bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning in Automating Breast Cancer Diagnosis from Microscopy Images
Authors: Gu Qiangqiang , Prodduturi Naresh , Hart Steven N.
Published: August 2024

Breast cancer is one of the most common cancers in women. With early diagnosis, some breast cancers are highly curable. Classifying normal versus tumor breast tissues from microscopy images is an ideal case to use for deep learning and could help diagnose breast cancer with higher reproducibility. Since data preprocessing and hyperparameter tuning have impacts on breast cancer classification accuracies, training a classifier with appropriate data preprocessing and optimized hyperparameters could improve breast cancer classification accuracy. Using 12 combinations of model architectures, data preprocessing, and hyperparameter configurations, the validation accuracy was calculated using the BreAst Cancer Histology (BACH) dataset. The DenseNet201, a non-specialized model architecture, with transfer learning approach achieved 98.61% validation accuracy compared to only 64.00% for the digital pathology (DP)-specialized model architecture. The combination of image data preprocessing and hyperparameters have a profound impact on the performance of deep neural networks for image classification. To identify a well-performing neural network to classify tumor versus normal breast histology, researchers should not only focus on developing new models specifically for DP, since hyperparameter tuning for existing deep neural networks in the computer vision field could also achieve a better prediction accuracy.
SCAN, AIM, GO: A Compact Brain Device Guide for Accelerating Minimally-Invasive Image Guided Neurosurgeries
Authors: Lilieholm Thomas , Oakes Terrence , Lake Wendell , Ahmed Azam , Alexander Andrew L , Block Walter F
Published: August 2024

Workflows for MRI-guided minimally-invasive neurosurgeries are often time-consuming and complex. Many minimally-invasive interventions utilize magnetic resonance imaging (MRI) to noninvasively visualize internal anatomy and pathologies. This, in conjunction with external trajectory guides, can be used to internally position devices to perform complex surgeries with minimal disruption to the patients’ healthy anatomy.

These trajectory guides are typically rigidly attached to the skull and feature adjustable channels through which drills, needles, and /or catheters may be introduced. Trajectories are oriented by iterating between imaging and manipulation of device settings. MRI scans, while offering a great deal of valuable anatomic information, are slow to acquire. Scans of a sufficient resolution for neurosurgery can take on the order of 10 minutes to acquire, depending on field of view. Noniterative approaches could reduce complexity and anesthesia time.

This work describes efforts to create and validate a new trajectory guide that enables faster, accurate trajectory guidance in minimally-invasive neurosurgeries. Using new hardware and software, a single scan approach was used to perform drill guidance and device insertion on phantoms and cadaver heads.

The proposed methodology accurately guided needles to targets within phantoms and human cadaver brains using a single targeting scan. The initial design produced a radial error of 1.4±0.8mm in phantoms and 1.5±0.8mm in cadaver brains.

The proposed device and software accelerate trajectory guidance in minimally-invasive neurosurgeries by reducing the number of acquired scans and procedural steps. This in turn minimizes time under anesthesia.
Multi-Platform Patient Monitor System
Authors: Ozturk Ertan , Yapıcı Ozan Emre , Unal Mehmet , Bozacı Ilgın , Çakıcı Osman
Published: August 2024

Patient Monitors (PM) provide momentarily display of the multiple physiological signals of patients interpreted by medical professionals for diagnostic purposes. Clinical Research and academic have brought new techniques for illness diagnosis, therefore traditional patient monitors are required to be adapted for new diagnosis techniques to help medical practitioners. Besides, it is required to access patient’s monitored data by medical doctors from anywhere, anytime.

In this paper, we present the state of art architecture of our, commercially available, multi-platform patient monitor system, which can run on various hardware and software platforms, meaning that the application software can run on all available personal computers and mobile devices. Moreover, we show its flexibility to include new algorithms for diagnosis of illnesses by presenting the detection of Sepsis disease. Consequently, our patient monitor system is also a research tool to implement new algorithms and observe the results in a full-scale system.
Coronary Access and Perfusion Following Transcatheter Aortic Valve Replacement: The Effects of Relative Coronary Ostium Positioning
Authors: Bielecki Michael , Belding Samuel , Iaizzo Paul A.
Published: August 2024

With the goal of commissural alignment becoming a major goal with transcatheter aortic valve replacement (TAVR) becoming more prevalent, the native positionings of the coronary ostia and aortic valve cusps should be considered in the pre-procedural planning. Coronary access and perfusion post-TAVR are paramount to a patient's long-term outcomes with such procedures. In certain cases of unsymmetrical coronary cusps, commissural alignment may still leave a particularly eccentric coronary, that lays close to the native commissure of the valve, which is then susceptible to coronary obstruction. The Visible Heart® Laboratories have access to over 600 human heart specimens that have been used to analyze the native positionings of the coronary ostia. These specimens have been micro-CT scanned to make 3D-computational models with resolutions ranging from 80-100 microns. Additionally, reanimated swine hearts have been utilized to assess the relative effects of TAVR on coronary perfusion and access in living tissues. To do so, coronary pressure wires have been placed in these swine hearts before and after TAVR to assess how the coronary position could affect coronary perfusion following TAVR. The data collected here should be an educational aid to those performing such procedures as well as those developing the technologies to do so.
Rapid Thermal Control of Liquids (Realcool) Design and Testing for Heating and Cooling Milk
Authors: Hannon Nadia , Mehrabi Melika , Rylander Marissa Nichole , McGuire Michelle , McGuire Mark , Rylander Chris
Published: August 2024

RealCooL is a device that can rapidly modify the temperature of many liquids to a desired target value. Extensive interviews revealed that there is a need for a device that can rapidly cool or heat liquids, specifically for the use of rewarming or chilling human milk for babies. Commercially available devices such as freezers or baby bottle warmers provide slow rates of chilling and lack the ability for temperature control of the milk. The heating and cooling rates of RealCooL were compared to two commercially available devices: a standard LG freezer for cooling and a Thermo Fisher water bath for heating. Bovine milk was used to simulate human milk in these experiments. Results indicate that RealCooL results in a 6-fold higher cooling rate and a 45-fold higher warming rate compared to commercial devices. Next steps include examination of whether RealCooL affects nutritive and biologically active components in human milk and determination of optimal cooling and heating rates for HM.
Development of a Self-Powered Sensory Neuroprosthesis with Pneumatic Actuators
Authors: Campos Bianca , Schoeppner Mollie , Trader William , Arena Sara , Arena Christopher B.
Published: August 2024

Peripheral neuropathy results from damage to the nerves in the peripheral nervous system [1] and can cause loss of feeling or numbness in the hands and feet [2]. This leads to several challenges, including difficulty walking. Our goal was to create a device that gives sensory feedback during gait to a portion of the limb that still has sensation and ultimately reduces the chance of trips and falls. Additional constraints were placed on the system being cost-effective and easy to use. We have composed a device using a closed, human-actuated air bladder system. An underfoot input air bladder compresses during walking, which in turn, inflates an air bladder on the leg that stimulates sensory nerves. To test the device, an Instron was used to apply a load to the input bladder, and the force generated by an output bladder was measured on a mannequin leg. Four devices were evaluated in total, with two different output bladder designs and two different fluid connection systems between the bladders. It was found that both output bladder designs were effective and the connection system consisting of polyurethane tubing was superior in translating the input force onto the leg. This design also had the fastest force release, which could prove beneficial during the naturally cyclical process of walking.
Open-Source Accelerometer-Based Device and Data Analysis for Precision Monitoring of Sleep Apnea Events
Authors: Khan Faizaan , Rashidi Keyvon , Dongre Roshan , Razmi Samuel E. , Shenoi Jason , Ahmed Omar G. , Takashima Masayoshi
Published: August 2024

Background: Sleep apnea, encompassing obstructive, central, and complex forms, significantly impacts global health, affecting a broad segment of the population. This condition can lead to serious cardiovascular and neurological damage due to recurrent hypoxia. Despite its prevalence, many individuals remain undiagnosed, partly due to the absence of accessible and accurate screening tools.

Objective: To record and quantify sleep events in patients with an accelerometer that will be placed on the sternal notch.

Method: A Python algorithm was developed to collect data from an open-source biosensor which was displaced 6 consecutive times across 20 trials along the y-axis to mimic movement along the anteroposterior axis. This algorithm then processed the data and displayed the results in a user interface, allowing for simple determination of OSA events with timestamps for reference along with plotting.

Results: The system demonstrated 100% accuracy, consistently identifying all six disruptions per trial with no false detections despite the variability in displacements.

Conclusion: This study validates the potential of an advanced monitoring system in diagnosing and understanding sleep apnea, proposing a promising avenue for improving patient care through precise detection and analysis.
Flexible Precision: Design and Testing of a Snake-Inspired Robotic Arm for Large Organ and Tissue Retraction During Robot-Assisted Surgery
Authors: Alias Basil P. , Bageshwar Raaghav
Published: August 2024

In the realm of robot-assisted surgery, maneuverability in confined spaces remains a critical challenge. This paper presents the development of a snake-like robotic arm designed specifically for large organ and tissue retraction during minimally invasive surgeries. Emulating the flexible movements of a snake, the robotic arm aims to push the boundaries of current surgical robots. Key objectives include compatibility with existing minimally invasive ports, capacity to hold up to 2 pounds of tissue without deformation, axial stability under 10N force at full extension, compatibility with articulate-by-wire robotic systems, and a minimum of 4 degrees of freedom.

The design and construction involve three segments: the base attachment, middle links, and the end manipulator. Finite Element Analysis (FEA) validates the design and demonstrates the device’s ability to handle up to 10N before the onset of deformation. The arm, manufactured using stereolithography printing, handled 2 lbs (~10N) of distal-segment load thus providing real-world evidence to reinforce the FEA data. The actuation base, powered by high-torque servo motors controlled by a separate control module, provides precise and responsive movement. Extensive testing, both in simulated computational environments and physical stress tests, demonstrates the arm's proficiency in handling surgical tasks within minimally invasive procedures.
Coupling and Crosstalk Challenges for Garment-Based Sensor Characterization: Sensing Knee Valgus Using a Stitched Strain Sensor with Anchoring
Authors: Beaudette Eric , Tompkins Marc , Dunne Lucy
Published: August 2024

Valgus angles during knee movements are a measure of interest both for rehabilitation and injury prevention applications. Soft, garment-like movement-sensing devices can improve patient experience with enhanced donning and comfort while supporting rehabilitation regimens and collecting valuable recovery metrics. However, textile-based sensing is generally less accurate than traditional methods for measuring joint angles.

This study (n=3 participants) tested medial knee sensor responses during optical motion capture with prototype variants with and without circumferential anchors. Test participants performed non-valgus and valgus-induced squats. Correlation coefficients and regression were used to understand the relationships between knee valgus and sensor responses. Findings included mixed effects from anchoring, affected by participant and type of squat. Crosstalk from large flexion angles could be a primary contributor to the variability in medial sensor response. The ability to effectively sense and disambiguate these out-of-plane rotational effects remains a primary challenge for sensing complex movements with garment-integrated textile sensors.
Design and Analysis of a Semi-Robotic Tool Support System for Laparoscopic Surgery
Authors: Fournelis Nicolette , Song Sang-Eun
Published: August 2024

Laparoscopy is a surgical method that involves the use of several tools inserted into the body through small incisions, and a small camera to provide visualization of the surgical field. This method allows for decreased risk of infection, rapid healing time, and reduced scarring of the incision sites. Currently, the most advanced form of this technique is robotic laparoscopic surgery, where a robot controlled by a surgeon. While very precise, this system is very expensive and requires special facilities, therefore, undesirable for smaller hospitals to implement. Thus, an intermediary device that bridges the gap between traditional laparoscopic surgery and robotic laparoscopic surgery, while remaining cost effective and practical, could be a solution.
An online decoupling-whitening frequency domain filtered-error least mean square algorithm for active road noise control
Authors: Lian Siyuan , Li Tianyou , Gu Jincheng , Hu Yuxiang , Zhu Changbao , Wang Shuping , Lu Jing
Published: August 2024

Active road noise control (ARNC) systems have been widely investigated for low-frequency road noise attenuation in vehicle cabins. Multiple reference and error sensors are usually required to ensure noticeable noise reduction. However, this tends to slow down the convergence speed of adaptive algorithms due to the coupling of secondary paths and the cross correlation of reference signals. Furthermore, the high computational burden of normally utilized multichannel control algorithms exacerbates the difficulty of practical implementations. In this paper, an online decoupling-whitening frequency domain filtered-error least mean square (ODW-FDFeLMS) algorithm is proposed to address the aforementioned problems. Secondary path decoupling through inner-outer product decomposition and online reference whitening through spectral factorization effectively accelerate the convergence rate. Additionally, the utilization of the filtered-error algorithm based on frequency domain processing mitigates the computational complexity. Simulations with measured road noise data confirm the superiority of the ODW-FDFeLMS algorithm over existing algorithms in terms of convergence speed and computational complexity. Real-time experiments in a vehicle cabin further confirm the effectiveness of the proposed algorithm.
Psychometric Properties of the Turkish Version of the Pictorial Scale of Perceived Movement Skill Competence for Turkish Young Children
Authors: Yaren Kırcı Neslişah , Çağlar Emine , Karabulut Erdem , Boz Menekşe , Demirhan Gıyasettin , Karaca Ayda
Published: August 2024

The aim of this study was to determine the psychometric properties of the pictorial scale of Perceived Movement Skill Competence for Turkish children. A total of 255 children aged 5–10 years (131 girls and 124 boys) participated in this study. One week later, a random subsample (n = 40) was implemented the scale again for test–retest reliability. We conducted confirmatory factor analysis to test the construct validity of the Turkish version of the scale and calculated the omega (ω) internal consistency and intraclass correlation coefficients (ICCs) to ascertain reliabilities of the subscales. The confirmatory factor analysis showed good fit index values for the model with 13 items indicating a similar factor structure to the original scale’s two-factor structure (χ2/df = 1.56; root mean square error of approximation  = .048; Tucker–Lewis index  = .97; comparative-fit index  = .97). The test–retest reliabilities were excellent for the perceived locomotor (ICC = .95) and object control (ICC = .93) skills. An adequate internal consistency coefficient was found for locomotor (ω = 0.69) and object control (ω = 0.82) skills. Subsequent analyses supported the construct, metric, partial scalar and strict invariance of responses to the scale as a function of sex. Overall, the pictorial scale of Perceived Movement Skill Competence has acceptable psychometric properties and can be confidently used in research or practice to assess Turkish children’s perceived movement skill competence.
Discovery of SARS-CoV-2 papain-like protease (PL
pro
) inhibitors with efficacy in a murine infection model
Authors: Garnsey Michelle R. , Robinson Matthew C. , Nguyen Luong T. , Cardin Rhonda , Tillotson Joseph , Mashalidis Ellene , Yu Aijia , Aschenbrenner Lisa , Balesano Amanda , Behzadi Amin , Boras Britton , Chang Jeanne S. , Eng Heather , Ephron Andrew , Foley Tim , Ford Kristen K. , Frick James M. , Gibson Scott , Hao Li , Hurst Brett , Kalgutkar Amit S. , Korczynska Magdalena , Lengyel-Zhand Zsofia , Gao Liping , Meredith Hannah R. , Patel Nandini C. , Polivkova Jana , Rai Devendra , Rose Colin R. , Rothan Hussin , Sakata Sylvie K. , Vargo Thomas R. , Qi Wenying , Wu Huixian , Liu Yiping , Yurgelonis Irina , Zhang Jinzhi , Zhu Yuao , Zhang Lei , Lee Alpha A.
Published: August 2024

Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL
pro
) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PL
pro
inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL
pro
translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning–driven discovery of potent, selective, and orally available SARS-CoV-2 PL
pro
inhibitors, with lead compound PF-07957472 (
4
) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Immunization with germ line–targeting SOSIP trimers elicits broadly neutralizing antibody precursors in infant macaques
Authors: Nelson Ashley N. , Shen Xiaoying , Vekatayogi Sravani , Zhang Shiyu , Ozorowski Gabriel , Dennis Maria , Sewall Leigh M. , Milligan Emma , Davis Dominique , Cross Kaitlyn A. , Chen Yue , van Schooten Jelle , Eudailey Joshua , Isaac John , Memon Saad , Weinbaum Carolyn , Gao Hongmei , Stanfield-Oakley Sherry , Byrd Alliyah , Chutkan Suni , Berendam Stella , Cronin Kenneth , Yasmeen Anila , Alam S. , LaBranche Celia C. , Rogers Kenneth , Shirreff Lisa , Cupo Albert , Derking Ronald , Villinger Francois , Klasse Per Johan , Ferrari Guido , Williams Wilton B. , Hudgens Michael G. , Ward Andrew B. , Montefiori David C. , Van Rompay Koen K. A. , Wiehe Kevin , Moore John P. , Sanders Rogier W. , De Paris Kristina , Permar Sallie R.
Published: August 2024

Adolescents are a growing population of people living with HIV. The period between weaning and sexual debut presents a low-risk window for HIV acquisition, making early childhood an ideal time for implementing an immunization regimen. Because the elicitation of broadly neutralizing antibodies (bnAbs) is critical for an effective HIV vaccine, our goal was to assess the ability of a bnAb B cell lineage–designed HIV envelope SOSIP (protein stabilized by a disulfide bond between gp120-gp41—named “SOS”—and an isoleucine-to-proline point mutation—named “IP”—at residue 559) to induce precursor CD4 binding site (CD4bs)–targeting bnAbs in early life. Infant rhesus macaques received either a BG505 SOSIP, based on the infant BG505 transmitted/founder virus, or the CD4bs germ line–targeting BG505 SOSIP GT1.1 (
n
= 5 per group). Although both strategies induced durable, high-magnitude plasma autologous virus neutralization responses, only GT1.1-immunized infants (
n
= 3 of 5) exhibited VRC01-like CD4bs bnAb precursor development. Thus, a multidose immunization regimen with bnAb lineage–designed SOSIPs shows promise for inducing early B cell responses with the potential to mature into protective HIV bnAbs before sexual debut.
DDX RNA helicases: key players in cellular homeostasis and innate antiviral immunity
Authors: Tapescu Iulia , Cherry Sara
Published: August 2024

RNA helicases are integral in RNA metabolism, performing important roles in cellular homeostasis and stress responses. In particular, the DExD/H-box (DDX) helicase family possesses a conserved catalytic core that binds structural features rather than specific sequences in RNA targets. DDXs have critical roles in all aspects of RNA metabolism including ribosome biogenesis, translation, RNA export, and RNA stability. Importantly, functional specialization within this family arises from divergent N and C termini and is driven at least in part by gene duplications with 18 of the 42 human helicases having paralogs. In addition to their key roles in the homeostatic control of cellular RNA, these factors have critical roles in RNA virus infection. The canonical RIG-I-like receptors (RLRs) play pivotal roles in cytoplasmic sensing of viral RNA structures, inducing antiviral gene expression. Additional RNA helicases function as viral sensors or regulators, further diversifying the innate immune defense arsenal. Moreover, some of these helicases have been coopted by viruses to facilitate their replication. Altogether, DDX helicases exhibit functional specificity, playing intricate roles in RNA metabolism and host defense. This review will discuss the mechanisms by which these RNA helicases recognize diverse RNA structures in cellular and viral RNAs, and how this impacts RNA processing and innate immune responses.
Development of an intestinal mucosa
ex vivo
co-culture model to study viral infections
Authors: Barreto-Duran Emilia , Synowiec Aleksandra , Szczepański Artur , Gałuszka-Bulaga Adrianna , Węglarczyk Kazimierz , Baj-Krzyworzeka Monika , Siedlar Maciej , Bochenek Michał , Dufva Martin , Dogan Asli Aybike , Lenart Marzena , Pyrc Krzysztof
Published: August 2024

Studying viral infections necessitates well-designed cell culture models to deepen our understanding of diseases and develop effective treatments. In this study, we present a readily available
ex vivo
3D co-culture model replicating the human intestinal mucosa. The model combines fully differentiated human intestinal epithelium (HIE) with human monocyte-derived macrophages (hMDMs) and faithfully mirrors the
in vivo
structural and organizational properties of intestinal mucosal tissues. Specifically, it mimics the lamina propria, basement membrane, and the air-exposed epithelial layer, enabling the pioneering observation of macrophage migration through the tissue to the site of viral infection. In this study, we applied the HIE-hMDMs model for the first time in viral infection studies, infecting the model with two globally significant viruses: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human norovirus GII.4. The results demonstrate the model’s capability to support the replication of both viruses and show the antiviral role of macrophages, determined by their migration to the infection site and subsequent direct contact with infected epithelial cells. In addition, we evaluated the production of cytokines and chemokines in the intestinal niche, observing an increased interleukin-8 production during infection. A parallel comparison using a classical
in vitro
cell line model comprising Caco-2 and THP-1 cells for SARS-CoV-2 experiments confirmed the utility of the HIE-hMDMs model in viral infection studies. Our data show that the
ex vivo
tissue models hold important implications for advances in virology research.

IMPORTANCE

The fabrication of intricate
ex vivo
tissue models holds important implications for advances in virology research. The co-culture model presented here provides distinct spatial and functional attributes not found in simplified models, enabling the evaluation of macrophage dynamics under severe acute respiratory syndrome coronavirus 2 and human norovirus (HuNoV) infections in the intestine. Moreover, these models, comprised solely of primary cells, facilitate the study of difficult-to-replicate viruses such as HuNoV, which cannot be studied in cell line models, and offer the opportunity for personalized treatment evaluations using patient cells. Similar co-cultures have been established for the study of bacterial infections and different characteristics of the intestinal tissue. However, to the best of our knowledge, a similar intestinal model for the study of viral infections has not been published before.
Endogenous nege-like viral elements in arthropod genomes reveal virus–host coevolution and ancient history of two plant virus families
Authors: Lu Gang , Ye Zhuang-Xin , Qi Yu-Hua , Lu Jia-Bao , Mao Qian-Zhuo , Zhuo Ji-Chong , Huang Hai-Jian , He Yu-Juan , Li Yi-Yuan , Xu Zhong-Tian , Chen Jian-Ping , Zhang Chuan-Xi , Li Jun-Min
Published: August 2024

Negevirus is a recently proposed taxon of arthropod-infecting virus, which is associated with plant viruses of two families (
Virgaviridae
and
Kitaviridae
). Nevertheless, the evolutionary history of negevirus–host and its relationship with plant viruses remain poorly understood. Endogenous nege-like viral elements (ENVEs) are ancient nege-like viral sequences integrated into the arthropod genomes, which can serve as the molecular fossil records of previous viral infection. In this study, 292 ENVEs were identified in 150 published arthropod genomes, revealing the evolutionary history of nege-like viruses and two related plant virus families. We discovered three novel and eight strains of nege-like viruses in 11 aphid species. Further analysis indicated that 10 ENVEs were detected in six aphid genomes, and they were divided into four types (ENVE1-ENVE4). Orthologous integration and phylogenetic analyses revealed that nege-like viruses had a history of infection of over 60 My and coexisted with aphid ancestors throughout the Cenozoic Era. Moreover, two nege-like viral proteins (CP and SP24) were highly homologous to those of plant viruses in the families
Virgaviridae
and
Kitaviridae
. CP- and SP24-derived ENVEs were widely integrated into numerous arthropod genomes. These results demonstrate that nege-like viruses have a long-term coexistence with arthropod hosts and plant viruses of the two families,
Virgaviridae
and
Kitaviridae
, which may have evolved from the nege-like virus ancestor through horizontal virus transfer events. These findings broaden our perspective on the history of viral infection in arthropods and the origins of plant viruses.

IMPORTANCE

Although negevirus is phylogenetically related to plant virus, the evolutionary history of negevirus–host and its relationship with plant virus remain largely unknown. In this study, we used endogenous nege-like viral elements (ENVEs) as the molecular fossil records to investigate the history of nege-like viral infection in arthropod hosts and the evolution of two related plant virus families (
Virgaviridae
and
Kitaviridae
). Our results showed the infection of nege-like viruses for over 60 My during the arthropod evolution. ENVEs highly homologous to viral sequences in
Virgaviridae
and
Kitaviridae
were present in a wide range of arthropod genomes but were absent in plant genomes, indicating that plant viruses in these two families possibly evolved from the nege-like virus ancestor through cross-species horizontal virus transmission. Our findings provide a new perspective on the virus–host coevolution and the origins of plant viruses.
Loopy virus or controlled contortionist? 3D regulation of HCMV gene expression by CTCF-driven chromatin interactions
Authors: Groves Ian J. , O’Connor Christine M.
Published: August 2024

Three-dimensional chromatin control of eukaryotic transcription is pivotal for regulating gene expression. This additional layer of epigenetic regulation is also utilized by DNA viruses, including herpesviruses. Dynamic, spatial genomic organization often involves looping of chromatin anchored by host-encoded CCCTC-binding factor (CTCF) and other factors, which control crosstalk between promoters and enhancers. Herein, we review the contribution of CTCF-mediated looping in regulating transcription during herpesvirus infection, with a specific focus on the betaherpesvirus, human cytomegalovirus (HCMV).
UBE3C restricts EV-A71 replication by ubiquitination-dependent degradation of 2C
Authors: Cui Boming , Yang Ge , Yan Haiyan , Wu Shuo , Wang Kun , Wang Huiqiang , Li Yuhuan
Published: August 2024

Ubiquitin modification of viral proteins to degrade or regulate their function is one of the strategies of the host to resist viral infection. Here, we report that ubiquitin protein ligase E3C (UBE3C), an E3 ubiquitin ligase, displayed inhibitory effects on EV-A71 replication. UBE3C knockdown resulted in increased viral protein levels and virus titers, whereas overexpression of UBE3C reduced EV-A71 replication. To explore the mechanism by which UBE3C affected EV-A71 infection, we found that the C-terminal of UBE3C bound to 2C protein and facilitated K33/K48-linked ubiquitination degradation of 2C K268. Moreover, UBE3C lost its ability to degrade 2C K268R and had a diminished inhibitory impact against the replication of recombinant EV-A71-FY-2C K268R. In addition, UBE3C also promoted ubiquitination degradation of the 2C protein of CVB3 and CVA16 and inhibited viral replication. Thus, our findings reveal a novel mechanism that UBE3C acts as an enterovirus host restriction factor, including EV-A71, by targeting the 2C protein.

IMPORTANCE

The highly conserved 2C protein of EV-A71 is a multifunctional protein and plays a key role in the replication cycle. In this study, we demonstrated for the first time that UBE3C promoted the degradation of 2C K268
via
K33/K48-linked ubiquitination, thereby inhibiting viral proliferation. Our findings advance the knowledge related to the roles of 2C in EV-A71 virulence and the ubiquitination pathway in the host restriction of EV-A71 infection.
Guanylate-binding protein 5 antagonizes viral glycoproteins independently of furin processing
Authors: Veler Hana , Lun Cheng Man , Waheed Abdul A. , Freed Eric O.
Published: August 2024

Guanylate-binding protein (GBP) 5 is an interferon-inducible cellular factor with broad anti-viral activity. Recently, GBP5 has been shown to antagonize the glycoproteins of a number of enveloped viruses, in part by disrupting the host enzyme furin. Here we show that GBP5 strongly impairs the infectivity of virus particles bearing not only viral glycoproteins that depend on furin cleavage for infectivity—the envelope (Env) glycoproteins of HIV-1 and murine leukemia virus and the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—but also viral glycoproteins that do not depend on furin cleavage: vesicular stomatitis virus glycoprotein and SARS-CoV S. We observe that GBP5 disrupts proper
N
-linked protein glycosylation and reduces the incorporation of viral glycoproteins into virus particles. The glycosylation of the cellular protein CD4 is also altered by GBP5 expression. Flow cytometry analysis shows that GBP5 expression reduces the cell-surface levels of HIV-1 Env and the S glycoproteins of SARS-CoV and SARS-CoV-2. Our data demonstrate that, under the experimental conditions used, inhibition of furin-mediated glycoprotein cleavage is not the primary anti-viral mechanism of action of GBP5. Rather, the antagonism appears to be related to impaired trafficking of glycoproteins to the plasma membrane. These results provide novel insights into the broad antagonism of viral glycoprotein function by the cellular host innate immune response.

IMPORTANCE

The surface of enveloped viruses contains viral envelope glycoproteins, an important structural component facilitating virus attachment and entry while also acting as targets for the host adaptive immune system. In this study, we show that expression of GBP5 in virus-producer cells alters the glycosylation, cell-surface expression, and virion incorporation of viral glycoproteins across several virus families. This research provides novel insights into the broad impact of the host cell anti-viral factor GBP5 on protein glycosylation and trafficking.
Allosteric coupling of substrate binding and proton translocation in MmpL3 transporter from
Mycobacterium tuberculosis
Authors: Babii Svitlana , Li Wei , Yang Lixinhao , Grzegorzewicz Anna E. , Jackson Mary , Gumbart James C. , Zgurskaya Helen I.
Published: August 2024

Infections caused by
Mycobacterium
spp. are very challenging to treat, and multidrug-resistant strains rapidly spread in human populations. Major contributing factors include the unique physiological features of these bacteria, drug efflux, and the low permeability barrier of their outer membrane. Here, we focus on MmpL3 from
Mycobacterium tuberculosis
, an essential inner membrane transporter of the resistance–nodulation–division superfamily required for the translocation of mycolic acids in the form of trehalose monomycolates (TMM) from the cytoplasm or plasma membrane to the periplasm or outer membrane. The MmpL3-dependent transport of TMM is essential for the growth of
M. tuberculosis in vitro
, inside macrophages, and in
M. tuberculosis-
infected mice. MmpL3 is also a validated target for several recently identified anti-mycobacterial agents. In this study, we reconstituted the lipid transport activity of the purified MmpL3 using a two-lipid vesicle system and established the ability of MmpL3 to actively extract phospholipids from the outer leaflet of a lipid bilayer. In contrast, we found that MmpL3 lacks the ability to translocate the same phospholipid substrate across the plasma membrane indicating that it is not an energy-dependent flippase. The lipid extraction activity was modulated by substitutions in critical charged and polar residues of the periplasmic substrate-binding pocket of MmpL3, coupled to the proton transfer activity of MmpL3 and inhibited by a small molecule inhibitor SQ109. Based on the results, we propose a mechanism of allosteric coupling wherein substrate translocation by MmpL3 is coupled to the energy provided by the downhill transfer of protons. The reconstituted activities will facilitate understanding the mechanism of MmpL3-dependent transport of lipids and the discovery of new therapeutic options for
Mycobacterium
spp. infections.

IMPORTANCE

MmpL3 from
Mycobacterium tuberculosis
is an essential transporter involved in the assembly of the mycobacterial outer membrane. It is also an important target in undergoing efforts to discover new anti-tuberculosis drugs effective against multidrug-resistant strains spreading in human populations. The recent breakthrough structural studies uncovered features of MmpL3 that suggested a possible lipid transport mechanism. In this study, we reconstituted and characterized the lipid transport activity of MmpL3 and demonstrated that this activity is blocked by MmpL3 inhibitors and substrate mimics. We further uncovered the mechanism of how the binding of a substrate in the periplasmic domain is communicated to the transmembrane proton relay of MmpL3. The uncovered mechanism and the developed assays provide new opportunities for mechanistic analyses of MmpL3 function and its inhibition.
Whole-genome sequence and annotation of
Diaporthe australafricana
strain CBS 118571
Authors: Li Xin , Wang Xinyi , Li Limei , Lei Rong
Published: August 2024

We report the whole-genome sequence of
Diaporthe australafricana
Crous & J.M. van Niekerkusing using Oxford Nanopore long-read sequencing and Illumina short-read sequencing. The hybrid genome consists of 11 contigs with a total length of 53.509 Mb, and a GC content of 52.40%.
Probing the function of C-terminal region of recombinant α-amylase BmaN1 from
Bacillus megaterium
NL3
Authors: Frima Fina Khaerunnisa , Thufail Muhammad Akbar , Madhani Indri Novia , Nafisah Zahrotun , Shofiyah Sofi Siti , Ulpiyana Ayra , Puspasari Fernita , Aditama Reza , Ihsanawati Ihsanawati , Natalia Dessy
Published: August 2024

The α-amylase BmaN1 from
Bacillus megaterium
NL3 is a member of GH13_45 subfamily that has a conserved C-terminal region of approximately 30 residues. This region features a motif of five aromatic amino acids predicted to play a role in starch binding. This study aimed to unravel the role of the C-terminal region in starch hydrolysis. The full-length and C-terminally truncated forms of BmaN1 (BmaN1∆C) were expressed in
Escherichia coli
ArcticExpress (DE3), resulting in proteins with molecular weights of 56 kDa and 49 kDa, respectively. They exhibited comparable enzymatic activity in the hydrolysis of soluble starch, displaying versatility across a wide range of pH values, temperatures, and NaCl concentrations. BmaN1 and BmaN1∆C activities were inhibited by acarbose and were reduced by SDS and EDTA. In terms of binding and degrading the starch granules, BmaN1∆C showed lower affinity and activity in comparison to BmaN1. Our study indicates that the C-terminal region of BmaN1 significantly enhances its binding affinity and degrading the raw starches.

IMPORTANCE

α-Amylase (EC 3.2.1.1) stands as an endo-acting enzyme, essential for catalyzing the hydrolysis of α-1,4 glycosidic bonds within starch molecules. The relevance of α-amylases in biotechnological applications is substantial, constituting approximately 30% of the global enzyme market. Among these enzymes, BmaN1 was the first α-amylase identified to possess distinct catalytic residues within the GH13 family. BmaN1 from
B. megaterium
NL3 belongs to the GH13_45 subfamily. This subfamily is characterized by a conserved C-terminal region consisting of approximately 30 residues that contains a motif of five aromatic residues predicted to be involved in starch binding. Our study shows that the C-terminal effectively contributes to binding and degrading the raw starch granules. This pioneering research on BmaN1 expands our understanding of α-amylases and holds promise for innovative biotechnological advancements.
Synthesis and Spectral Properties of Conjugated Bis-1,3-diketo Derivatives of Calix[4]arene in the 1,3-alternate Isomeric Form and Their Complexes with Eu3+
Authors: Shvedova А. E. , Deltsov I. D. , Sudakova S. N. , Masliy A. N. , Syakaev V. V. , Vatsouro I. M. , Mambetova G. Sh. , Kuznetsov A. M. , Kovalev V. V. , Mustafina A. R. , Podyachev S. N.
Published: August 2024

Distally substituted bis-1,3-diketone derivatives of calix[4]arene were synthesized, in which chelate groups are attached via a carbonyl carbon atom to the p-positions of phenolic fragments of a macrocycle fixed in 1,3-alternate isomeric form. 1,3-Diketone derivatives were obtained by acylation of magnesium enolate of a calix[4]arene ketone with 1-benzoylbenzotriazoles. In the synthesized compounds, 1,3-diketone groups are conjugated with the π-aromatic system of calix[4]arene. It was found by means of UV spectroscopy and NMR diffusion methods in combination with quantum chemical (DFT) calculations that a mononuclear complex with bis-chelate coordination of the lanthanide ion is predominantly formed in the solution. The formation of the complex leads to a decrease in the conjugation degree in the ligand. The most effective sensitization of Eu3+ luminescence, compared to the p-F- or p-CF3-phenyl-substituted complexes is observed for calix[4]arene complexes with H-phenyl-substituted 1,3-diketone groups.
Unilateral tongue swelling: an unusual presentation of angiotensin-converting enzyme inhibitor-related angioedema
Authors: Eloff Julian Robert Paul , Oosthuizen Almero
Published: August 2024

Angioedema is a rare but potentially fatal complication of angiotensin-converting enzyme inhibitor (ACEi) treatment. This class of drugs is widely used in the treatment of hypertension, cardiac failure and other common conditions.

This case report discusses a male patient in his 60s who presented with acute swelling of the right side of his tongue, an unusual manifestation of angioedema, which typically involves bilateral swelling of orofacial structures.

Accurate and early identification of this complication affords the opportunity for early, potentially life-saving intervention during the acute episode and also cessation of the treatment, reducing the risk of recurrence in the future.

This case is one of only a few reported in English language medical literature and the first from Africa, suggesting either rarity or under-reporting. The case contributes to the understanding of ACEi-induced angioedema, particularly in Africa where hypertension is prevalent and ACEi is commonly used.
Cavitary lung lesions caused byPneumocystis jiroveciiin a patient with myelofibrosis on ruxolitinib
Authors: Ritter Austin , Kensey Nicholas , Higgs James , Zainah Hadeel
Published: August 2024

We report a rare case of a patient with Janus kinase 2-positive myelofibrosis on ruxolitinib, presenting with indolent pneumonia and cavitary lung lesions. Initial transthoracic biopsy was non-specific, but thoracoscopic biopsy revealed necrotising granulomatous disease caused byPneumocystis jiroveciipneumonia (PJP). The patient, initially treated with trimethoprim–sulfamethoxazole, was switched to atovaquone due to gastrointestinal intolerance. Given the patient’s immunosuppression and extensive cavitary lesions, an extended course of atovaquone was administered, guided by serial imaging, resulting in clinical and radiological improvement. Unfortunately, the patient later passed away from a severe SARS-CoV-2 infection before complete radiographic resolution was observed. This case highlights the importance of recognising atypical PJP presentations causing granulomatous disease in immunosuppressed patients. While rare, documenting such cases may improve diagnosis using less invasive methods and help determine optimal treatment durations for resolution of these atypical infections.
Aquagenic urticaria in an adolescent: differential diagnosis and management
Authors: Bajoghli Amir , Parlak Ecem , Bajoghli Mehdi
Published: August 2024

Aquagenic urticaria, a rare variant of chronic-inducible urticaria, is triggered by direct contact with water. It is distinguished by its characteristic small wheals accompanied by a halo of erythema from other forms of urticaria. It typically manifests with a delayed diagnosis due to the atypical trigger and the potential for diverse clinical presentations. We present a case of aquagenic urticaria in an adolescent male that demonstrates the need for accurate differential diagnosis and appropriate management.
Modified nasopharyngeal airway for pressure support ventilation in airway management of a case of Robin sequence with bilateral temporomandibular joint ankylosis
Authors: Kumar Abhyuday , Kumari Babli , Kumar Ajeet , Kumar Neeraj
Published: August 2024

The association of Robin sequence (RS) with temporomandibular joint (TMJ) ankylosis is not a common occurrence. Due to restricted mouth opening, difficult bag valve mask ventilation and difficult intubation, such cases are always challenging for anaesthesiologists.

A male patient in early childhood with RS and bilateral TMJ ankylosis was scheduled for bilateral gap arthroplasty. Airway management was planned with fibreoptic intubation under sedation to preserve spontaneous ventilation. After sedating the patient, a nasopharyngeal airway modified by using an endotracheal tube connector was inserted in the left nostril and connected to the ventilator circuit with a 15 mm universal connector. Pressure support ventilation was given with continuous end-tidal CO2monitoring. Fibreoptic intubation was done through the right nostril with maintenance of spontaneous ventilation.

Nasal pressure support ventilation assembly can be made with available equipment in the operation theatre. It can be a substitute for a high-flow nasal cannula in particular cases.
Bilateral simultaneous acute angle closure glaucoma triggered by an over-the-counter cold and influenza medication
Authors: Chean Chung Shen , Ali Ali Ibrahim Ali Hassan , Malick Huzaifa
Published: August 2024

A woman in her mid-60s who is a high hypermetrope presented with bilateral eye pain and headache approximately 1 hour after taking a single dose of a widely available decongestant containing paracetamol, guaifenesin and phenylephrine hydrochloride for coryzal symptoms. She had previous successful bilateral peripheral iridotomies performed for narrow angles. At presentation, her intraocular pressures (IOPs) were significantly raised at 72 mm Hg and 66 mm Hg in the right and left eye, respectively, with bilateral corneal oedema. Her IOP was normalised with urgent treatment using 500 mg intravenous acetazolamide, pilocarpine 2%, dexamethasone 0.1% and IOP-lowering drops. She was listed for cataract surgery and was advised to avoid the precipitating agent and other over-the-counter decongestants. This is the first reported case of bilateral angle closure triggered by a decongestant with such a combination of ingredients. Clinicians should be aware of this rare side effect for prompt diagnosis and management.