Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer ...(HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor erythroid-derived 2-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage.
Perception and reconstruction of our 3D physical environment is an essential task with broad applications for Augmented Reality (AR) displays. For example, reconstructed geometries are commonly ...leveraged for displaying 3D objects at accurate positions. While camera-captured images are a frequently used data source for realistically reconstructing 3D physical surroundings, they are limited to line-of-sight environments, requiring time-consuming and repetitive data-capture techniques to capture a full 3D picture. For instance, current AR devices require users to scan through a whole room to obtain its geometric sizes. This optical process is tedious and inapplicable when the space is occluded or inaccessible. Audio waves propagate through space by bouncing from different surfaces, but are not 'occluded' by a single object such as a wall, unlike light. In this research, we aim to ask the question 'can one hear the size of a room?'. To answer that, we propose an approach for inferring room geometries only from a single sound, which we define as an audio wave sequence played from a single loud speaker, leveraging deep learning for decoding implicitly-carried spatial information from a single speaker-and-microphone system. Through a series of experiments and studies, our work demonstrates our method's effectiveness at inferring a 3D environment's spatial layout. Our work introduces a robust building block in multi-modal layout reconstruction.
Background:Little is known about the effect of the coronavirus disease 2019 (COVID-19) pandemic and the outbreak response measures on door-to-balloon time (D2B). This study examined both D2B and ...clinical outcomes of patients with STEMI undergoing primary percutaneous coronary intervention (PPCI).Methods and Results:This was a retrospective study of 303 STEMI patients who presented directly or were transferred to a tertiary hospital in Singapore for PPCI from October 2019 to March 2020. We compared the clinical outcomes of patients admitted before (BOR) and during (DOR) the COVID-19 outbreak response. The study outcomes were in-hospital death, D2B, cardiogenic shock and 30-day readmission. For direct presentations, fewer patients in the DOR group achieved D2B time <90 min compared with the BOR group (71.4% vs. 80.9%, P=0.042). This was more apparent after exclusion of non-system delay cases (DOR 81.6% vs. BOR 95.9%, P=0.006). Prevalence of both out-of-hospital cardiac arrest (9.5% vs. 1.9%, P=0.003) and acute mitral regurgitation (31.6% vs. 17.5%, P=0.006) was higher in the DOR group. Mortality was similar between groups. Multivariable regression showed that longer D2B time was an independent predictor of death (odds ratio 1.005, 95% confidence interval 1.000–1.011, P=0.029).Conclusions:The COVID-19 pandemic and the outbreak response have had an adverse effect on PPCI service efficiency. The study reinforces the need to focus efforts on shortening D2B time, while maintaining infection control measures.
In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both ...are divergent from the bat-borne HNV members, Nipah (NiV) and Hendra (HeV) viruses. The spillover of LayV is the first instance of a HNV zoonosis to humans outside of NiV and HeV, highlighting the continuing threat this genus poses to human health. In this work, we determine the prefusion structures of MojV and LayV F proteins via cryogenic electron microscopy to 2.66 and 3.37 Å, respectively. We show that despite sequence divergence from NiV, the F proteins adopt an overall similar structure but are antigenically distinct as they do not react to known antibodies or sera. Glycoproteomic analysis revealed that while LayV F is less glycosylated than NiV F, it contains a glycan that shields a site of vulnerability previously identified for NiV. These findings explain the distinct antigenic profile of LayV and MojV F, despite the extent to which they are otherwise structurally similar to NiV. Our results carry implications for broad-spectrum HNV vaccines and therapeutics, and indicate an antigenic, yet not structural, divergence from prototypical HNVs.
CASE PRESENTATION An 80-year-old, Chinese male presented with multiple nontender, nonpruritic, skin-coloured subcutaneous nodules over the chest, back, left flank, left thigh and right forearm that ...developed over the course of 2 months (Figure ). CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ETHICS STATEMENT All patients in this manuscript have given written informed consent for participation in the study and the use of their de-identified, anonymized, aggregated data and their case details (including photographs) for publication.
A small PCR-generated DNA fragment was introduced into a pharmaceutical grade ink as a molecular taggant, and the DNA tagged ink was delivered onto the surface of capsules by standard high-speed ...offset printing. The amount of DNA in the ink on each capsule is roughly 10-12 fold lower than that allowed as safe by the United States Food and Drug Administration (FDA) and the WHO with regards to acceptable limits of residual DNA. The printed ink on the capsule surface was sampled by swabbing, followed by direct analysis of the DNA-swab complex, without subsequent DNA purification. It was shown that DNA recovered from the ink by swabbing was suitable for PCR-CE analysis-a widely used method in forensic science and was also suitable for qPCR and isothermal DNA amplification, when coupled with portable devices similar to those used for environmental sampling and food safety testing. The data set a precedent: A small DNA fragment could be introduced as an excipient into a pharmaceutical application, and thereafter tracked through the pharmaceutical supply chain via forensic DNA authentication.
The number of glomeruli and glomerulosclerosis evaluated on kidney biopsy slides constitute standard components of a renal pathology report. Prevailing methods for glomerular assessment remain ...manual, labor intensive, and nonstandardized. We developed a deep learning framework to accurately identify and segment glomeruli from digitized images of human kidney biopsies.
Trichrome-stained images (
= 275) from renal biopsies of 171 patients with chronic kidney disease treated at the Boston Medical Center from 2009 to 2012 were analyzed. A sliding window operation was defined to crop each original image to smaller images. Each cropped image was then evaluated by at least 3 experts into 3 categories: (i) no glomerulus, (ii) normal or partially sclerosed (NPS) glomerulus, and (iii) globally sclerosed (GS) glomerulus. This led to identification of 751 unique images representing nonglomerular regions, 611 images with NPS glomeruli, and 134 images with GS glomeruli. A convolutional neural network (CNN) was trained with cropped images as inputs and corresponding labels as output. Using this model, an image processing routine was developed to scan the test images to segment the GS glomeruli.
The CNN model was able to accurately discriminate nonglomerular images from NPS and GS images (performance on test data: Accuracy: 92.67% ± 2.02% and Kappa: 0.8681 ± 0.0392). The segmentation model that was based on the CNN multilabel classifier accurately marked the GS glomeruli on the test data (Matthews correlation coefficient = 0.628).
This work demonstrates the power of deep learning for assessing complex histologic structures from digitized human kidney biopsies.
Cancellous screw fixation is often used in fracture fixation. When this screw is over-tightened, damage to the bone and other non-linear processes such as fracture and construct failure would be ...involved. The objectives of this study were (1) to determine the reduction in pull-out strength when a cancellous screw spins and (2) to determine how much pull-out strength can be restored by revising with a larger diameter screw.
A biomechanical study using synthetic polyurethane foam (320 kg/m3) was performed to assess (1) the pull-out strength of a 6.5 mm cancellous screw, (2) the pull-out strength of a loosened 6.5 mm cancellous screw and (3) the pull-out strength of a loosened 6.5 mm cancellous screw revised with a 7.3 mm cancellous screw.
The baseline pull-out strength of the 6.5 mm cancellous screw was 2213.91 ± 200.51 N. There was a 79.1% (463.79 ± 99.95 N) reduction in pull-out strength once spinning occurs (p = 0.027). When a spinning 6.5 mm cancellous screw was revised to a 7.3 mm cancellous screw, the pull-out strength increased to 1313.65 ± 93.23 N, 59.3% of the baseline pull-out strength (2213.91 ± 200.51 N) (p = 0.027).
A loosened 6.5 mm cancellous screw results in a 79.1% reduction in pull-out strength. Revising a loosened cancellous screw by inserting a larger 7.3 mm diameter screw partially improves the pull-out strength to 59.3% of the baseline. Surgeons should consider the use of “two-finger tight” torque when inserting a screw to avoid stripping.
•Spinning a 6.5 mm cancellous screw results in 79.1% loss of pull-out strength.•Revising a spinning cancellous screw with a larger screw partially improves the pull-out strength.•Surgeons should consider the use of “two-finger tight” torque when inserting a screw to avoid stripping.
The pandemic has led to adverse short-term outcomes for patients with ST-segment elevation myocardial infarction (STEMI). It is unknown if this translates to poorer long-term outcomes. In Singapore, ...the escalation of the outbreak response on February 7, 2020 demanded adaptation of STEMI care to stringent infection control measures. A total of 321 patients presenting with STEMI and undergoing primary percutaneous coronary intervention at a tertiary hospital were enrolled and followed up over 1-year. They were allocated into three groups based on admission date—(1) Before outbreak response (BOR): December 1, 2019–February 6, 2020, (2) During outbreak response (DOR): February 7–March 31, 2020, and (3) control group: November 1–December 31, 2018. The incidence of cardiac-related mortality, cardiac-related readmissions, and recurrent coronary events were examined. Although in-hospital outcomes were worse in BOR and DOR groups compared to the control group, there were no differences in the 1-year cardiac-related mortality (BOR 8.7%, DOR 7.1%, control 4.8%, p = 0.563), cardiac-related readmissions (BOR 15.1%, DOR 11.6%, control 12.0%, p = 0.693), and recurrent coronary events (BOR 3.2%, DOR 1.8%, control 1.2%, p = 0.596). There were higher rates of additional PCI during the index admission in DOR, compared to BOR and control groups (p = 0.027). While patients admitted for STEMI during the pandemic may have poorer in-hospital outcomes, their long-term outcomes remain comparable to the pre-pandemic era.
Cancers and neurological disorders are two major types of diseases in humans. We developed the concept called the "Aberrant Cell Cycle Disease (ACCD)" due to the accumulating evidence that shows that ...two different diseases share the common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncoprotein activation and tumor suppressor (TS) inactivation, which are associated with both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase/oncogene inhibition and TS elevation) can be leveraged for neurological treatments. MicroRNA (miR/miRNA) provides a new style of drug-target binding. For example, a single tumor suppressor miRNA (TS-miR/miRNA) can bind to and decrease tens of target kinases/oncogenes, producing much more robust efficacy to block cell cycle re-entry than inhibiting a single kinase/oncogene. In this review, we summarize the miRNAs that are altered in both cancers and neurological disorders, with an emphasis on miRNA drugs that have entered into clinical trials for neurological treatment.
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