bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 exploits cellular RAD51 to promote viral propagation: implication of RAD51 inhibitor as a potential drug candidate against COVID-19
Authors: Pham Thuy X. , Huynh Trang T. X. , Choi Jiwon , Lee Jae-Bong , Park Seok-Chan , Kim Bumseok , Lim Yun-Sook , Hwang Soon B. 
Published: December 2023

ABSTRACT

RAD51 is an important factor involved in the homologous recombination and repair of DNA breaks, which has also been implicated in various virus replication processes. We have previously reported that hepatitis C virus (HCV) exploits cellular RAD51 to promote viral propagation. Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also an RNA virus, we interrogated whether SARS-CoV-2 could coopt RAD51 for its propagation. Here, we showed that silencing of RAD51 impaired SARS-CoV-2 propagation. We further demonstrated that RAD51 colocalized with SARS-CoV-2 RNA in Vero E6 cells. Interestingly, RAD51 interacted with SARS-CoV-2 3CL protease. This suggests that RAD51 inhibitors may block SARS-CoV-2 propagation. Hence, we evaluated multiple RAD51 inhibitors as potential drug candidates for coronavirus disease 2019 (COVID-19). Among these, B02, 4
'
-diisothiocyanostilbene-2,2
'
-disulfonic acid (DIDS), IBR2, and RI(dl)-2 significantly decreased RNA, protein, and infectious virion levels of Wuhan and variants of SARS-CoV-2. Antiviral activity of DIDS was further confirmed in the Syrian hamster model. Molecular docking model showed that these chemicals interfered with RAD51 through dimerization interface. These data suggest that SARS-CoV-2 exploits host RAD51 to facilitate viral propagation, and hence, RAD51 inhibitor may serve as a putative novel therapeutic agent for the treatment of COVID-19.

IMPORTANCE
Viruses are constantly evolving to promote propagation in the host. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes host RAD51 for replication. Silencing of RAD51 impaired SARS-CoV-2 propagation. Viral RNA colocalized with RAD51 in the cytoplasm of SARS-CoV-2-infected cells, suggesting that both viral RNA and RAD51 may form a replication complex. We, therefore, evaluated RAD51 inhibitors as possible therapeutic agents against SARS-CoV-2. Indeed, RAD51 inhibitors exerted antiviral activities against not only Wuhan but also variants of SARS-CoV-2. Molecular docking model shows that RAD51 inhibitors impede SARS-CoV-2 propagation by interfering with dimerization of RAD51. These data suggest that RAD51 may represent a novel host-based drug target for coronavirus disease 2019 treatment.
The mating pilus of
E. coli
pED208 acts as a conduit for ssDNA during horizontal gene transfer
Authors: Beltrán Leticia , Torsilieri Holly , Patkowski Jonasz B. , Yang Jie E. , Casanova James , Costa Tiago R. D. , Wright Elizabeth R. , Egelman Edward H. 
Published: December 2023

ABSTRACT
Bacterial conjugation, a process of horizontal gene transfer, plays a key role in promoting the spread of antimicrobial resistance among human pathogens. The mechanism of conjugation involves the development of a conjugative pilus that forms a physical bridge between two bacterial cells and the subsequent unidirectional transfer of single-stranded DNA (ssDNA) complexed with a protein from the donor to the recipient cell. Atomic structures exist for many of the components of the type IV secretion system (T4SS), responsible for the nucleoprotein secretion, but little is known about the events preceding gene transfer, specifically what is the extent of the participation of the conjugative pilus in ssDNA transfer? There has been a longstanding debate about whether its main role is to bring a donor and a recipient cell into physical juxtaposition and form a mating junction that allows for ssDNA transfer via the T4SS machinery complex or whether ssDNA is actually transferred through the lumen of the pilus. Here, through a combination of maleimide labeling of the conjugative pilus and SeqA-YFP labeling of the transferred ssDNA, we visualize the process of bacterial conjugation in real time. We discover that the conjugative pilus is capable of transferring the ssDNA at a distance, between physically separated cells, and thus conclude that a physical mating junction is not essential for conjugative gene transfer.

IMPORTANCE

Bacteria are constantly exchanging DNA, which constitutes horizontal gene transfer. While some of these occurs by a non-specific process called natural transformation, some occurs by a specific mating between a donor and a recipient cell. In specific conjugation, the mating pilus is extended from the donor cell to make contact with the recipient cell, but whether DNA is actually transferred through this pilus or by another mechanism involving the type IV secretion system complex without the pilus has been an open question. Using
Escherichia coli
, we show that DNA can be transferred through this pilus between a donor and a recipient cell that has not established a tight mating junction, providing a new picture for the role of this pilus.
Draft genome sequence of endophytic fungus
Talaromyces purpureogenus
strain YAFEF302, isolated from
Juglans sigillata
Authors: Wang Yi , Yang Yuexian , Yuan Xiaolong , Ma Shanjun , Wang Dong , Qiao Lu 
Published: December 2023

ABSTRACT

Here, we report a draft genome sequence of endophytic fungus
Talaromyces purpureogenus
strain YAFEF302, isolated from
Juglans sigillata
. The genome resource will support future research into potential secondary metabolite diversity of this fungus.
Evidence of the simultaneous replications of active viruses in specimens positive for multiple respiratory viruses
Authors: Kawase Miyuki , Suwa Reiko , Sugimoto Satoko , Kakizaki Masatoshi , Kume Yohei , Chishiki Mina , Ono Takashi , Okabe Hisao , Norito Sakurako , Ujike Makoto , Hosoya Mitsuaki , Hashimoto Koichi , Shirato Kazuya 
Published: December 2023

ABSTRACT
Genetic diagnostic assays for the detection of respiratory viruses sometimes show simultaneous multiple infections with low copy numbers. In such cases, the disease is considered caused by a single etiologic agent and others are nonspecific reactions and/or contaminations. Interferon-dependent interference is seen in dual infections of influenza and respiratory syncytial virus, which are the main causes of respiratory infections. Virus isolation is one of the answers in detecting other active viruses present in specimens, and the air–liquid interface culture of human bronchial/tracheal epithelial cells (HBTEC-ALI) is optimal for the isolation of respiratory viruses owing to its wide range of susceptibility. In this study, we successfully confirmed the replications of various viruses from specimens with low copy numbers and simultaneous passage of two to three viruses using HBTEC-ALI cultures, mainly including human bocavirus 1 and/or human rhinovirus.

IMPORTANCE
Since the pandemic of coronavirus diseases 2019, the use of real-time PCR assay has become widespread among people who were not familiar with it in virus detection. As a result, whether a high real-time PCR value in one time test indicates virus transmissibly became a complicated social problem, regardless of the difference in assays and/or amplification conditions, the time and number of diagnostic test during the time course of infection. In addition, the multiple positives in the test of respiratory viruses further add to the confusion in the interpretation of the infection. To address this issue, we performed virus isolation using pediatric SARI (severe acute respiratory infections) specimens on air–liquid interface culture of human bronchial/tracheal epithelial cell culture. The result of this study can be a strong evidence that the specimens showing positivity for multiple agents in real-time PCR tests possibly contain infectious viruses.
Over-winter body mass and conceptions of white-tailed deer in central Texas
Authors: Weckerly F.W. , Reitz R. , Pfeffer D. 
Published: December 2023

At lower latitudes ungulate reproduction is often seasonal, but the duration of mating and parturition seasons can be long. To further understand the adaptive significance of synchrony in reproductive events, we examined two hypotheses to link over-winter body mass with lower synchrony of conceptions in a wild population of white-tailed deer ( Odocoileus virginianus (Zimmermann, 1780)) in central Texas. If females maintain over-winter body mass, then the window of time that conception occurs should be relaxed and longer relative to females where over-winter body mass declines. Across 9 years, we measured body mass in 1.5-year-old and older females in November ( n = 170) and in March (118). In March, we also measured forehead–rump lengths in offspring of gravid females and calculated conception dates. Over-winter body mass did not decline but was maintained, on average, across the years of study. Conception dates ranged over 50 days and 52% of conceptions occurred in a 2-week period centered on the median conception date. Relative to northern populations of deer, there was lower synchrony in conception dates. White-tailed deer across the geographic range appear to be flexible in over-winter body mass dynamics that affects duration of reproductive events such as conception.
Effective interactions and phase behavior of protein solutions in the presence of hexamine cobalt(III) chloride
Authors: Senft Maximilian D. , Maier Ralph , Hiremath Anusha , Zhang Fajun , Schreiber Frank 
Published: December 2023

AbstractIt is well established that deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) exhibit a reentrant condensation (RC) phase behavior in the presence of the trivalent hexamine cobalt(III) cations (Hac) which can be important for their packing and folding. A similar behavior can be observed for negatively charged globular proteins in the presence of trivalent metal cations, such as Y3+ or La3+. This phase behavior is mainly driven by charge inversion upon an increasing salt concentration for a fixed protein concentration (cp). However, as Hac exhibits structural differences compared to other multivalent metal cations, with six ammonia ligands (NH3) covalently bonded to the central cobalt atom, it is not clear that Hac can induce a similar phase behavior for proteins. In this work, we systematically investigate whether negatively charged globular proteins β-lactoglobulin (BLG), bovine serum albumin (BSA), human serum albumin (HSA) and ovalbumin (OVA) feature Hac-induced RC. Effective protein–protein interactions were investigated by small-angle X-ray scattering. The reduced second virial coefficient (B2/B2HS) was obtained as a function of salt concentration. The virial coefficient analysis performed confirms the reentrant interaction (RI) behavior for BLG without actually inducing RC, given the insufficient strengths of the interactions for the latter to occur. In contrast, the strength of attraction for BSA, HSA and OVA are too weak to show RC. Model free analysis of the inverse intensity $$1/I\left( {q \to 0} \right)$$

1
/
I

q
→
0

also supports this finding. Looking at different q-range by employing static (SLS) and dynamic light scattering experiments, the presence of RI behavior can be confirmed. The results are further discussed in view of metal cation binding sites in nucleic acids (DNA and RNA), where Hac induced RC phase behavior.
Graphical abstract
Toward an environmental friendly operation of the CBM-TOF system
Authors: Deppner Ingo , Bogdan Claudia , Brad Sebastian , Brill Cătălin , Dorobanţu Daniel , Grafov Aleksandr , Han Dong , Herrmann Norbert , Hu Dongdong , Lazar Alin , Li Wen , Petriş Mariana , Petrovici Mihai , Rozhenstev Andrii , Sirosh Oleksandr , Söhngen Yannick , Sun Kai , Sun Yongjie , Vijulie Mihai , Wang Botan , Wang Kaiyang , Wang Xinjian , Wang Yi , Yao Ming , Zhou Jian , Zhou Yingjie 
Published: December 2023

AbstractThe future fixed target high-rate compressed baryonic matter (CBM) experiment is one of the experimental pillars of the Facility for Antiproton and Ion Research (FAIR) located in Darmstadt/Germany. In order to provide an excellent particle identification (PID) of charged hadrons, the CBM-time-of-flight (TOF) group has developed a concept of a 120 m$$^2$$

2

large TOF wall with a system time resolution below 80 ps based on multi-gap resistive plate chambers (MRPC). Currently, timing MRPC systems are operated with a gas mixture based on tetrafluoroethane (R134a, C$$_2$$

2

H$$_2$$

2

F$$_4$$

4

) with additions of few vol% quencher gases, e.g., sulfur hexafluoride (SF$$_6$$

6

) or/and isobutane (i-C$$_4$$

4

H$$_10$$

1

0

). Unfortunately, these gas mixtures have a high global warming potential (GWP) in the order of 1500, and therefore, strategies to reduce the environmental impact have to be developed. The various possibilities, including studies on eco-friendly gases, and the considered strategy by the CBM-TOF group will be elaborated in this article.
Topology Guaranteed B-Spline Surface/Surface Intersection
Authors: Yang Jieyin , Jia Xiaohong , Yan Dong-Ming 
Published: December 2023

The surface/surface intersection technique serves as one of the most fundamental functions in modern Computer Aided Design (CAD) systems. Despite the long research history and successful applications of surface intersection algorithms in various CAD industrial software, challenges still exist in balancing computational efficiency, accuracy, as well as topology correctness. Specifically, most practical intersection algorithms fail to guarantee the correct topology of the intersection curve(s) when two surfaces are in near-critical positions, which brings instability to CAD systems. Even in one of the most successfully used commercial geometry engines ACIS, such complicated intersection topology can still be a tough nut to crack.
In this paper, we present a practical topology guaranteed algorithm for computing the intersection loci of two B-spline surfaces. Our algorithm well treats all types of common and complicated intersection topology with practical efficiency, including those intersections with multiple branches or cross singularities, contacts in several isolated singular points or highorder contacts along a curve, as well as intersections along boundary curves. We present representative examples of these hard topology situations that challenge not only the open-source geometry engine OCCT but also the commercial engine ACIS. We compare our algorithm in both efficiency and topology correctness on plenty of common and complicated models with the open-source intersection package in SISL, OCCT, and the commercial engine ACIS.
C-Shells: Deployable Gridshells with Curved Beams
Authors: Becker Quentin , Suzuki Seiichi , Ren Yingying , Pellis Davide , Panetta Julian , Pauly Mark 
Published: December 2023

We introduce a computational pipeline for simulating and designing
C-shells
, a new class of planar-to-spatial deployable linkage structures. A C-shell is composed of curved flexible beams connected at rotational joints that can be assembled in a stress-free planar configuration. When actuated, the elastic beams deform and the assembly deploys towards the target 3D shape.

We propose two alternative computational design approaches for C-shells: (i) Forward exploration simulates the deployed shape from a planar beam layout provided by the user. Once a satisfactory overall shape is found, a subsequent design optimization adapts the beam geometry to reduce the elastic energy of the linkage while preserving the target shape. (ii) Inverse design is facilitated by a new geometric flattening method that takes a design surface as input and computes an initial layout of piecewise straight linkage beams. Our design optimization algorithm then calculates the smooth curved beams to best reproduce the target shape at minimal elastic energy.
We find that C-shells offer a rich space for design and show several studies that highlight new shape topologies that cannot be achieved with existing deployable linkage structures.
Evaluation of Antimicrobial Activity and Cytotoxicity of an Epoxy Resin-Based Endodontic Sealer Containing Nanoparticles Amorphous Calcium Phosphate
Authors: Ibrahim Bilal H. , Al-Huwaizi Hussain 
Published: December 2023

Background. The main cause of posttreatment disease in endodontics is the remaining of microorganisms within the root canal walls after endodontic therapy. Therefore, it is essential to use root canal sealers with potent antibacterial properties. These sealers play a vital role in eradicating any remaining microorganisms and preventing recontamination, especially in situations where there might be microleakage. Aim. The objective of this research was to examine the antimicrobial properties of epoxy root canal sealers containing nanoparticle amorphous calcium phosphate (NACP) against planktonic Enterococcus faecalis in a controlled laboratory environment. Furthermore, the study aimed to assess the potential cytotoxic effects of these sealers. Method. In order to determine the antimicrobial activity, the epoxy resin sealer (AH Plus, Dentsply, Germany) was supplemented with NACP from Sigma–Aldrich, at a concentration of 3wt.%, as per the previous flowability tests. The agar well diffusion assay method was employed to evaluate the antibacterial efficacy. For this, cultured plates (n = 8) were prepared, with each plate containing three wells: one with AH Plus, one with AH Plus + NACP, and one with NACP alone. Subsequently, the plates were sited at 37°C in an incubator and allowed to incubate overnight. The width of the inhibition zones was then analyzed and recorded by the SPSS statistical software package (Version 20.0 for Windows, SPSS, Chicago, IL, USA). The cytotoxicity of the NACP incorporated AH Plus and AH Plus sealers were tested indirectly by MTT assay and directly by the multiparametric high content screening toxicology assay using fibroblast-like cells as cell lines. Results. AH Plus + NACP showed a higher antimicrobial activity than AH Plus with significant difference (

P
<
0.0001

). Both materials showed nonsignificant difference compared to negative control, which indicated lower cytotoxicities. For AH Plus,

P
=
0.3599
,
0.5959
,

and

0.4071

, with time intervals 24, 72, and 168 hr, respectively. For AH Plus + NACP,

P
=
0.4386
,
0.6182
,

and

0.2080

, with 24, 72, and 168 hr, respectively. Conclusions. NACP incorporation with epoxy resin sealer AH PLUS had a higher antimicrobial activity with lower cytotoxic effect indicating their potential therapeutic values.
A Systems Biology Approach to Understand the Racial Disparities in Colorectal Cancer
Authors: Nwaokorie Annabelle , Kolch Walter , Fey Dirk 
Published: December 2023

Abstract

Racial disparities between Black/African Americans (AA) and White patients in colorectal cancer are an ever-growing area of concern. Black/AA show the highest incidence and have the highest mortality among major U.S. racial groups. There is no definite cause other than possible sociodemographic, socioeconomic, education, nutrition, delivery of healthcare, screening, and cultural factors. A primary limitation in this field is the lack of and small sample size of Black/AA studies. Thus, this study aimed to investigate whether differences in gene expression contribute to this ongoing unanswered racial disparity issue. In this study, we examined transcriptomic data of Black/AA and White patient cohorts using a bioinformatic and systems biology approach. We performed a Kaplan–Meier overall survival analysis between both patient cohorts across critical colorectal cancer signal transduction networks (STN), to determine the differences in significant genes across each cohort. Other bioinformatic analyses performed included PROGENy (pathway responsive genes for activity inference), RNA sequencing differential expression using DESeq2, multivariable-adjusted regression, and other associated Kaplan–Meier analyses. These analyses identified novel prognostic genes independent from each cohort, 176 differentially expressed genes, and specific patient cohort STN survival associations. Despite the overarching limitation, the results revealed several novel differences in gene expression between the colorectal cancer Black/AA and White patient cohorts, which allows one to dive deeper into and understand the behavior on a systems level of what could be driving this racial difference across colorectal cancer. Concretely, this information can guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.

Significance:
The purpose of this work is to investigate the racial disparities in colorectal cancer between Black/AA and White patient cohorts using a systems biology and bioinformatic approach. Our study investigates the underlying biology of each patient cohort. Concretely, the findings of this study include disparity-associated genes and pathways, which provide a tangible starting point to guide precision medicine approaches tailored specifically for colorectal cancer racial disparities.
Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors
Authors: Kazi Aslamuzzaman , Ranjan Alok , Kumar M.V. Vasantha , Agianian Bogos , Garcia Chavez Martin , Vudatha Vignesh , Wang Rui , Vangipurapu Rajanikanth , Chen Liwei , Kennedy Perry , Subramanian Karthikeyan , Quirke Jonathan C.K. , Beato Francisca , Underwood Patrick W. , Fleming Jason B. , Trevino Jose , Hergenrother Paul J. , Gavathiotis Evripidis , Sebti Said M. 
Published: December 2023

Abstract

Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pulldown and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiotherapy. These results warrant further development of KRB-456 for pancreatic cancer.

Significance:
There are no clinically approved drugs directly abrogating mutant KRAS G12D. Here, we discovered a small molecule, KRB-456, that binds a dynamic allosteric binding pocket within the switch-I/II region of KRAS G12D. KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer. This discovery warrants further advanced preclinical and clinical studies in pancreatic cancer.