”, previously unnoticed new players in cell signaling by this emerging post-translational modification. We propose that this family, including its human member LRRC9, may be involved in an ancient defense mechanism, with analogies to the innate immune system, and coupling pathogen detection to ADP-ribosyltransfer signalling.
Sex-specific gut microbiota modulation of aversive conditioning and basolateral amygdala dendritic spine density
Authors: Geary Caroline Grace , Wilk Victoria Christina , Barton Katherine Louise , Jefferson Parvaneh Ottavia , Binder Tea , Bhutani Vasvi , Baker Claire , Fernando-Peiris Achal James , Lee Mousley Alexa , Rozental Stefano Freitas Andrade , Thompson Hannah Mae , Touchon Justin Charles , Esteban David Justin , Bergstrom Hadley Creighton
Published: July 2020

Gut microbiota influence numerous aspects of host biology, including brain structure and function. Growing evidence implicates gut microbiota in aversive conditioning and anxiety-related behaviors, but research has focused almost exclusively on males. To investigate sex-specific effects of gut dysbiosis on aversive learning and memory, adult female and male C57BL/6N mice were orally administered a moderate dose of non-absorbable antimicrobial medications (ATMs; neomycin, bacitracin, pimaricin) or a control over 10 days. Changes in gut microbiome composition were analyzed by 16S rRNA sequencing. Open field behavior, cued aversive learning, context recall, and cued recall were assessed. Following behavioral testing, the morphology of basolateral amygdala (BLA) principal neuron dendrites and spines was characterized. Results revealed that ATMs induced distinct but overlapping patterns of gut dysbiosis across sex, with stronger effects in females. There were also sex-specific effects on behavior and neuroanatomy. Treated males but not females exhibited altered locomotor and anxiety-like behavior in the novel open field test. Treated females but not males showed impairments in aversive memory acquisition and cued recall. Context recall remained intact in both sexes, as did dendritic structure of BLA principal neurons. However, ATMs exerted sex-specific effects on spine density. A second experiment was conducted to isolate gut perturbation to cued recall. Results revealed no effect of ATMs on recall of a previously consolidated fear memory, suggesting that gut dysbiosis preferentially impacts aversive learning. These data shed new light on how gut microbiota interact with sex to influence aversive conditioning, anxiety-like behavior, and BLA dendritic spine architecture.

Significance

Gut microbiota can influence brain function and behavior, including trauma and anxiety-related disorders. Although these disorders disproportionately affect women, preclinical research has focused almost exclusively on male rodent models. We investigated the impact of antimicrobial administration on gut microbiome structure, aversive conditioning, open field behavior, and basolateral amygdala principal neuron morphology in female and male mice. Results showed that treatment exerted wide-ranging effects, many of which were sex-specific. Our findings underscore the importance of studying sex differences and support a role for microbial modulation of aversive learning, anxiety-like behavior, and amygdala spine patterning.
DORGE: Discovery of Oncogenes and Tumor SuppressoR Genes Using Genetic and Epigenetic Features
Authors: Lyu Jie , Li Jingyi Jessica , Su Jianzhong , Peng Fanglue , Chen Yiling , Ge Xinzhou , Li Wei
Published: July 2020

Comprehensive data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important contributors to tumor initiation and progression, most known driver genes were identified based on genetic alterations alone, and it remains unclear to what the extent epigenetic features would facilitate the identification and characterization of cancer driver genes. Here we developed a prediction algorithm DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), which integrates the most comprehensive collection of tumor genetic and epigenetic data to identify TSGs and OGs, particularly those with rare mutations. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancer percentages, and methylation differences between cancer and normal samples as strong predictors for OGs. We extensively validated novel cancer driver genes predicted by DORGE using independent functional genomics data. We also found that the dual-functional genes, which are both TSGs and OGs predicted by DORGE, are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed a previously undetected repertoire of cancer driver genes.
DreamAI: algorithm for the imputation of proteomics data
Authors: Ma Weiping , Kim Sunkyu , Chowdhury Shrabanti , Li Zhi , Yang Mi , Yoo Seungyeul , Petralia Francesca , Jacobsen Jeremy , Li Jingyi Jessica , Ge Xinzhou , Li Kexin , Yu Thomas , Calinawan Anna P. , Edwards Nathan , Payne Samuel H. , Boutros Paul C. , Rodriguez Henry , Stolovitzky Gustavo , Zhu Jun , Kang Jaewoo , Fenyo David , Saez-Rodriguez Julio , Wang Pei
Published: July 2020

Deep proteomics profiling using labeled LC-MS/MS experiments has been proven to be powerful to study complex diseases. However, due to the dynamic nature of the discovery mass spectrometry, the generated data contain a substantial fraction of missing values. This poses great challenges for data analyses, as many tools, especially those for high dimensional data, cannot deal with missing values directly. To address this problem, the NCI-CPTAC Proteogenomics DREAM Challenge was carried out to develop effective imputation algorithms for labeled LC-MS/MS proteomics data through crowd learning. The final resulting algorithm, DreamAI, is based on an ensemble of six different imputation methods. The imputation accuracy of DreamAI, as measured by Pearson correlation, is about 15%-50% greater than existing tools among less abundant proteins, which are more vulnerable to be missed in proteomics data sets. This new tool notably enhances data analysis capabilities in proteomics research.
Identification of chromatin loops from Hi-C interaction matrices by CTCF-CTCF topology classification
Authors: Galan Silvia , Serra François , Marti-Renom Marc A.
Published: July 2020

Genome-wide profiling of long-range interactions has revealed that the CCCTC-Binding factor (CTCF) often anchors chromatin loops and is enriched at boundaries of the so-called Topologically Associating Domains, which suggests that CTCF is essential in the 3D organization of chromatin. However, the systematic topological classification of pairwise CTCF-CTCF interactions has not been yet explored.

Here, we developed a computational pipeline able to classify all CTCF-CTCF pairs according to their chromatin interactions from Hi-C experiments. The interaction profiles of all CTCF-CTCF pairs were further structurally clustered using self-organizing feature maps and their functionality characterized by their epigenetic states. The resulting clusters were then input to a convolutional neural network aiming at thede novodetecting chromatin loops from Hi-C interaction matrices.

Our new method, called LOOPbit, is able to automatically detect significant interactions with a higher proportion of enhancer-promoter loops compared to any other callers. Our highly specific loop caller adds a new layer of detail to the link between chromatin structure and function.
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants
Authors: Weisblum Yiska , Schmidt Fabian , Zhang Fengwen , DaSilva Justin , Poston Daniel , Lorenzi Julio C. C. , Muecksch Frauke , Rutkowska Magdalena , Hoffmann Hans-Heinrich , Michailidis Eleftherios , Gaebler Christian , Agudelo Marianna , Cho Alice , Wang Zijun , Gazumyan Anna , Cipolla Melissa , Luchsinger Larry , Hillyer Christopher D. , Caskey Marina , Robbiani Davide F. , Rice Charles M. , Nussenzweig Michel C. , Hatziioannou Theodora , Bieniasz Paul D.
Published: July 2020

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.
AscA (YecA) is a molecular chaperone involved in Sec-dependent protein translocation inEscherichia coli
Authors: Smith Tamar Cranford , Wynne Max , Carter Cailean , Jiang Chen , Jamshad Mohammed , Milner Mathew T. , Djouider Yousra , Hutchinson Emily , Lund Peter A. , Henderson Ian , Huber Damon
Published: July 2020

Proteins that are translocated across the cytoplasmic membrane by Sec machinery must be in an unfolded conformation in order to pass through the protein-conducting channel during translocation. Molecular chaperones assist Sec-dependent protein translocation by holding substrate proteins in an unfolded conformation in the cytoplasm until they can be delivered to the membrane-embedded Sec machinery. For example, inEscherichia coli, SecB binds to a subset of unfolded Sec substrates and delivers them to the Sec machinery by interacting with the metal-binding domain (MBD) of SecA, an ATPase required for translocation in bacteria. Here, we describe a novel molecular chaperone involved Sec-dependent protein translocation, which we have named AscA (foraccessorySeccomponent). AscA contains a metal-binding domain (MBD) that is nearly identical to the MBD of SecA.In vitrobinding studies indicated that AscA binds to SecB and ribosomes in an MBD-dependent fashion.

Saturated transposon mutagenesis and genetics studies suggested that AscA is involved in cell-envelope biogenesis and that its function overlaps with that of SecB. In support of this idea, AscA copurified with a range of proteins and prevented the aggregation of citrate synthasein vitro. Our results suggest that AscA is molecular chaperone and that it enhances Sec-dependent protein translocation by delivering its substrate proteins to SecB.

IMPORTANCE

This research describes the discovery of a novel molecular chaperone, AscA (YecA). The function of AscA was previously unknown. However, it contains a small domain, known as the MBD, suggesting it could interact with the bacterial Sec machinery, which is responsible for transporting proteins across the cytoplasmic membrane. The work described this study indicates that the MBD allows AscA to bind to both the protein synthesis machinery and the Sec machinery. The previously function of the previously uncharacterised N-terminal domain is that of a molecular chaperone, which binds to unfolded substrate proteins. We propose that AscA binds to protein substrates as they are still be synthesised by ribosomes in order to channel them into the Sec pathway.
Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compound inhibitors
Authors: Zhang Yali , Wang Shaojuan , Wu Yangtao , Hou Wangheng , Yuan Lunzhi , Sheng Chenguang , Wang Juan , Ye Jianghui , Zheng Qingbing , Ma Jian , Xu Jingjing , Wei Min , Li Zonglin , Nian Sheng , Xiong Hualong , Zhang Liang , Shi Yang , Fu Baorong , Cao Jiali , Yang Chuanlai , Li Zhiyong , Yang Ting , Liu Lei , Yu Hai , Hu Jianda , Ge Shengxiang , Chen Yixin , Zhang Tianying , Zhang Jun , Cheng Tong , Yuan Quan , Xia Ningshao
Published: July 2020

The ongoing COVID-19 pandemic, caused by SARS-CoV-2 infection, has resulted in hundreds of thousands of deaths. Cellular entry of SARS-CoV-2, which is mediated by the viral spike protein and host ACE2 receptor, is an essential target for the development of vaccines, therapeutic antibodies, and drugs. Using a mammalian cell expression system, we generated a recombinant fluorescent protein (Gamillus)-fused SARS-CoV-2 spike trimer (STG) to probe the viral entry process. In ACE2-expressing cells, we found that the STG probe has excellent performance in the live-cell visualization of receptor binding, cellular uptake, and intracellular trafficking of SARS-CoV-2 under virus-free conditions. The new system allows quantitative analyses of the inhibition potentials and detailed influence of COVID-19-convalescent human plasmas, neutralizing antibodies and compounds, providing a versatile tool for high-throughput screening and phenotypic characterization of SARS-CoV-2 entry inhibitors. This approach may also be adapted to develop a viral entry visualization system for other viruses.
Electric field mediated fibronectin-hydroxyapatite interaction: A molecular insight
Authors: Basu Subhadip , Gorai Biswajit , Basu Bikramjit , Maiti Prabal K.
Published: July 2020

In experimental research driven biomaterials science, the influence of different material properties (elastic stiffness, surface energy, etc.), and to a relatively lesser extent, the biophysical stimulation (electric/magnetic) on the cell-material interaction has been extensively investigated. Considering the central importance of the protein adsorption on cell-material interaction, the role of physiochemical factors on the protein adsorption is also probed. Despite its significance, the quantitative analysis of many such aspects remains largely unexplored in biomaterials science. In recent studies, the critical role of electric field stimulation towards modulation of cell functionality on implantable biomaterials has been experimentally demonstrated. Given this background, we investigated the influence of external electric field stimulation (upto 1.00 V/nm) on fibronectin (FN) adsorption on hydroxyapatite, HA (100) surface at 300K using all-atom MD simulation method. Fibronectin adsorption was found to be governed by the attractive electrostatic interaction, which changed with the electric field strength. Non-monotonous changes in structural integrity of fibronectin were recorded with the change in field strength and direction. This can be attributed to the spatial rearrangement of local charges and global structural changes of the protein. The dipole moment vectors of fibronectin, water and HA quantitatively exhibited similar pattern of orienting themselves parallel to the field direction, with field strength dependent increase in their magnitudes. No significant change has been recorded for radial distribution function of water surrounding fibronectin. Field dependent variation in the salt bridge nets and number of hydrogen bonds between fibronectin and hydroxyapatite were also examined. One of the important results in the context of the cell-material interaction is that the RGD sequence of FN was exposed to solvent side, when the field was applied along a direction outward perpendicular to HA (001) surface. Summarizing, the present study provides quantitative insights into the influence of electric field stimulation on biomolecular interactions involved in fibronectin adsorption on hydroxyapatite surface.
Inadequate level of knowledge, mixed outlook and poor adherence to COVID-19 prevention guideline among Ethiopians
Authors: Negera Edessa , Demissie Tesfaye Moti , Tafess Ketema
Published: July 2020

COVID-19 has a potential to cause chaos in Ethiopia due to the country’s already daunting economic and social challenges. Living and working conditions are highly conducive for transmission, as people live in crowded inter-generational households that often lack running water and other basic sanitary facilities. Thus, the aim of this study was to investigate the knowledge, attitudes and practices (KAP) of Ethiopians toward COVID-19 following the introduction of state of emergency by the Ethiopian government to curb the spread of the disease. A cross-sectional study design was conducted in nine reginal states and two chartered cities. Data for demographic, Knowledge, attitude and practice toward COVID-19 were collected through telephone interview from 1570 participants. Descriptive and bivariate analyses using chi-square test, t-test or analysis of variance were performed as appropriate. Binary and multiple logistic regression analysis were used to measure the relationship between the categorical dependent variables and one or more socio-demographic independent variables with two-tailed at α=0.05 significance level and 95% of confidence interval. The level of good knowledge, favourable attitude and good practice among the respondents were 42%, 53.8% and 24.3% respectively. Being rural resident, older than 50 years, having at least primary education, being resident of Amhara and Oromia regions were independent predictors of knowledge level. While being rural resident, married, employed, having at least basic education, being residents of Afar, Amhara, Gambela, Oromia and Somali regions were found to be the best predictors of the attitude, being rural resident, government employee, having at least basic education, and living outside of the capital were the independent predictors of practice level of the respondents. The finding revealed that Ethiopians have inadequate level of knowledge and are generally have a mixed outlook on overcoming the pandemic with poor adherence to COVID-19 prevention practice. reinforcing preventive measures and intensifying sensitization campaigns to fill the knowledge gap and persuading people to follow the preventive measures set by the government with concurrent evaluation of the impacts of these measures on knowledge and practice is highly recommended to mitigate the disease.
Selective Expression of Variant Surface Antigens EnablesPlasmodium falciparumto Evade Immune Clearancein vivo
Authors: Chew Marvin , Ye Weijian , Omelianczyk Radoslaw Igor , Pasaje Charisse Flerida , Hoo Regina , Chen Qingfeng , Niles Jacquin C. , Chen Jianzhu , Preiser Peter
Published: July 2020

Plasmodium falciparumhas developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based onin vitrostudies of individual parasite variant surface antigens and how this relates to the processesin vivois not well-understood. Here, we have used a humanized mouse model to identify parasite factors important forin vivogrowth. We show that upregulation of the specific PfEMP1, VAR2CSA and the RIFIN PF3D7_1254800 provides the parasite with protection from macrophage phagocytosis and natural killer cell mediated killing. Taken together, these findings reveal new insights on the molecular and cellular mechanisms that coordinate the immune escape process the parasite utilizesin vivo. As immune evasion may be particularly important during the establishment of the blood stage infection when parasite numbers are still relatively small, identification of specific parasite variant surface antigens provides targets for developing more effective vaccines by targeting parasite immune evasion.
Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties
Authors: Miranda-Barrientos Jorge , Chambers Ian , Mongia Smriti , Liu Bing , Wang Hui-Ling , Mateo-Semidey Gabriel E , Margolis Elyssa B , Zhang Shiliang , Morales Marisela
Published: July 2020

The ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of doublevglut2-Cre/vgat-Flptransgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+VGaT−and VGluT2+VGaT+neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2−VGaT+neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+VGaT−and VGluT2−VGaT+neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.

Impact Statement

Some physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.
Asymmetric localization of the cell division machinery duringBacillus subtilissporulation
Authors: Khanna Kanika , López-Garrido Javier , Sugie Joseph , Pogliano Kit , Villa Elizabeth
Published: July 2020

The mechanistic details of bacterial cell division are poorly understood. The Gram-positive bacteriumBacillus subtiliscan divide via two modes. During vegetative growth, the division septum is formed at the mid cell to produce two equal daughter cells. However, during sporulation, the division septum is formed closer to one pole to yield a smaller forespore and a larger mother cell. We use cryo-electron tomography to visualize the architectural differences in the organization of FtsAZ filaments, the major orchestrators of bacterial cell division during these conditions. We demonstrate that during vegetative growth, FtsAZ filaments are present uniformly around the leading edge of the invaginating septum but during sporulation, they are only present on the mother cell side. Our data show that the sporulation septum is thinner than the vegetative septum during constriction, and that this correlates with half as many FtsZ filaments tracking the division plane during sporulation as compared to vegetative growth. We further find that a sporulation-specific protein, SpoIIE, regulates divisome localization and septal thickness during sporulation. Our data provide first evidence of asymmetric localization of the cell division machinery, and not just septum formation, to produce different cell types with diverse fates in bacteria.
A modular two yeast species secretion system for the production and preparative application of fungal peroxygenases
Authors: Püllmann Pascal , Knorrscheidt Anja , Münch Judith , Palme Paul R. , Hoehenwarter Wolfgang , Marillonnet Sylvestre , Alcalde Miguel , Westermann Bernhard , Weissenborn Martin J.
Published: July 2020

Fungal unspecific peroxygenases (UPOs) are biocatalysts of outstanding interest. Providing access to novel UPOs using a modular secretion system was the central goal of this work. UPOs represent an enzyme class, catalysing versatile oxyfunctionalisation reactions on a broad substrate scope. They are occurring as secreted, glycosylated proteins bearing a haem-thiolate active site and solely rely on hydrogen peroxide as the oxygen source. Fungal peroxygenases are widespread throughout the fungal kingdom and hence a huge variety of UPO gene sequences is available. However, the heterologous production of UPOs in a fast-growing organism suitable for high throughput screening has only succeeded once—enabled by an intensive directed evolution campaign. Here, we developed and applied a modular Golden Gate-based secretion system, allowing the first yeast production of four active UPOs, their one-step purification and application in an enantioselective conversion on a preparative scale. The Golden Gate setup was designed to be broadly applicable and consists of the three module types: i) a signal peptide panel guiding secretion, ii) UPO genes, and iii) protein tags for purification and split-GFP detection. We show that optimal signal peptides could be selected for successful UPO secretion by combinatorial testing of 17 signal peptides for each UPO gene. The modular episomal system is suitable for use inSaccharomyces cerevisiaeand was transferred to episomal and chromosomally integrated expression cassettes inPichia pastoris. Shake flask productions inPichia pastorisyielded up to 24 mg/L secreted UPO enzyme, which was employed for the preparative scale conversion of a phenethylamine derivative reaching 98.6 %ee. Our results demonstrate a rapid workflow from putative UPO gene to preparative scale enantioselective biotransformations.
T cell subset-selectiveIL2RAenhancers shape autoimmune diabetes risk
Authors: Simeonov Dimitre R. , Wong Harikesh S. , Cortez Jessica T. , Young Arabella , Li Zhongmei , Nguyen Vinh , Park Kyemyung , Umhoefer Jennifer , Indart Alyssa C. , Woo Jonathan M. , Anderson Mark S. , Germain Ronald N. , Marson Alexander
Published: July 2020

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants inIL2RAhave been linked to multiple autoimmune disorders4. We previously tiled across theIL2RAlocus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.
Isoprenoid biosynthesis regulation in poplars by methylerythritol phosphate and mevalonic acid pathways
Authors: Movahedi Ali , Wei Hui , Pucker Boas , Jiang Tingbo , Sun Weibo , Li Dawei , Yang Liming , Zhuge Qiang
Published: July 2020

The isoprenoids found in plants are extremely important to survive with various human applications, such as flavoring, fragrance, dye, pharmaceuticals, and biomass used for biofuels. Methylerythritol phosphate (MEP) and mevalonic acid (MVA) pathways are critical in plants, responsible for isoprenoid biosynthesis. 1-deoxy-D-xylulose5-phosphate synthase (DXS) and 1-deoxy-D-xylulose5-phosphate reductoisomerase (DXR) catalyze the rate-limiting steps in the MEP pathway, while 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the rate-limiting step in the MVA pathway. Here, we showed whilePtHMGRoverexpressors (OEs) exhibited different MEP- and MVA-related gene expressions compared with non-transgenic poplars (NT), thePtDXR-OEsrevealed upregulated MEP-related and downregulated MVA-related gene expressions.PtDXRandPtHMGR overexpressions caused changes in MVA-derived trans-zeatin-riboside, isopentenyl adenosine, castasterone, and 6-deoxocastasterone well as MEP-derived carotenoids and gibberellins. InPtHMGR-OEs, the accumulated geranyl diphosphate synthase (GPS) and geranyl pyrophosphate synthase (GPPS)transcript levels in the MEP pathway led to an accumulation of MEP-derived isoprenoids. In contrast, upregulation of farnesyl diphosphate synthase (FPS) expression in the MVA pathway contributed to increased levels of MVA-derived isoprenoids. In addition,PtHMGR-OEs increased MEP-relatedGPSandGPPStranscript levels, expanded MEP-derived isoprenoid levels, changedFPStranscript levels, and affected MVA-derived isoprenoid yields. These results demonstrate the contribution of MVA and MEP pathways regulating isoprenoid biosynthesis in poplars.
Crystal structures of the anhydrous and two solvated forms of methyl 4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
Authors: Cleetus Annie , Rani Gulshan , Dharma Rao G. B. , Chopra Deepak
Published: July 2020

Methyl 4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, (I), was found to exhibit solvatomorphism. The compound was prepared using a classic Biginelli reaction under mild conditions, without using catalysts and in a solvent-free environment. Single crystals of two solvatomorphs and one anhydrous form of (I) were obtained through various crystallization methods. The anhydrous form, C13H13FN2O3, was found to crystallize in the monoclinic space group C2/c. It showed one molecule in the asymmetric unit. The solvatomorph with included carbon tetrachloride, C13H13FN2O3·0.25CCl4, was found to crystallize in the monoclinic space group P2/n. The asymmetric unit revealed two molecules of (I) and one disordered carbon tetrachloride solvent molecule that lies on a twofold axis. A solvatomorph including ethyl acetate, C13H13FN2O3·0.5C4H8O2, was found to crystallize in the triclinic space group P\overline{1} with one molecule of (I) and one solvent molecule on an inversion centre in the asymmetric unit. The solvent molecules in the solvatomorphs were found to be disordered, with a unique case of crystallographically induced disorder in (I) crystallized with ethyl acetate. Hydrogen-bonding interactions, for example, N—H...O=C, C—H...O=C, C—H...F and C—H...π, contribute to the crystal packing with the formation of a characteristic dimer through N—H...O=C interactions in all three forms. The solvatomorphs display additional interactions, such as C—F...N and C—Cl...π, which are responsible for their molecular arrangement. The thermal properties of the forms were analysed through differential scanning calorimetry (DSC), hot stage microscopy (HSM) and thermogravimetric analysis (TGA) experiments.
Examining preservice teachers' levels of self-efficacy perceptions regarding Web
Authors: Basaran Bulent , Yalman Murat
Published: July 2020

Purpose

This study aims to focus on how preservice teachers' academic achievements, their frequencies of connecting to the distance learning management system, their gender and the related sub-scales influence their Web-based self-efficacies (WEB-PCK) and their attitudes towards distance education (WBI).

Design/methodology/approach

In the study, the structural equality model was used. In the path analysis, the maximum likelihood estimation method was used to predict the parameters of the model. This method allows determining the highest values for the population and the probability of the sample value to occur.

Findings

It was found that the sub-scale of Web communication (WEB-C) had a high level of direct and positive influence on the male preservice teachers' self-efficacy perceptions. As for the female preservice teachers, WEB-C did not have any direct influence on their self-efficacy perceptions. For the male preservice teachers, Web pedagogy (WEB-PC) had positive influence on their self-efficacy perceptions (β = 0.193), while the sub-scale of WEB-PC had a high level of influence on the female preservice teachers' self-efficacy perceptions (β = 0.534).

Originality/value

In the study, the purpose of was to examine the effects of the attitudes of the preservice teachers towards Web general (WEB-G), Web-Communication (WEB-C), Web pedagogical knowledge (WEB-PK), Web pedagogical self-efficacy (WEB-PCK) and Web-based instruction (WBI) with the help of the structural equation model with respect to gender, frequency of connection to the internet and academic achievement grades.
The discounted money value of human lives lost due to COVID-19 in Spain
Authors: Kirigia Joses Muthuri , Muthuri Rose Nabi Deborah Karimi
Published: July 2020

Purpose

To estimate the discounted money value of human lives lost (DMVHL) due to COVID-19 in Spain.

Design/methodology/approach

The study employs the human capital approach to estimate the DMVHL (assuming Spain's life expectancy of 83 years and a 3% discount rate) of the 20,453 human lives lost in Spain from COVID-19 as of 19 April 2020. Sensitivity analysis was conducted alternately assuming (a) 5% and 10% discount rate; and (b) global life expectancy of 72 years, and the world's highest life expectancy of 87.1 years.

Findings

The 20,453 human lives lost due to COVID-19 had a total DMVHL of Int$ 9,629,234,112, and an average of Int$ 470,798 per human life lost. Alternate re-estimation of the economic model with a 5% and 10% discount rates led to 19.8% and 47.4% reductions in the DMVHL, respectively. Re-calculation of the economic model using the global life expectancy of 72 years, while holding the discount rate constant at 3%, diminished the DMVHL by 41%. While the re-run of the same model using the world's highest life expectancy of 87.1 years instead, it increased the DMVHL by 18%.

Research limitations/implications

The study omits the value of health systems inputs used in preventing, diagnosing and treating COVID-19 cases; and the negative impact of COVID-19 on the agriculture, education, finance, manufacturing, travel, tourism, and trade sectors.

Social implications

There is a need to use this kind of evidence to advocate for increased investments into the strengthening of the national health system, IHR capacities, and coverage of safe water and sanitation facilities.

Originality/value

In Spain, no other study had attempted to estimate the net present value of human lives lost from COVID-19.
Consequences of the implementation of expanded audit reports with key audit matters (KAMs) on audit quality
Authors: Kitiwong Weerapong , Sarapaivanich Naruanard
Published: July 2020

Purpose

This paper aims to ask whether the implementation of the expanded auditor’s report, which included a requirement to disclose key audit matters (KAMs) in Thailand since 2016, has improved audit quality.

Design/methodology/approach

To answer this question, the authors examined audit quality two years before and two years after its adoption by analysing 1,519 firm-year observations obtained from 312 companies. The authors applied logistic regression analyses to the firm-year observations.

Findings

The authors found some weak evidence that KAMs disclosure improved audit quality because of auditors putting more effort into their audits and audits being performed thoroughly after the implementation of KAMs. Interestingly, the number of disclosed KAMs and the most common types of disclosed KAMs are not associated with audit quality. Only disclosed KAMs related to acquisitions are more informative because the presence of this type of disclosed KAMs signals the greater likelihood of financial restatements being made in a later year.

Originality/value

Unlike previous studies on the impact of KAMs disclosure on audit quality, which used discretionary accruals as proxy for audit quality, this study used the occurrence of financial restatements.