bluuebunny/crossref_metadata_2025 huggingface dataset:
Seroprevalence and Dynamics of anti-SARS-CoV-2 antibody among healthcare workers following ChAdOx1 nCoV-19 vaccination
Authors: Sarkar Soma , Das Shantanab , Choudhury Kabita , Mukherjee Saibal , Chatterjee Raghunath
Published: July 2021

Background

The serological evaluations of IgG, IgM, and IgA to the SARS-CoV-2 proteins are widely used for the epidemiological assessment of COVID-19. The Health Care Workers (HCWs) are presumably exposed to a higher risk of acquiring the disease owing to their regular contact with the patients.

Methods

COVID-19 prevalence was investigated by classifying 313 HCWs into four groups based on their degree of exposure and estimating the IgG and total antibody. The serological assessment of the anti-SARS-CoV-2 antibody was conducted 21 days post-vaccination of first or both doses of the ChAdOx1 nCoV-19 vaccine among 174 HCWs. The vaccinated HCWs were followed up for 3 months for SARS-CoV-2 infection.

Findings

The levels of anti-SARS-CoV-2 IgG were comparable among different groups, but the seroprevalence gradually decreased from the most exposed to the less exposed group. The neutralizing antibody was positively correlated with IgG as well as total antibody. IgG was marginally decreased after 2 months followed by a significant drop after 4-6 months post-infection. However, 80% of the HCWs developed a detectable amount of IgG after the first dose of vaccination, the median titer of which was comparable to the seropositive HCWs after natural infection. Almost 100% of the HCWs developed antibodies after the second dose of vaccine with boosting effect among the seropositive HCWs. Although ∼11.5% of the vaccinated HCWs were infected with the SARS-CoV-2, ∼94% of them showed mild symptoms and recovered in home isolation without any O2support.

Interpretations

The varying level of seroprevalence among the four groups suggested stratified spread of the disease. One dose of SARS-CoV-2 vaccination was found to be effective in terms of the antibody titer, while the second dose was required to cover the larger population. The effectiveness of the ChAdOx1 nCoV-19 vaccine was noticeable due to the low rate of post-vaccination infection with moderate or severe symptoms.
Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis
Authors: Dhanabalan Kaamini M. , Dravid Ameya A. , Agarwal Smriti , Sharath Ramanath K. , Padmanabhan Ashok K. , Agarwal Rachit
Published: July 2021

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.

Graphical Abstract
Mechanism of tissue expansion in the early stage of the migration
Authors: Kiran Abhimanyu , Kumar Navin , Mehandia Vishwajeet
Published: July 2021

The collective cell migration is observed in many biological processes such as wound healing, embryogenesis, and cancer metastasis. Despite extensive theoretical and experimental studies on collective cell motion, there is no unified mechanism to explain it. In this work, we experimentally report the collectively growing cell colonies in the sub-marginal region of a freely expanding cell monolayer. These colonies could be responsible for the highly aligned collective cell migration observed in front cell rows. Our results provide a basic framework to understand the physical mechanism responsible for collective cell migration in the freely expanding monolayer.
A novel PD-L1-targeted shark VNAR single domain-based CAR-T strategy for treating breast cancer and liver cancer
Authors: Li Dan , English Hejiao , Hong Jessica , Liang Tianyuzhou , Merlino Glenn , Day Chi-Ping , Ho Mitchell
Published: July 2021

Chimeric antigen receptor (CAR)-T cell therapy shows great potency against hematological malignancies, whereas it remains difficult to treat solid tumors mainly due to lack of appropriate antigenic targets and immunosuppressive tumor microenvironment (TME). Checkpoint molecule PD-L1 is widely overexpressed on multiple tumor types, and the PD-1/PD-L1 interaction is a key mediator of immunosuppression in TME. Here, we isolated anti-PD-L1 single domain antibodies from a newly constructed semi-synthetic nurse shark VNAR phage library. We found that one VNAR, B2, showed cross-reactivity to human, mouse, and canine PD-L1 antigens, and it partially blocked the interaction of human PD-1 to PD-L1. Furthermore, CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1, and also hindered tumor metastasis. Importantly, the combination of CAR (B2) T cells with CAR-T cells targeting liver cancer-specific antigen GPC3 regress liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single domain-based CAR-T therapy is a novel strategy to treat breast cancer and liver cancer. This provides a rationale for potential use of CAR (B2) T cells as a monotherapy or combination with a tumor-specific therapy in clinical studies.
Mutations in coral soma and sperm imply lifelong stem cell renewal and cell lineage selection
Authors: López-Nandam Elora H. , Albright Rebecca , Hanson Erik A. , Sheets Elizabeth A. , Palumbi Stephen R.
Published: July 2021

In many animals, the germline differentiates early in embryogenesis, so only mutations that accumulate in germ cells are inherited by offspring1. Exceptions to this developmental process may indicate that other mechanisms have evolved to limit the effects of deleterious mutation accumulation2. Stony corals are animals that can live for hundreds of years3 and have long been thought to produce gametes from somatic tissue4. To clarify conflicting evidence about germline-soma distinction in corals, we sequenced high coverage, full genomes with technical replicates for parent coral branches and their sperm pools. We identified post-embryonic single nucleotide variants (SNVs) unique to each parent branch, then checked if each SNV was shared by the respective sperm pool: 26% of post-embryonic SNVs were shared by the sperm but 74% were not. We also identified germline SNVs, those that were present in the sperm but not in the parent. These data suggest that self-renewing stem cells in corals differentiate into germ and soma throughout the adult life of the colony, with SNV rates and patterns differing markedly in stem, soma, and germ lineages. In addition to informing the important place in the evolutionary spectrum from non-Weismannian to Weismmanian animals that corals occupy, these insights inform how corals may generate adaptive diversity necessary in the face of global climate change.
Synergistic regulation of bZIP53 and dimerizing partners results in abnormal seed phenotype in Arabidopsis: Use of a designed dominant negative protein A-ZIP53
Authors: Jain Prateek , Rishi Vikas
Published: July 2021

In Arabidopsis, basic leucine zipper (bZIP) family of transcription factors (TFs) are key proteins to regulate the expression of seed maturation (MAT) genes. bZIPs are functionally redundant and their DNA-binding activity is dependent on dimerization partner. The intervention of loss of function mutation is inadequate to understand and regulate the redundant behavior of TFs and one such example is bZIP53, which is known as a key regulator of seed maturation phenomena. Here, to examine the consequences of hindering the function of bZIP53 and its known and unknown heterodimerizing partners, a transgenic Arabidopsis constitutively expressing a novel dominant negative (DN) protein A-ZIP53 was raised. Transgenic plants demonstrated a delayed growth and retarded seed phenotype. The in vivo inhibition of DNA binding of bZIP53, bZIP10, and bZIP25 to the G-box demonstrated the efficacy of A-ZIP53 protein. In first generation, majority of plants failed to survive beyond four weeks suggesting a pleiotropic nature of bZIP53. Plants expressing A-ZIP53 have small flower, shorter siliques, and small-seeded phenotype. RNA seq analysis of the transgenic lines revealed the reduced expression of target genes of bZIP53 and its heterodimerizing partners. Furthermore, immunoprecipitation followed by mass spectrometry (IP-MS/MS) of transgenic plants helped to identify the additional heterodimerizing partners of the A-ZIP53. The interactions were subsequently confirmed with the transient transfection experiments. Unlike other gene knock out technologies, DN protein can inhibit the function of members of the same group of bZIP TFs.
Two redundant ubiquitin-dependent pathways of BRCA1 localization to DNA damage sites
Authors: Sherker Alana , Chaudhary Natasha , Adam Salomé , Noordermeer Sylvie M. , Fradet-Turcotte Amélie , Durocher Daniel
Published: July 2021

The tumor suppressor BRCA1 accumulates at sites of DNA damage in a ubiquitin-dependent manner. In this work, we revisit the role of the ubiquitin-binding protein RAP80 in BRCA1 recruitment to damaged chromatin. We found that RAP80, or the phosphopeptide-binding residues in the BRCA1 BRCT domains, act redundantly with the BRCA1 RING domain to promote BRCA1 recruitment to DNA double-strand break sites. We show that that RNF8 E3 ubiquitin ligase acts upstream of both the RAP80- and RING-dependent activities whereas RNF168 acts uniquely upstream of the RING domain. The function of the RING domain in BRCA1 recruitment is not solely linked to its role in mediating an interaction with BARD1 since RING mutations that do not impact BARD1 interaction, such as the E2-binding deficient Ile26Ala (I26A) mutation, produce a BRCA1 protein unable to accumulate at DNA damage sites in the absence of RAP80. Cells that combine the BRCA1 I26A mutation and mutations that disable the RAP80-BRCA1 interaction are deficient in RAD51 filament formation and are hypersensitive to poly (ADP-ribose) polymerase inhibition. Our results suggest that in the absence of RAP80, the BRCA1 E3 ligase activity is necessary for the recognition of unmethylated histone H4 Lys20 and histone H2A Lys13/Lys15 ubiquitylation by BARD1 although we cannot rule out the possibility that the RING- E2 complex itself may facilitate ubiquitylated nucleosome recognition in other ways. Finally, given that tumors expressing RING-less BRCA1 isoforms readily acquire resistance to therapy, this work suggests that targeting RAP80, or its interaction with BRCA1, could represent a novel strategy for restoring sensitivity of such tumors to DNA damaging agents.
Gram-positive bacteria secrete RNA aptamers to activate human STING for IL-1β release
Authors: Duduskar Shivalee N. , Ghait Mohamed , Westermann Martin , Guo Huijuan , Ramoji Anuradha , Sponholz Christoph , Göhrig Bianca , Bruns Tony , Neugebauer Ute , Popp Jurgen , Tuchscherr Lorena P N , Löffler Bettina , Ueberschaar Nico , Beemelmanns Christine , Singer Mervyn , Bauer Michael , Deshmukh Sachin D.
Published: July 2021

Molecular mechanisms through which Gram-positive bacteria induce the canonical inflammasome are poorly understood. Here, we studied the effects of Group B streptococci (GBS) and Staphylococcus aureus (SA) on inflammasome activation in human macrophages. Dinucleotide binding small RNA aptamers released by SA and GBS were shown to trigger increased IL-1β generation by inflammasomes. The stimulator of interferon genes-STING as a central mediator of innate immune responses has been identified as the key target of pathogenic RNA. Multi-lamellar lipid bodies (MLBs) produced by SA function as vehicles for the RNA aptamers. Notably, expression of RNA aptamers is controlled by an accessory gene regulator quorum sensing system of the bacteria. These findings have been translated to patients with Gram-positive sepsis showing hallmarks of MLB-RNA-mediated inflammasome activation. Together our findings may provide a new perspective for the pathogenicity of Gram-positive bacterial infection in man.
A pair of transporters controls mitochondrial Zn2+ levels to maintain mitochondrial homeostasis
Authors: Ma Tengfei , Zhao Liyuan , Zhang Jie , Tang Ruofeng , Wang Xin , Liu Nan , Zhang Qian , Wang Fengyang , Li Meijiao , Shan Qian , Yang Yang , Yin Qiuyuan , Yang Limei , Gan Qiwen , Yang Chonglin
Published: July 2021

Zn2+ is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn2+ level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn2+. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn2+ exporter. Loss of SLC-30A9 leads to mitochondrial Zn2+ accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn2+ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn2+ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn2+ pool from which mitochondrial Zn2+ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn2+ levels for normal mitochondrial structure and functions.

Zn2+ is a trace ion essential for the function of many mitochondrial proteins. It is not known how mitochondrial Zn2+ levels are regulated. Ma at al. identify transporters that mediate mitochondrial Zn2+ export and import to maintain mitochondrial homeostasis.
Egg size variation in a long-lived polyandrous shorebird in the context of senescence and breeding phenology
Authors: Eberhart-Hertel Luke J. , Rodrigues Lourenço Falcão , Krietsch Johannes , Eberhart-Hertel Anne G. , Cruz-López Medardo , Vázquez-Rojas Karina Alejandra , González-Medina Erick , Schroeder Julia , Küpper Clemens
Published: July 2021

We have withdrawn this manuscript due to a duplicate posting of manuscript number 240150. Therefore, we do not wish this work to be cited as reference for the project. If you have any questions, please contact Luke J. Eberhart-Hertel atluke.eberhart@orn.mpg.de
Systematic analysis of the R2R3-MYB family of transcription factors in Camellia sinensis: evidence for species-specific catechin biosynthesis regulation
Authors: Li Jingyi , Liu Shaoqun , Chen Peifen , Cai Jiarong , Tang Song , Yang Wei , Cao Fanrong , Zheng Peng , Sun Binmei
Published: July 2021

The R2R3-MYB transcription factor family regulates metabolism of phenylpropanoids in various plant lineages. Species-expanded or specific MYB transcription factors may regulate species-specific metabolite biosynthesis including phenylpropanoid-derived bioactive products. C. sinensis produces an abundance of specialized metabolites, which makes it an excellent model for digging into the genetic regulation of plant-specific metabolite biosynthesis. The most abundant health-promoting metabolites in tea are galloylated catechins, and the most bioactive of the galloylated catechins, epigallocatechin gallate (EGCG), is exclusively found in C. sinensis. However, the transcriptional regulation of galloylated catechin biosynthesis remains elusive. This study mined the R2R3-MYB transcription factors associated with galloylated catechin biosynthesis in C. sinensis. A total of 118 R2R3-MYB proteins, classified into 38 subgroups, were identified. R2R3-MYB subgroups specific to or expanded in C. sinensis were hypothesized to be essential to evolutionary diversification of tea-specific metabolites. Notably, nine of these R2R3-MYB genes were expressed preferentially in apical buds and young leaves, exactly where galloylated catechins accumulate. Three putative R2R3-MYB genes displayed strong correlation with key galloylated catechin biosynthesis genes, suggesting a role in regulating biosynthesis of epicatechin gallate (ECG) and EGCG. Overall, this study paves the way to reveal the transcriptional regulation of galloylated catechins in C. sinensis.
The RNA m6A binding protein YTHDF2 promotes the B cell to plasma cell transition
Authors: Turner David J. , Saveliev Alexander , Salerno Fiamma , Matheson Louise S. , Screen Michael , Lawson Hannah , Wotherspoon David , Kranc Kamil R. , Turner Martin
Published: July 2021

To identify roles of RNA binding proteins (RBPs) in the differentiation of B cells to antibody-secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the emergence of differentiated CD138+ cells in vitro. We identified RBPs that promoted the appearance of CD138+ cells including CSDE1 and STRAP, as well as RBPs that inhibited CD138+ cell appearance such as EIF3 subunits EIF3K and EIF3L. Furthermore, we identified RBPs that share the property of recruiting the CCR4-NOT complex to their target transcripts have the potential to mediate opposing outcomes on B cell differentiation. One such RBP, the m6A binding protein YTHDF2 promotes the appearance of CD138+ cells in vitro. In chimeric mouse models YTHDF2-deficient B cells formed germinal centers in a cell-autonomous manner, however plasma cells failed to accumulate.
Characterization of brown-black pigment isolated from soil bacteria,Beijerinckia fluminensis
Authors: Joshi Mahesh H. , Patil Ashwini A. , Adivarekar Ravindra V.
Published: July 2021

Melanin is a ubiquitous pigment found in most organisms, it is a dark-brown or black pigment formed by the oxidation of phenolic compounds. They are negatively charged amorphous compounds having quinone groups. In this study; melanin-producing microorganism was isolated from soil obtained from iron ore mine. The soil was enriched in modified Ashby’s glucose broth for 15 days at 30°C further to which it was isolated on modified Ashby’s agar at 30°C for seven days; the colonies showing pigmentation were selected for further study. Conditions were optimized for maximal production of melanin pigment. The effect of carbon, nitrogen, tyrosine, and metal salts on pigment production was studied. Alkaline conditions were used to extract the pigment from cells, further characterized by UV-VIS spectroscopy for λ-max. FTIR was done to identify the native functional groups, and XRD was performed to determine the melanin’s structure. TGA analysis was done to check its thermal stability. SEM was carried out to check the size and shape of the melanin pigment. The melanin pigment was also analyzed for UV protectant property which was studied by exposure of both melanized and non-melanized cells to UV light at 254nm.
VAL1 as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC
Authors: Mikulski Pawel , Wolff Philip , Lu Tiancong , Zhu Danling , Dean Caroline
Published: July 2021

Polycomb (PcG) silencing is crucial for development across eukaryotes, but how PcG targets are regulated is still incompletely understood. The slow timescale of cold-induced PcG silencing at Arabidopsis thaliana FLOWERING LOCUS C (FLC) makes it an excellent system to dissect this mechanism. Binding of the DNA binding protein VAL1 to an FLC intronic RY motif within the PcG nucleation region is an early step in the silencing process. VAL1 interacts with APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and POLYCOMB REPRESSIVE COMPLEX 1 (PRC1). Here, we show that ASAP and PRC1 function as co-repressors that quantitatively regulate FLC transcription. Upon the shift to cold PRC1-mediated H2Aub accumulates only at the nucleation region, is transiently maintained after transfer back to warm, but unlike the PRC2-delivered H3K27me3 does not spread across the locus. H2K27me3 thus provides long-term epigenetic silencing, whereas H2Aub is a transient repression signal. Overall, our work highlights how a DNA sequence-specific binding protein can act as an assembly platform co-ordinating the co-transcriptional repression and chromatin regulation necessary for Polycomb silencing.
Conserved Circuits for Direction Selectivity in the Primate Retina
Authors: Patterson Sara S. , Bembry Briyana N. , Mazzeferri Marcus A. , Neitz Maureen , Rieke Fred , Soetedjo Robijanto , Neitz Jay
Published: July 2021

The detection of motion direction is a fundamental visual function and a classic model for neural computation1,2. In the non-primate mammalian retina, direction selectivity arises in starburst amacrine cell (SAC) dendrites, which provide selective inhibition to ON and ON-OFF direction selective retinal ganglion cells (dsRGCs)3,4. While SACs are present in primates5, their connectivity is unknown and the existence of primate dsRGCs remains an open question. Here we present a connectomic reconstruction of the primate ON SAC circuit from a serial electron microscopy volume of macaque central retina. We show that the structural basis for the SAC’s ability to compute and confer directional selectivity on post-synaptic RGCs6 is conserved in primates and that SACs selectively target a single ganglion cell type, a candidate homolog to the mammalian ON-sustained dsRGCs that project to the accessory optic system and contribute to gaze-stabilizing reflexes7,8. These results indicate that the capacity to compute motion direction is present in the retina, far earlier in the primate visual system than classically thought, and they shed light on the distinguishing features of primate motion processing by revealing the extent to which ancestral motion circuits are conserved.
Toxoplasma gondii subverts the host ESCRT machinery for parasite uptake of host cytosolic proteins
Authors: Rivera-Cuevas Yolanda , Mayoral Joshua , Di Cristina Manlio , Lawrence Anna-Lisa E. , Olafsson Einar B. , Thornhill Dishari , Waldman Benjamin S. , Ono Akira , Sexton Jonathan , Lourido Sebastian , Weiss Louis M. , Carruthers Vern B.
Published: July 2021

Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole, the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T. gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of GRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T. gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PVM. These findings provide new insight into how T. gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission.

Author summary

Intracellular pathogens exploit their host to gain the resources necessary to sustain infection; however, precisely how the intracellular parasite Toxoplasma gondii acquires essential nutrients from its host remains poorly understood. Previous work showed that T. gondii is capable of internalizing host derived cytosolic proteins and delivering them to its lysosome-like compartment for degradation. However, the mechanism by which the material is trafficked across the membrane delimiting the replicative vacuole in which the parasite resides remained unclear. Here, we report a role for the parasite effector protein TgGRA14 in the recruitment of the host ESCRT machinery for the uptake of host cytosolic proteins. Important human pathogens have developed strategies for exploiting the host ESCRT machinery for intracellular subsistence. Our study sheds lights on the strategy used by a eukaryotic pathogen in subverting the host ESCRT machinery for the internalization of resources from its host cells.
Efficient inhibition of HIV using CRISPR/Cas13d nuclease system
Authors: Nguyen Hoang , Wilson Hannah , Jayakumar Sahana , Kulkarni Viraj , Kulkarni Smita
Published: July 2021

Recently discovered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas13 proteins are programmable RNA-guided ribonucleases that target single-stranded RNA (ssRNA). CRISPR/Cas13 mediated RNA targeting has emerged as a powerful tool for detecting and eliminating RNA viruses. Here, we demonstrate the effectiveness of CRISPR/Cas13d to inhibit HIV-1 replication. We designed guide RNAs (gRNAs) targeting highly conserved regions of HIV-1. RfxCas13d (CasRx) in combination with HIV-specific gRNAs efficiently inhibited HIV-1 replication in cell line models. Furthermore, simultaneous targeting of four distinct sites in the HIV-1 transcript resulted in robust inhibition of HIV-1 replication. We also show the effective HIV-1 inhibition in primary CD4+T-cells and suppression of HIV-1 reactivated from latently infected cells using the CRISPR/Cas13d system. Our study demonstrates the utility of the CRISPR/Cas13d nuclease system to target acute and latent HIV infection and provides an alternative treatment modality against HIV.
Developmental stage-specific spontaneous activity contributes to callosal axon projections
Authors: Tezuka Yuta , Hagihara Kenta M. , Ohki Kenichi , Hirano Tomoo , Tagawa Yoshiaki
Published: July 2021

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a “critical period”: restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that the spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex. (150)
TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling
Authors: Sivakumar Sushama , Qi Shutao , Cheng Ningyan , Sathe Adwait A. , Kanchwala Mohammed , Kumar Ashwani , Evers Bret M. , Xing Chao , Yu Hongtao
Published: July 2021

Aneuploidy, defective differentiation, and inactivation of the tumor suppressor TP53 all occur frequently during tumorigenesis. Here, we probe the potential links among these cancer traits by inactivating TP53 in human embryonic stem cells (hESCs). TP53−/− hESCs exhibit increased proliferation rates, mitotic errors, and low-grade structural aneuploidy; produce poorly differentiated immature teratomas in mice; and fail to differentiate into neural progenitor cells (NPC) in vitro. Genome-wide CRISPR screen reveals requirements of ciliogenesis and sonic hedgehog (Shh) pathways for hESC differentiation into NPCs. TP53 deletion causes abnormal ciliogenesis in neural rosettes. In addition to restraining cell proliferation through CDKN1A, TP53 activates the transcription of BBS9, which encodes a ciliogenesis regulator required for proper Shh signaling and NPC formation. This developmentally regulated transcriptional program of TP53 promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages.
miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts
Authors: Xue Bin , Chuang Chen-Hua , Prosser Haydn M. , Fuziwara Cesar Seigi , Chan Claudia , Sahasrabudhe Neil , Kühn Maximilian , Wu Yalei , Chen Jingqi , Biton Anne , Chen Caifu , Wilkinson John Erby , McManus Michael T. , Bradley Allan , Winslow Monte M. , Su Bo , He Lin
Published: July 2021

Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.
The dimensional linkage between public service motivation and innovative behavior in public sector institutions; the mediating role of psychological empowerment
Authors: Rafique Muhammad Asim , Hou Yumei , Chudhery Muhammad Adnan Zahid , Gull Nida , Ahmed Syed Jameel
Published: July 2021

Purpose

Innovations are imperative for organizational growth and sustainability. This study focuses on the employees' innovative behavior, a source of organizational innovations, which has received substantial attention from the researchers. Based on the psychological empowerment theory, the study exposes the effect of the various dimensions of public service motivation (PSM) on employees' innovative behavior (IB) in public sector institutions especially in the context of developing countries such as Pakistan. Moreover, the study also investigates the mediating role of psychological empowerment (PSE) between the dimensions of PSM and IB.

Design/methodology/approach

This study used the cross-sectional research design. By using random sampling, the adapted survey questionnaires were used to collect data from 346 faculty members of public sector universities located in provincial capitals of Pakistan. A partial least square–structural equation modeling (PLS-SEM) tool was used to assess the proposed hypotheses through SMART-PLS software.

Findings

Results revealed that attraction to policymaking (APM), compassion (COM), self-sacrifice (SS) have a significant impact on employees' PSE and their innovative behavior, while the relationship of commitment to the public interest (CPI) with PSE and IB was found insignificant. Moreover, PSE partially mediated the relationship between PSM dimensions and employees' IB.

Originality/value

There was a scarcity of research on IB especially in public sector institutions such as academia. This study theoretically contributed to the literature by providing a refined picture in assessing the proposed relationship of the constructs. This is also one of the original studies that examine the relationship between the dimensions of PSM and IB.
Higher education student engagement in times of pandemic: the role of e-learning system usability and teacher behavior
Authors: Dahleez Khalid Abed , El-Saleh Ayman A. , Al Alawi Abrar Mohammed , Abdelmuniem Abdelfattah Fadi
Published: July 2021

Purpose

This research examined the factors affecting several types of student engagement, namely agentic, behavioral, emotional and cognitive engagement. Specifically, it examined the effect of e-learning system usability on student engagement and explored teacher behavior's possible intervening impact on this relationship.

Design/methodology/approach

Data were collected from 418 students studying at different specializations at Omani private academic institutions. This study employed a quantitative methodology and utilized the Smart-PLS for data analyses.

Findings

The findings showed that e-learning system usability influenced significantly and positively agentic, behavioral and cognitive engagement. However, the link between e-learning system usability and emotional engagement was not significant. Moreover, teacher behavior mediated the relationship between e-learning system usability and the four types of engagement.

Originality/value

This study improves one’s understanding of how the interaction of e-learning system usability and teacher behavior affects several aspects of student engagement. It also helps higher education administrators and policymakers by exploring the influential effects of e-learning systems usability and teacher behavior on facilitating students' engagement.
Determinants of environmental degradation in Saudi Arabia: exploring the unexplored
Authors: Tahir Muhammad , Hayat Arshad , Burki Umar
Published: July 2021

Purpose

Environmental degradation is recognized as a serious problem globally, and hence, Saudi Arabia is no exception. This paper aims to focus on the economy of Saudi Arabia to identify the determinants of environmental degradation.

Design/methodology/approach

Time series data spanning from 1971 to 2014 is used and analyzed using the recently developed autoregressive distributed lag modeling approach.

Findings

The obtained results reflected that natural resources, per person income and urbanization, have impacted environmental degradation both positively and significantly in the long run. Similarly, an insignificant negative relationship is established between trade openness and environmental degradation. Moreover, energy consumption has positively but insignificantly affected environmental degradation. In the short run, only per capita income has positively influenced environmental degradation while the rest of the variables have lost either significance levels or their direction of relationship has reversed.

Originality/value

As this is a pioneering study on the economy of Saudi Arabia, therefore, the authors assume that policymakers will find the findings of the current study very useful while formulating and implementing policies to control environmental degradation.
Lesson study as a research approach: a case study
Authors: Jansen Susanne , Knippels Marie-Christine P.J. , van Joolingen Wouter R.
Published: July 2021

Purpose

The purpose of this paper is to explore the merits of lesson study (LS) as a research approach for research in (science) education. A lesson was developed to introduce students to model-based reasoning: a higher order thinking skill that is seen as one of the major reasoning strategies in science.

Design/methodology/approach

Participants of the LS team were three secondary school teachers and two educational researchers. Additionally, one participant fulfilled both roles. Both qualitative and quantitative data were used to investigate the effect of the developed lesson on students and to formulate focal points for using the LS as a research approach.

Findings

The developed lesson successfully familiarized students with model-based reasoning. Three main focal points were formulated for using LS as a research approach: (1) make sure that the teachers support the research question that the researchers bring into the LS cycle, (2) take into account that the lesson is supposed to answer a research question that might cause extra stress for the teachers in an LS team and (3) state the role of both researchers and teachers in an LS team clearly at the beginning of the LS cycle.

Originality/value

This study aims to investigate whether LS can be used as a research approach by the educational research community.
Data-driven performance management of business units using process mining and DEA: case study of an Iranian chain store
Authors: Maddah Negin , Roghanian Emad
Published: July 2021

Purpose

The underlying purpose of this paper is to propose a comprehensive framework evaluating the performance of business units of an organization with a process perspective, identifying the most influential performance indicators, enabling managers to make more informed decisions based on data recording every day in their operational information systems.

Design/methodology/approach

For proposing the conceptual framework of performance evaluation a synchronized analysis of selected process' data, obtained from an integrated information system of an Iranian chain store, was performed.

Findings

The superiority of the proposed framework results is demonstrated in comparison to applying the process mining solely; principal component analysis was identified as an efficient link between process mining and data envelopment analysis. Also, based on the final data analytics, the units' throughput times and the variety of brands and suppliers had the most impact on their performances.

Research limitations/implications

The data of abundant business units and performance indicators, which would have allowed adding data prediction and other data analytics techniques for more insight, was not able to be accessed.

Practical implications

Organizations' managers can use the framework to evaluate their business units' current status and then prioritize their resources based on the most influential performance indicators for overall improvement.

Originality/value

The study contributes to the research on performance management and process mining by presenting a comprehensive framework with two levels of data analytics. It stresses discovering what is happening in business units, and how to prioritize their improvement opportunities learning the significant correlations between performance indicators and units' performance.
Calculating lifetime expected loss for IFRS 9: which formula is measuring what?
Authors: Engelmann Bernd
Published: July 2021

Purpose

The purpose of this article is to derive formulas for lifetime expected credit loss of loans that are required for the calculation of loan loss reserves under IFRS 9. This is done both for fixed-rate and floating rate loans under different assumptions on LGD modeling, prepayment, and discount rates.

Design/methodology/approach

This study provides exact formulas for lifetime expected credit loss derived analytically together with the mathematical proofs of each expression.

Findings

This articles shows that the formula most commonly applied in the literature for calculating lifetime expected credit loss is inconsistent with measuring expected loss based on expected discounted cash flows. Formulas based on discounted cash flows always lead to more conservative numbers.

Practical implications

For banks reporting under IFRS 9, the implication of this research is a better understanding of the different approaches used for computing lifetime expected loss, how they are connected, and what assumptions are underlying each approach. This may lead to corrections in existing frameworks to make applications of risk management systems more consistent.

Originality/value

While there is a lot of literature explaining IFRS 9 and evaluating its impact, none of the existing research has systematically analyzed the calculation of lifetime expected credit loss for this purpose and how the formula changes under different modeling assumptions. This gap is filled by this study.
Exploring the occupational lives of Syrians under temporary protection in Turkey
Authors: Altuntaş Onur , Azizoğlu Vecihe , Davis Jane A.
Published: July 2021

Introduction

Persons who become displaced due to situations such as war and natural disasters face extreme challenges in maintaining their occupational repertoires. This study aimed to explore the occupational lives of Syrians under temporary protection in Turkey.

Methods

This mixed method study used a cross‐sectional design with a predominantly qualitative focus. Syrians living under temporary protection in Turkey were interviewed using the Canadian Occupational Performance Measure (COPM) to identify their perceived performance problems in the areas of self‐care, productivity, and leisure. Additional probes were used to explore participants' reasoning for the choice of occupations and scoring, and occupational changes since arriving in Turkey. Socio‐demographics were collected on the participants' age, gender, educational level, marital status, monthly house budget, social security, and number of persons within the household. Thematic analysis was used to undercover themes from the qualitative data.

Results

Thirty Syrians living under temporary protection in Turkey in Hatay province participated in this study (mean age: 29.66 ± 7.97 years [range = 18 to 50 years]): 16 women (mean age: 28.64 ± 8.04 years) and 14 men (mean age: 30.56 ± 8.05 years). Participants identified more significant problems in their performance of productive and leisure occupations than in self‐care occupations. The following themes emerged: (a) having a house of our own: meeting basic needs and completing activities of daily living; (b) no money for shopping: past everyday occupations now luxuries; (c) feeling valued and important: having the ability but no job; (d) living day to day: Education, career, and marriage on hold; and (e) enjoyment in life: leaving behind family, friends, and occupational spaces.

Conclusion

Syrians living in temporary protection in Turkey experience uncertainty within their occupational lives. Participants were able to meet their basic needs; however, precarity of employment limited their participation in previous occupations contracting their repertoires.
Pharmacological characterization of the chronic phase of the monoiodoacetate‐induced rat model of osteoarthritis pain in the knee joint
Authors: Han Felicity Y. , Brockman David A. , Nicholson Janet R. , Corradini Laura , Smith Maree T.
Published: July 2021

For patients with osteoarthritis (OA) of the knee, pain is the most debilitating symptom. Although it has been proposed that the chronic phase of the monoiodoacetate (MIA)‐induced rodent model of knee joint pain may be superior to other chronic or acute OA models for assessing the analgesic efficacy of novel molecules, relatively few pharmacological studies have been conducted in the chronic phase of this model. Hence, this study was designed to use pharmacological methods to characterize the chronic phase of the MIA‐induced rat model of knee joint OA pain. Rats received a single intraarticular injection of MIA at 2.5 mg or vehicle (saline) into the left (ipsilateral) knee joint. Pain behaviour was assessed by measuring paw withdrawal thresholds (PWTs) in the hindpaws pre‐MIA injection and twice‐weekly until study completion on day 42. Mechanical allodynia was fully developed in the ipsilateral hindpaws (PWTs ≤6 g) from day 7 and it persisted until day 42. MIA‐injected rats with PWTs ≤6 g in the ipsilateral hindpaws received single doses of one of four clinically available drugs that represent four distinct pharmacological classes, viz gabapentin, amitriptyline, meloxicam and morphine, according to a ‘washout’ protocol with at least 48 hours between successive doses. Gabapentin evoked dose‐dependent anti‐allodynia as did morphine whereas amitriptyline and meloxicam were inactive. Our findings are aligned with clinical data showing that gabapentin and morphine alleviated OA pain in the knee. The lack of efficacy of amitriptyline is consistent with the loss of descending diffuse noxious inhibitory controls reported by others in this model.
Immune‐checkpoint inhibitor‐associated diabetes compared to other diabetes types ‐ A prospective, matched control study
Authors: Tittel Sascha R. , Laubner Katharina , Schmid Sebastian M. , Kress Stefan , Merger Sigrun , Karges Wolfram , Wosch Frank J. , Altmeier Marcus , Pavel Marianne , Holl Reinhard W. ,   DPV Initiative
Published: July 2021

Background

To describe checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) and to compare with regular type 1 (T1DM), type 2 (T2DM), and medication‐induced diabetes mellitus (MI‐DM).

Methods

We included 88 177 adult patients from the Diabetes Patient Follow‐Up (DPV) registry with diabetes manifestation between 2011 and 2020. Inclusion criteria were T1DM, T2DM, MI‐DM, or CPI‐DM. Because of the heterogeneity between the groups, we matched patients by age, sex, and diabetes duration using propensity scores. Patient data were aggregated in the respective first documented treatment year.

Results

The matched cohort consisted of 24 164 patients; T1DM: 29, T2DM: 24000, MI‐DM: 120, CPI‐DM: 15 patients. Median age at manifestation of CPI‐DM patients was 63.6 (57.2‐72.8) years (53.3% male). Body mass index in CPI‐DM patients was significantly lower (26.8 [23.9‐28.1] kg/m2) compared with T2DM patients (29.8 [26.2‐34.3] kg/m2, P = 0.02). At manifestation, HbA1c was significantly higher in CPI‐DM compared with MI‐DM, but there was no difference during follow‐up. Diabetic ketoacidosis (DKA) was documented in six CPI‐DM patients (T1DM: 0%, T2DM: 0.4%, MI‐DM: 0.0%). Fourteen CPI‐DM patients were treated with insulin, and three received additional oral antidiabetics. The most common therapy in T2DM was lifestyle modification (38.8%), insulin in MI‐DM (52.5%). Concomitant autoimmune thyroid disease was present in four CPI‐DM patients (T1DM: 0.0%, T2DM: 1.0%, MI‐DM: 0.8%).

Conclusions

The data from this controlled study show that CPI‐DM is characterized by a high prevalence of DKA, autoimmune comorbidity, and metabolic decompensation at onset. Structured diagnostic monitoring is warranted to prevent DKA and other acute endocrine complications in CPI‐treated patients.
Ancient South arabian inscription BynM 5: A new interpretation and semitic parallels
Authors: Mazzini Giovanni
Published: July 2021

The subject of this article is the Sabaic inscription BynM 5 and a new interpretation is proposed considering Ancient South Arabian and other Semitic sources. The document is a funerary stela concluding with a curse. It is suggested that this curse reflects a magical belief which can be closely compared to Qur 113, 4. This contributes to shed light on the ancient Arabian magical practices.