Uncoupling transcription and translation through miRNA-dependent poly(A) length control in haploid male germ cells.

As one of the post-transcriptional regulatory mechanisms, uncoupling of transcription and translation plays an essential role in development and adulthood physiology. However, it remains elusive how thousands of mRNAs get translationally silenced while stability is maintained for hours or even days before translation. In addition to oocytes and neurons, developing spermatids display significant uncoupling of transcription and translation for delayed translation. Therefore, spermiogenesis represents an excellent in vivo model for investigating the mechanism underlying uncoupled transcription and translation. Through full-length poly(A) deep sequencing, we discovered dynamic changes in poly(A) length through deadenylation and re-polyadenylation. Deadenylation appeared to be mediated by microRNAs (miRNAs), and transcripts with shorter poly(A) tails tend to be sequestered into ribonucleoprotein (RNP) granules for translational repression and stabilization. In contrast, re-polyadenylation might allow for translocation of the translationally repressed transcripts from RNP granules to polysomes. Overall, our data suggest that miRNA-dependent poly(A) length control represents a previously unreported mechanism underlying uncoupled translation and transcription in haploid male mouse germ cells.

DNA Mechanics: From Single Stranded to Self-Assembled.

DNA encodes genetic information and forms various structural conformations with distinct physical, chemical, and biological properties. Over the past 30 years, advancements in force manipulation technology have enabled the precise manipulation of DNA at nanometer and piconewton resolutions. This mini-review discusses these force manipulation techniques for exploring the mechanical properties of DNA at the single-molecule level. We summarize the distinct mechanical features of different DNA forms while considering the impact of the force geometry. We highlight the role of DNA mechanics in origami structures that serve as self-assembled building blocks or mechanically responsive/active nanomachines. Accordingly, we emphasize how DNA mechanics are integral to the functionality of origami structures for achieving mechanical capabilities. Finally, we provide an outlook on the intrinsic mechanical properties of DNA, from single stranded to self-assembled higher-dimensional structures. This understanding is expected to inspire new design strategies in DNA mechanics, paving the way for innovative applications and technologies.

Advancing cerebral small vessel disease diagnosis: Integrating quantitative susceptibility mapping with MRI-based radiomics.

Cerebral small vessel disease (CSVD) is a neurodegenerative disease with hidden symptoms and difficult to diagnose. The diagnosis mainly depends on clinical symptoms and neuroimaging. Therefore, we explored the potential of combining clinical detection with MRI-based radiomics features for the diagnosis of CSVD in a large cohort. A total of 118 CSVD patients and 127 healthy controls underwent quantitative susceptibility mapping and 3D-T1 scans, and all completed multiple cognitive tests. Lasso regression was used to select features, and the radiomics model was constructed based on the regression coefficients of these features. Clinical cognitive and motor tests were added to the model to construct a hybrid model. All models were cross-validated to analyze the generalization ability of the models. The AUCs of the radiomics and hybrid models in the internal test set were 0.80 and 0.87, respectively. In the validation set, the AUCs were 0.77 and 0.79, respectively. The hybrid model demonstrated higher decision efficiency. The Trail Making Test, which enhances the diagnostic performance of the model, is associated with multiple brain regions, particularly the right cortical nuclei and the right fimbria. The hybrid model based on radiomics features and cognitive tests can achieve quantitative diagnosis of CSVD and improve the diagnostic efficiency. Furthermore, the reduced processing capacity due to atrophy of the right cortical nucleus and right fimbria suggests the importance of these regions in improving the diagnostic accuracy of the model.

Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol.

Chimeric antigen receptor (CAR)-engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)-responsive transactivator and a transrepressor to develop a repressible transgene expression (RESrep) device and an inducible transgene expression (RESind) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RESrep-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RESind-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RESind-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RESrep and RESind devices as effective tools for transgene expression and illustrates the potential of RESrep-CAR and RESind-CAR devices to enhance patient safety in precision cancer immunotherapies.

Design and synthesis of iso-allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase.

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 µM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.

Design of OMC-Sagnac Loop Using PDMS and Different Package Structures to Improve Sensing Performance and Optimize the Ill-Conditioned Matrix.

In the process of ocean exploration, highly accurate and sensitive measurements of seawater temperature and pressure significantly impact the study of seawater's physical, chemical, and biological processes. In this paper, three different package structures, V-shape, square-shape, and semicircle-shape, are designed and fabricated, and an optical microfiber coupler combined Sagnac loop (OMCSL) is encapsulated in these structures with polydimethylsiloxane (PDMS). Then, the temperature and pressure response characteristics of the OMCSL, under different package structures, are analyzed by simulation and experiment. The experimental results show that structural change hardly affects temperature sensitivity, and square-shape has the highest pressure sensitivity. In addition, with an input error of 1% F.S., temperature and pressure errors were calculated, which shows that a semicircle-shape structure can increase the angle between lines in the sensitivity matrix method (SMM), and reduce the effect of the input error, thus optimizing the ill-conditioned matrix. Finally, this paper shows that using the machine learning method (MLM) effectively improves demodulation accuracy. In conclusion, this paper proposes to optimize the ill-conditioned matrix problem in SMM demodulation by improving sensitivity with structural optimization, which essentially explains the cause of the large errors for multiparameter cross-sensitivity. In addition, this paper proposes to use the MLM to solve the problem of large errors in the SMM, which provides a new method to solve the problem of the ill-conditioned matrix in SMM demodulation. These have practical implications for engineering an all-optical sensor that can be used for detection in the ocean environment.

gcaPDA: a haplotype-resolved diploid assembler.

BACKGROUND: Generating chromosome-scale haplotype resolved assembly is important for functional studies. However, current de novo assemblers are either haploid assemblers that discard allelic information, or diploid assemblers that can only tackle genomes of low complexity. RESULTS: Here, Using robust programs, we build a diploid genome assembly pipeline called gcaPDA (gamete cells assisted Phased Diploid Assembler), which exploits haploid gamete cells to assist in resolving haplotypes. We demonstrate the effectiveness of gcaPDA based on simulated HiFi reads of maize genome which is highly heterozygous and repetitive, and real data from rice. CONCLUSIONS: With applicability of coping with complex genomes and fewer restrictions on application than most of diploid assemblers, gcaPDA is likely to find broad applications in studies of eukaryotic genomes.

Oxygen extraction fraction (OEF) assesses cerebral oxygen metabolism of deep gray matter in patients with pre-eclampsia.

OBJECTIVES: The objective of this study was to compare oxygen extraction fraction (OEF) values in the deep gray matter (GM) of pre-eclampsia (PE) patients, pregnant healthy controls (PHCs), and non-pregnant healthy controls (NPHCs) to explore their brain oxygen metabolism differences in GM. METHODS: Forty-seven PE patients, forty NPHCs, and twenty-one PHCs were included. Brain OEF values were computed from quantitative susceptibility mapping (QSM) plus quantitative blood oxygen level-dependent magnitude (QSM + qBOLD = QQ)-based mapping. One-way ANOVA was used to compare mean OEF values in the three groups. The area under the curve of the mean OEF value in each region of interest was estimated using a receiver operating characteristic curve analysis. RESULTS: We found that the mean OEF values in the thalamus, putamen, caudate nucleus, pallidum, and substantia nigra were significantly different in these three groups (F = 5.867, p = 0.004; F = 5.142, p = 0007; F = 6.158, p = 0.003; F = 6.319, p = 0.003; F = 5.491, p = 0.005). The mean OEF values for these 5 regions were higher in PE patients than in NPHCs and in PHCs (p < 0.05). The AUC of these ROIs ranged from 0.673 to 0.692 (p < 0.01) and cutoff values varied from 35.1 to 36.6%, indicating that the OEF values could discriminate patients with and without PE. Stepwise multivariate analysis revealed that the OEF values correlated with hematocrit in pregnant women (r = 0.353, p = 0.003). CONCLUSION: OEF values in the brains of pregnant women can be measured in clinical practice using QQ-based OEF mapping for noninvasive assessment of hypertensive disorders. KEY POINTS: • Pre-eclampsia is a hypertensive disorder associated with abnormalities in brain oxygen extraction. • Oxygen extraction fraction (OEF) is an indicator of brain tissue viability and function. QQ-based mapping of OEF is a new MRI technique that can noninvasively quantify brain oxygen metabolism. • OEF values in the brains of pregnant women can be measured for noninvasive assessment of hypertensive disorders in clinical practice.

Improvement of Rice Agronomic Traits by Editing Type-B Response Regulators.

Type-B response regulator proteins in rice contain a conserved receiver domain, followed by a GARP DNA binding domain and a longer C-terminus. Some type-B response regulators such as RR21, RR22 and RR23 are involved in the development of rice leaf, root, flower and trichome. In this study, to evaluate the application potential of type-B response regulators in rice genetic improvement, thirteen type-B response regulator genes in rice were respectively knocked out by using CRISPR/Cas9 genome editing technology. Two guide RNAs (gRNAs) were simultaneously expressed on a knockout vector to mutate one gene. T0 transformed plants were used to screen the plants with deletion of large DNA fragments through PCR with specific primers. The mutants of CRISPR/Cas9 gene editing were detected by Cas9 specific primer in the T1 generation, and homozygous mutants without Cas9 were screened, whose target regions were confirmed by sequencing. Mutant materials of 12 OsRRs were obtained, except for RR24. Preliminary phenotypic observation revealed variations of various important traits in different mutant materials, including plant height, tiller number, tillering angle, heading date, panicle length and yield. The osrr30 mutant in the T2 generation was then further examined. As a result, the heading date of the osrr30 mutant was delayed by about 18 d, while the yield was increased by about 30%, and the chalkiness was significantly reduced compared with those of the wild-type under field high temperature stress. These results indicated that osrr30 has great application value in rice breeding. Our findings suggest that it is feasible to perform genetic improvement of rice by editing the type-B response regulators.

Artificial intelligence for prediction of donor liver allograft steatosis and early post-transplantation graft failure.

BACKGROUND: Donor livers undergo subjective pathologist review of steatosis before transplantation to mitigate the risk for early allograft dysfunction (EAD). We developed an objective, computer vision artificial intelligence (CVAI) platform to score donor liver steatosis and compared its capability for predicting EAD against pathologist steatosis scores. METHODS: Two pathologists scored digitized donor liver biopsy slides from 2014 to 2019. We trained four CVAI platforms with 1:99 training:prediction split. Mean intersection-over-union (IU) characterized CVAI model accuracy. We defined EAD using liver function tests within 1 week of transplantation. We calculated separate EAD logistic regression models with CVAI and pathologist steatosis and compared the models' discrimination and internal calibration. RESULTS: From 90 liver biopsies, 25,494 images trained CVAI models yielding peak mean IU = 0.80. CVAI steatosis scores were lower than pathologist scores (median 3% vs 20%, P < 0.001). Among 41 transplanted grafts, 46% developed EAD. The median CVAI steatosis score was higher for those with EAD (2.9% vs 1.9%, P = 0.02). CVAI steatosis was independently associated with EAD after adjusting for donor age, donor diabetes, and MELD score (aOR = 1.34, 95%CI = 1.03-1.75, P = 0.03). CONCLUSION: The CVAI steatosis EAD model demonstrated slightly better calibration than pathologist steatosis, meriting further investigation into which modality most accurately and reliably predicts post-transplantation outcomes.