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Background. The anterior cruciate ligament (ACL) is a structure that is vital to preserving the knee's normal stability. However, because the ACL is the ligament that sustains injuries the most frequently, it is essential to distinguish between complete and incomplete tears in order to treat patients with incomplete tears without surgery. To diagnose cruciate ligament tears, knee joint magnetic resonance imaging (MRI) is frequently used. But sometimes it's difficult because edema may hide the ligament fibers. ADC mapping may be useful to confirm whether or not the ligament is continuous for an appropriate diagnosis of incomplete tears because it has been demonstrated that ligament fibers are better visible on diffusion weighted imaging (DWI) and ADC mapping. Objective. To ascertain how anterior cruciate ligament (ACL) tears are diagnosed and classified as partial or complete using diffusion-weighted (DW) magnetic resonance imaging (MRI) and to compare it with conventional MRI sequences. Results. For partial tears, 10 cases (50%) were identified using arthroscopy/follow-up, while observer 1 identified 12 cases (60%) and observer 2 identified 9 cases (45%) using DWI/ADC. For complete tears, 10 cases (50%) were identified using arthroscopy/follow-up, while observer 1 identified 8 cases (40%) and observer 2 identified 11 cases (55%) using DWI/ADC. Conclusions. DWI and ADC are useful tools for diagnosing tears, particularly complete tears, but that caution should be exercised when using these techniques to diagnose partial tears.

Background: Biliary neoplasms are commonly encountered in the day-to-day radiological practice and can be benign or malignant. Multidetector CT (MDCT) is a noninvasive imaging modality for evaluation of patients with biliary obstruction, to localize the cause of obstruction, detect the presence of mass lesion, and define its extension and identify remote metastasis. Objective: To find out the role of MDCT scan in the evaluation of biliary neoplasms with respect to nature, cause and level of obstruction. Methods: During the period from January 2022 to August 2022, the present study included 30 patients with clinically suspected biliary obstruction and previously radiological or laboratory diagnosed cases of biliary malignancy after fulfilling the inclusion and exclusion criteria and taking written /verbal informed consent. 16 patients were males and 14 were females, their ages ranged between 36- 85 years with mean age of 64 years old. Results: The mean age of participants was 63.73±11.11 years old; and slight male predominance (53.3%). in correlation to histopathological findings, MDCT was 95.2% sensitive in detection of cholangiocarcinoma (20/21*100). It was 100% sensitive in detection of combined cholangiocarcinoma & HCC (1/1*100). Also it was 85.75 sensitive in detection of gall bladder carcinoma (6/7*100). While it was false positive in detection a case of HCC. The sensitivity of MDCT to detect biliary neoplasm is 96.4% (27/28*100) with specificity of 0% (0/2*100), the positive predictive value is 93.1% (27/29*100) while the negative predictive value is 0% (0/1%). We found significant association between MDCT Final outcome with resectability (P-value 0.002) and between resectability and TNM Staging (P-value <0.0001) Conclusion: Multidetector computed tomography MDCT can be considered a noninvasive fast with high sensitivity imaging tool in the assessment of patients with biliary neoplasms. The MDCT is satisfactory for staging of biliary neoplasms and for accurate preoperative assessment of the tumor extent. [ABSTRACT FROM AUTHOR]

To increase the utilization of Low-Speed Electric Vehicles (LS-EVs), rapid recharging of the EV’s battery pack turn out to be essential. This permits reduced charging times, greater vehicle utility, and broader adoption of LS-EVs. This paper presents a modular Input-Series Output-Parallel (ISOP) DC-DC converter for LS-EVs fast chargers. A generalized small-signal analysis applicable for any multimodule connection (Input-Series Input-Parallel Output-Series Output-Parallel (ISIP-OSOP) is introduced. The employed topology is a multimodule DC-DC converter based on Dual Active Bridge (DAB). Nonetheless, a single bridge is utilized at the primary side, and the modularity concept is applied to the high-frequency transformer and the second bridge where the connection of the modules is ISOP. In the presented system, 3-modules are employed where each module is rated at 1.5kWto achieve the desired power rating, which is 4.5kW. The charging process is achieved from a single-phase outlet. However, due to the high output current, a modular approach is required to avoid high losses. Uniform power-sharing is achieved through a direct output current sharing control, ensuring stability without the need for input voltage sharing loops, unlike the conventional ISOP converters. This is due to the fact that the proposed configuration uses only a single capacitor at the input side, avoiding the inherent instability problem caused by the output current sharing control. The controller is examined using a 3-module ISOP DC-DC converter, where the controlled current is following the reflex charging algorithm. Simulation results using the Matlab/Simulink platform are provided to elucidate the presented concept considering parameter mismatches, where the input voltage and the output current are equally shared among the three modules.

With the expansion of E-mobility technology, the demand for Medium-Voltage (MV) Electric Buses (E-buses) charging infrastructure has significantly increased. In this regard, the effective connection of E-bus chargers to a medium voltage power grid is essential to provide fast charging and carry out multiple charging processes simultaneously. One of the main building blocks for E-bus charging is the DC-DC converter stage responsible for regulating the power flow and matching the different voltage and power levels. Accordingly, this paper presents a comprehensive review of DC-DC converter topologies applicable to MV E-bus fast charging. This review discusses and compares the basic isolated DC-DC converter topologies. In addition, the DC-DC converters are classified based on their conversion stages. Moreover, isolated DC-DC converter topologies applicable for MV E-bus fast charging applications, including Dual Active Bridge (DAB) modular-based structure converter and Modular Multilevel Converter (MMC)-based DAB, are discussed where the merits and demerits of each topology are highlighted. Moreover, this review illustrates how DAB converters are employed in different power level applications through the multimodule converter or the MMC-based DAB structure. Furthermore, the challenges and required features for MV DC-DC converter topologies are discussed.

To increase the adoption of electric vehicles (EVs), significant efforts in terms of reducing the charging time are required. Consequently, ultrafast charging (UFC) stations require extensive investigation, particularly considering their higher power level requirements. Accordingly, this paper introduces a hybrid multimodule DC-DC converter-based dual-active bridge (DAB) topology for EV-UFC to achieve high-efficiency and high-power density. The hybrid concept is achieved through employing two different groups of multimodule converters. The first is designed to be in charge of a high fraction of the total required power, operating at a relatively low switching frequency, while the second is designed for a small fraction of the total power, operating at a relatively high switching frequency. To support the power converter controller design, a generalized small-signal model for the hybrid converter is studied. Also, cross feedback output current sharing (CFOCS) control for the hybrid input-series output-parallel (ISOP) converters is examined to ensure uniform power-sharing and ensure the desired fraction of power handled by each multimodule group. The control scheme for a hybrid eight-module ISOP converter of 200 kW is investigated using a reflex charging scheme. The power loss analysis of the hybrid converter is provided and compared to conventional multimodule DC-DC converters. It has been shown that the presented converter can achieve both high efficiency (99.6%) and high power density (10.3 kW/L), compromising between the two other conventional converters. Simulation results are provided using the MatLab/Simulink software to elucidate the presented concept considering parameter mismatches.

Electric Vehicles (EVs) play a significant role in the reduction of CO2 emissions and other health-threatening air pollutants Accordingly, several research studies are introduced owing to replacing conventional gasoline-powered vehicles with battery-powered EVs. However, the ultra-fast charging (UFC) of the battery pack or the rapid recharging of the battery requires specific demands, including both: the EV battery and the influence on the power grid. In this regard, advanced power electronics technologies are emerging significantly to replace the currently existing gas station infrastructures with the EV charging stations to move from conventional charging (range of hours) to UFC (range of minutes). Among these power electronics conversion systems, the DC-DC conversion stage plays an essential role in supplying energy to the EV via charging the EV’s battery. Accordingly, this paper aims to present possible architectures of connecting multiple Dual Active Bridge (DAB) units as the DC-DC stage of the EV fast charger and study their Small-Signal Modeling (SSM) and their control scheme. These are, namely, Input-Series Output-Series (ISOS), Input-Series Output-Parallel (ISOP), Input-Parallel Output-Parallel (IPOP), and Input-Parallel Output-Series (IPOS). The control scheme for each system is studied through controlling the output filter inductor current such that the current profile is based on Reflex Charging (RC). The main contribution of this paper can be highlighted in providing generalized SSM as well as providing a generalized control approach for the Input-Series Input-Parallel Output-Series Output-Parallel (ISIP-OSOP) connection. The generalized model is verified with three different architectures. The control strategy for each architecture is studied to ensure equal power sharing, where simulation results are provided to elucidate the presented concept considering a three-module ISOS, IPOP, ISOP, and IPOS DC-DC converters.

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions., (© 2024. The Author(s).)

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, in 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of two individuals with BCAs and additionally highlight six individuals with likely developmental etiologies due to lncRNA disruptions.

Specificity within the ubiquitin-proteasome system is primarily achieved through E3 ubiquitin ligases, but for many E3s their substrates-and in particular the molecular features (degrons) that they recognize-remain largely unknown. Current approaches for assigning E3s to their cognate substrates are tedious and low throughput. Here we developed a multiplex CRISPR screening platform to assign E3 ligases to their cognate substrates at scale. A proof-of-principle multiplex screen successfully performed ~100 CRISPR screens in a single experiment, refining known C-degron pathways and identifying an additional pathway through which Cul2 FEM1B targets C-terminal proline. Further, by identifying substrates for Cul1 FBXO38 , Cul2 APPBP2 , Cul3 GAN , Cul3 KLHL8 , Cul3 KLHL9/13 and Cul3 KLHL15 , we demonstrate that the approach is compatible with pools of full-length protein substrates of varying stabilities and, when combined with site-saturation mutagenesis, can assign E3 ligases to their cognate degron motifs. Thus, multiplex CRISPR screening will accelerate our understanding of how specificity is achieved within the ubiquitin-proteasome system., (© 2023. The Author(s).)

Despite the vast diversity of the antibody repertoire, infected individuals often mount antibody responses to precisely the same epitopes within antigens. The immunological mechanisms underpinning this phenomenon remain unknown. By mapping 376 immunodominant "public epitopes" at high resolution and characterizing several of their cognate antibodies, we concluded that germline-encoded sequences in antibodies drive recurrent recognition. Systematic analysis of antibody-antigen structures uncovered 18 human and 21 partially overlapping mouse germline-encoded amino acid-binding (GRAB) motifs within heavy and light V gene segments that in case studies proved critical for public epitope recognition. GRAB motifs represent a fundamental component of the immune system's architecture that promotes recognition of pathogens and leads to species-specific public antibody responses that can exert selective pressure on pathogens.

Although oxidative phosphorylation is best known for producing ATP, it also yields reactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2 FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2 FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family, which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation. FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis., Competing Interests: Declaration of interests M.R. and J.K. are co-founders and members of the SAB of Nurix Tx. M.R. is on the SAB of Monte Rosa Tx and an iPartner at The Column Group. J.K. is on the SAB of Revolution Medicine and Carmot Tx., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In order to understand the transmission and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the functions of each of the gene products encoded in the viral genome. One feature of the SARS-CoV-2 genome that is not present in related, common coronaviruses is ORF10, a putative 38-amino acid protein-coding gene. Proteomic studies found that ORF10 binds to an E3 ubiquitin ligase containing Cullin-2, Rbx1, Elongin B, Elongin C, and ZYG11B (CRL2 ZYG11B ). Since CRL2 ZYG11B mediates protein degradation, one possible role for ORF10 is to "hijack" CRL2 ZYG11B in order to target cellular, antiviral proteins for ubiquitylation and subsequent proteasomal degradation. Here, we investigated whether ORF10 hijacks CRL2 ZYG11B or functions in other ways, for example, as an inhibitor or substrate of CRL2 ZYG11B While we confirm the ORF10-ZYG11B interaction and show that the N terminus of ORF10 is critical for it, we find no evidence that ORF10 is functioning to inhibit or hijack CRL2 ZYG11B Furthermore, ZYG11B and its paralog ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. We conclude that the interaction between ORF10 and CRL2 ZYG11B is not relevant for SARS-CoV-2 infection in vitro., Competing Interests: Competing interest statement: S.J.E. is a cofounder of TSCAN Therapeutics, MAZE Therapeutics, ImmuneID, and Mirimus. S.J.E. is an advisor for MPM Capital and serves on the scientific advisory boards of Homology Medicines, Inc. and TSCAN Therapeutics. M.P. is a cofounder of Coho Therapeutics and serves on the scientific advisory board of Coho Therapeutics, CullGen Inc., Kymera Therapeutics, Santi Therapeutics, and SEED Therapeutics. A reviewer (E.O.) and the authors E.L.M., C.O., and S.J.E. share an affiliation at Harvard Medical School. Their primary appointments are at different institutions and they have no shared collaborative work., (Copyright © 2021 the Author(s). Published by PNAS.)

The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancer and underscores the potential therapeutic utility of targeting the UPS., Competing Interests: Declaration of interests S.J.E. is a member of the Molecular Cell advisory board. X.S.L. is a cofounder, board member, SAB, and consultant of GV20 Oncotherapy and its subsidiaries and the SAB of 3DMedCare; a consultant for Genentech; a stockholder of BMY, TMO, WBA, ABT, ABBV, and JNJ; and receives research funding from Takeda and Sanofi. M.B. is a consultant to and receives sponsored research support from Novartis. M.B. serves on the SAB of H3 Biomedicine, Kronos Bio, and GV20 Oncotherapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration 1 . Dimerization quality control further improves proteostasis by eliminating complexes of aberrant composition 2 , but how it detects incorrect subunits remains unknown. Here we provide structural insight into target selection by SCF-FBXL17, a dimerization-quality-control E3 ligase that ubiquitylates and helps to degrade inactive heterodimers of BTB proteins while sparing functional homodimers. We find that SCF-FBXL17 disrupts aberrant BTB dimers that fail to stabilize an intermolecular β-sheet around a highly divergent β-strand of the BTB domain. Complex dissociation allows SCF-FBXL17 to wrap around a single BTB domain, resulting in robust ubiquitylation. SCF-FBXL17 therefore probes both shape and complementarity of BTB domains, a mechanism that is well suited to establish quality control of complex composition for recurrent interaction modules.

Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCF FBXL17 , which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCF FBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We describe the design and implementation of the instrumentation required to perform DNP-NMR at higher field strengths than previously demonstrated, and report the first magic-angle spinning (MAS) DNP-NMR experiments performed at (1)H/e(-) frequencies of 700 MHz/460 GHz. The extension of DNP-NMR to 16.4 T has required the development of probe technology, cryogenics, gyrotrons, and microwave transmission lines. The probe contains a 460 GHz microwave channel, with corrugated waveguide, tapers, and miter-bends that couple microwave power to the sample. Experimental efficiency is increased by a cryogenic exchange system for 3.2 mm rotors within the 89 mm bore. Sample temperatures ≤85 K, resulting in improved DNP enhancements, are achieved by a novel heat exchanger design, stainless steel and brass vacuum jacketed transfer lines, and a bronze probe dewar. In addition, the heat exchanger is preceded with a nitrogen drying and generation system in series with a pre-cooling refrigerator. This reduces liquid nitrogen usage from >700 l per day to <200 l per day and allows for continuous (>7 days) cryogenic spinning without detrimental frost or ice formation. Initial enhancements, ε=-40, and a strong microwave power dependence suggests the possibility for considerable improvement. Finally, two-dimensional spectra of a model system demonstrate that the higher field provides excellent resolution, even in a glassy, cryoprotecting matrix., (Copyright © 2012 Elsevier Inc. All rights reserved.)