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1.
Nature ; 623(7987): 562-570, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37880372

ABSTRACT

Vision enables both image-forming perception, driven by a contrast-based pathway, and unconscious non-image-forming circadian photoentrainment, driven by an irradiance-based pathway1,2. Although two distinct photoreceptor populations are specialized for each visual task3-6, image-forming photoreceptors can additionally contribute to photoentrainment of the circadian clock in different species7-15. However, it is unknown how the image-forming photoreceptor pathway can functionally implement the segregation of irradiance signals required for circadian photoentrainment from contrast signals required for image perception. Here we report that the Drosophila R8 photoreceptor separates image-forming and irradiance signals by co-transmitting two neurotransmitters, histamine and acetylcholine. This segregation is further established postsynaptically by histamine-receptor-expressing unicolumnar retinotopic neurons and acetylcholine-receptor-expressing multicolumnar integration neurons. The acetylcholine transmission from R8 photoreceptors is sustained by an autocrine negative feedback of the cotransmitted histamine during the light phase of light-dark cycles. At the behavioural level, elimination of histamine and acetylcholine transmission impairs R8-driven motion detection and circadian photoentrainment, respectively. Thus, a single type of photoreceptor can achieve the dichotomy of visual perception and circadian photoentrainment as early as the first visual synapses, revealing a simple yet robust mechanism to segregate and translate distinct sensory features into different animal behaviours.


Subject(s)
Circadian Rhythm , Drosophila melanogaster , Photoreceptor Cells, Invertebrate , Visual Perception , Animals , Acetylcholine/metabolism , Biological Clocks/physiology , Biological Clocks/radiation effects , Circadian Rhythm/physiology , Circadian Rhythm/radiation effects , Drosophila melanogaster/cytology , Drosophila melanogaster/physiology , Drosophila melanogaster/radiation effects , Feedback, Physiological , Histamine/metabolism , Neurotransmitter Agents/metabolism , Photoreceptor Cells, Invertebrate/metabolism , Photoreceptor Cells, Invertebrate/radiation effects , Receptors, Cholinergic/metabolism , Receptors, Histamine/metabolism , Visual Perception/physiology , Visual Perception/radiation effects
2.
Proc Natl Acad Sci U S A ; 121(25): e2320066121, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38861605

ABSTRACT

How are the merits of innovative ideas communicated in science? Here, we conduct semantic analyses of grant application success with a focus on scientific promotional language, which may help to convey an innovative idea's originality and significance. Our analysis attempts to surmount the limitations of prior grant studies by examining the full text of tens of thousands of both funded and unfunded grants from three leading public and private funding agencies: the NIH, the NSF, and the Novo Nordisk Foundation, one of the world's largest private science funding foundations. We find a robust association between promotional language and the support and adoption of innovative ideas by funders and other scientists. First, a grant proposal's percentage of promotional language is associated with up to a doubling of the grant's probability of being funded. Second, a grant's promotional language reflects its intrinsic innovativeness. Third, the percentage of promotional language is predictive of the expected citation and productivity impact of publications that are supported by funded grants. Finally, a computer-assisted experiment that manipulates the promotional language in our data demonstrates how promotional language can communicate the merit of ideas through cognitive activation. With the incidence of promotional language in science steeply rising, and the pivotal role of grants in converting promising and aspirational ideas into solutions, our analysis provides empirical evidence that promotional language is associated with effectively communicating the merits of innovative scientific ideas.


Subject(s)
Language , Humans , Science , Financing, Organized , United States , Research Support as Topic , Creativity
3.
Proc Natl Acad Sci U S A ; 119(31): e2200223119, 2022 Aug 02.
Article in English | MEDLINE | ID: mdl-35901205

ABSTRACT

Phase-change materials (PCMs), as important energy storage materials (ESMs), have been widely used in heat dissipation for electronics. However, PCMs are encountering huge challenges since the extremely limited space in microelectronics largely suppresses the applied volume of PCMs, which demands excellent PCMs that can fully utilize the valuable latent heat. This work successfully found a universal strategy toward powerful ESMs from fluidic ternary metals (TMs, GaInSn as a representative TM in this work). TMs exhibit high thermal conductivity (20.3 W m-1 K-1) and significantly effective latent heat (115 J/cm3) and, more important, show continuous phase transition and full utilization of the valuable latent heat. Interestingly, theoretical prediction through ternary phase diagram is carried out to easily tune the melting range, latent heat, and fluidity (viscosity) of TMs to adapt with different service conditions. As a result, thermally conductive silicone grease can be conveniently fabricated via simple shear mixing of TM and polymers. Such thermally conductive TM grease inherits the merits of TM, exhibiting continuous thermal control over daily electronics according to thermal shock performance.

4.
Proc Natl Acad Sci U S A ; 119(25): e2119086119, 2022 Jun 21.
Article in English | MEDLINE | ID: mdl-35700358

ABSTRACT

Retracted papers often circulate widely on social media, digital news, and other websites before their official retraction. The spread of potentially inaccurate or misleading results from retracted papers can harm the scientific community and the public. Here, we quantify the amount and type of attention 3,851 retracted papers received over time in different online platforms. Comparing with a set of nonretracted control papers from the same journals with similar publication year, number of coauthors, and author impact, we show that retracted papers receive more attention after publication not only on social media but also, on heavily curated platforms, such as news outlets and knowledge repositories, amplifying the negative impact on the public. At the same time, we find that posts on Twitter tend to express more criticism about retracted than about control papers, suggesting that criticism-expressing tweets could contain factual information about problematic papers. Most importantly, around the time they are retracted, papers generate discussions that are primarily about the retraction incident rather than about research findings, showing that by this point, papers have exhausted attention to their results and highlighting the limited effect of retractions. Our findings reveal the extent to which retracted papers are discussed on different online platforms and identify at scale audience criticism toward them. In this context, we show that retraction is not an effective tool to reduce online attention to problematic papers.

5.
Proc Natl Acad Sci U S A ; 119(47): e2118046119, 2022 11 22.
Article in English | MEDLINE | ID: mdl-36395142

ABSTRACT

There are long-standing concerns that peer review, which is foundational to scientific institutions like journals and funding agencies, favors conservative ideas over novel ones. We investigate the association between novelty and the acceptance of manuscripts submitted to a large sample of scientific journals. The data cover 20,538 manuscripts submitted between 2013 and 2018 to the journals Cell and Cell Reports and 6,785 manuscripts submitted in 2018 to 47 journals published by the Institute of Physics Publishing. Following previous work that found that a balance of novel and conventional ideas predicts citation impact, we measure the novelty and conventionality of manuscripts by the atypicality of combinations of journals in their reference lists, taking the 90th percentile most atypical combination as "novelty" and the 50th percentile as "conventionality." We find that higher novelty is consistently associated with higher acceptance; submissions in the top novelty quintile are 6.5 percentage points more likely than bottom quintile ones to get accepted. Higher conventionality is also associated with acceptance (+16.3% top-bottom quintile difference). Disagreement among peer reviewers was not systematically related to submission novelty or conventionality, and editors select strongly for novelty even conditional on reviewers' recommendations (+7.0% top-bottom quintile difference). Manuscripts exhibiting higher novelty were more highly cited. Overall, the findings suggest that journal peer review favors novel research that is well situated in the existing literature, incentivizing exploration in science and challenging the view that peer review is inherently antinovelty.


Subject(s)
Peer Review, Research , Periodicals as Topic
6.
Stroke ; 55(11): 2652-2660, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39466896

ABSTRACT

BACKGROUND: Phenylacetylglutamine is implicated in platelet clotting and thrombosis, but its prognostic value in ischemic stroke remains unclear. We aimed to explore the associations of plasma phenylacetylglutamine levels with adverse outcomes after ischemic stroke in a multicenter prognostic cohort study. METHODS: Our multicenter prognostic cohort study included 3564 Chinese patients with ischemic stroke from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score, 3-6) at 3 months after ischemic stroke. RESULTS: During 3 months of follow-up, 877 participants experienced the primary outcome. After multivariate adjustment, each 500 ng/mL increase of phenylacetylglutamine was associated with a 7% (P=0.012), 6% (P=0.016), and 6% (P=0.028) increased risk of the primary outcome, major disability, and death, respectively. The odds ratios or hazard ratios in the highest versus the lowest quartile of plasma phenylacetylglutamine were 1.62 ([95% CI, 1.18-2.23]; Ptrend=0.001) for the primary outcome, 1.62 ([95% CI, 1.16-2.24]; Ptrend=0.001) for major disability, and 2.59 ([95% CI, 1.19-5.60]; Ptrend=0.025) for death, respectively. There was a significantly worse shift in the distribution of modified Rankin Scale score at 3 months with higher phenylacetylglutamine quartiles (Ptrend=0.003). Multiple-adjusted spline regression model showed a linear relationship between phenylacetylglutamine and primary outcome (P value for linearity<0.001). The addition of plasma phenylacetylglutamine to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement, 19.34%; P<0.001; integrated discrimination improvement, 0.23%; P=0.019). CONCLUSIONS: Elevated plasma phenylacetylglutamine levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that phenylacetylglutamine may be a promising prognostic biomarker for ischemic stroke. Further studies are needed to investigate whether phenylacetylglutamine is a stroke-specific biomarker.


Subject(s)
Glutamine , Ischemic Stroke , Humans , Female , Male , Middle Aged , Aged , Glutamine/analogs & derivatives , Glutamine/blood , Ischemic Stroke/blood , Prognosis , Prospective Studies , China , Biomarkers/blood , Cohort Studies , Follow-Up Studies , Brain Ischemia/blood
7.
J Am Chem Soc ; 2024 Nov 01.
Article in English | MEDLINE | ID: mdl-39485365

ABSTRACT

The bottleneck of Li metal batteries toward practical applications lies at inferior cyclability as well as Li dendrite issues. As a promising solution, an interface engineering strategy is proposed herein for the Li anode through constructing a hybrid artificial interface. It is assembled onto the Li anode using photocontrolled free radical polymerization (photo-CRP) of polyethylene glycol diacrylate-hexafluorobutyl methacrylate and hexafluorobutyl methacrylate-trifluoroethyl carbonate (PEGDA-HFMBA@HFMBA-FEMC or PH@HF layer). Among such hybrid interfaces, the interior layer of PEGDA-HFMBA exists as a protective shield with flexibility and fracture resistance, while the exterior layer of HFMBA-FEMC plays a role as a LiF reservoir to promote Li mass transfer and its even electrodeposition. In the meantime, some excess HFMBA and FEMC monomers further dissolve into the electrolyte as molecular additives, followed by in situ generation of a thin and robust LiF-rich cathode electrolyte interface (CEI). With the resulting Li anode, Li/NCM811 full cells showcase multifold cyclability amplification in comparison to cells using Bare-Li, covering durable cyclability with a capacity retention of 81.8% after 400 cycles. When the cutoff voltage is elevated to 4.5 V or the working temperature is elevated to 45 °C, the cells still maintain a stable operation for extending 300 cycles.

8.
Apoptosis ; 29(5-6): 898-919, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38411862

ABSTRACT

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC.


Subject(s)
Carcinoma, Hepatocellular , Gene Expression Regulation, Neoplastic , Liver Neoplasms , Sulfotransferases , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Sulfotransferases/genetics , Gene Knockdown Techniques , Humans , Animals , Mice , Mice, Inbred BALB C , Mutation , DNA Methylation , Drug Resistance, Neoplasm , Embryonic Stem Cells/metabolism , Embryonic Stem Cells/pathology , Prognosis , Cell Line, Tumor
9.
Anal Chem ; 96(1): 248-255, 2024 01 09.
Article in English | MEDLINE | ID: mdl-38113377

ABSTRACT

Rapid identification of fermented lactic acid bacteria has long been a challenge in the brewing industry. This study combined label-free surface-enhanced Raman scattering (SERS) and optical tweezer technology to construct a test platform within a microfluidic environment. Six kinds of lactic acid bacteria common in industry were tested to prove the stability of the SERS spectra. The results demonstrated that the utilization of optical tweezers to securely hold the bacteria significantly enhanced the stability of the SERS spectra. Furthermore, SVM and XGBoost machine learning algorithms were utilized to analyze the obtained Raman spectra for identification, and the identification accuracies exceeded 95% for all tested lactic acid bacteria. The findings of this study highlight the crucial role of optical tweezers in improving the stability of SERS spectra by capturing bacteria in a microfluidic environment, prove that this technology could be used in the rapid identification of lactic acid bacteria, and show great significance in expanding the applicability of the SERS technique for other bacterial testing purposes.


Subject(s)
Limosilactobacillus fermentum , Microfluidics , Optical Tweezers , Bacteria , Spectrum Analysis, Raman/methods
10.
Anal Chem ; 96(22): 8868-8874, 2024 06 04.
Article in English | MEDLINE | ID: mdl-38775341

ABSTRACT

Experimental methods to determine transition temperatures for individual base pair melting events in DNA duplexes are lacking despite intense interest in these thermodynamic parameters. Here, we determine the dimensions of the thymine (T) C2═O stretching vibration when it is within the DNA duplex via isotopic substitutions at other atomic positions in the structure. First, we determined that this stretching state was localized enough to specific atoms in the molecule to make submolecular scale measurements of local structure and stability in high molecular weight complexes. Next, we develop a new isotope-edited variable temperature infrared method to measure melting transitions at various locations in a DNA structure. As an initial test of this "sub-molecular scale thermometer", we applied our T13C2 difference infrared signal to measure location-dependent melting temperatures (TmL) in a DNA duplex via variable temperature attenuated total reflectance Fourier transform infrared (VT-ATR-FTIR) spectroscopy. We report that the TmL of a single Watson-Crick A-T base pair near the end of an A-T rich sequence (poly T) is ∼34.9 ± 0.7°C. This is slightly lower than the TmL of a single base pair near the middle position of the poly T sequence (TmL ∼35.6±0.2°C). In addition, we also report that the TmL of a single Watson-Crick A-T base pair near the end of a 50% G-C sequence (12-mer) is ∼52.5 ± 0.3°C, which is slightly lower than the global melting Tm of the 12-mer sequence (TmL ∼54.0±0.9°C). Our results provide direct physical evidence for end fraying in DNA sequences with our novel spectroscopic methods.


Subject(s)
Base Pairing , DNA , Thymine , Transition Temperature , DNA/chemistry , Thymine/chemistry , Spectroscopy, Fourier Transform Infrared , Spectrophotometry, Infrared/methods , Nucleic Acid Conformation , Temperature
11.
Biochem Biophys Res Commun ; 723: 150188, 2024 09 03.
Article in English | MEDLINE | ID: mdl-38824808

ABSTRACT

Steroid (glucocorticoid)-induced necrosis of the femoral head (SONFH) represents a prevalent, progressive, and challenging bone and joint disease characterized by diminished osteogenesis and angiogenesis. Omaveloxolone (OMA), a semi-synthetic oleanocarpane triterpenoid with antioxidant, anti-inflammatory, and osteogenic properties, emerges as a potential therapeutic agent for SONFH. This study investigates the therapeutic impact of OMA on SONFH and elucidates its underlying mechanism. The in vitro environment of SONFH cells was simulated by inducing human bone marrow mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) using dexamethasone (DEX).Various assays, including CCK-8, alizarin red staining, Western blot, qPCR, immunofluorescence, flow cytometry, and TUNNEL, were employed to assess cell viability, STING/NF-κB signaling pathway-related proteins, hBMSCs osteogenesis, HUVECs migration, angiogenesis, and apoptosis. The results demonstrate that OMA promotes DEX-induced osteogenesis, HUVECs migration, angiogenesis, and anti-apoptosis in hBMSCs by inhibiting the STING/NF-κB signaling pathway. This experimental evidence underscores the potential of OMA in regulating DEX-induced osteogenesis, HUVECs migration, angiogenesis, and anti-apoptosis in hBMSCs through the STING/NF-κB pathway, thereby offering a promising avenue for improving the progression of SONFH.


Subject(s)
Femur Head Necrosis , Glucocorticoids , Neovascularization, Physiologic , Osteogenesis , Humans , Angiogenesis , Apoptosis/drug effects , Cell Movement/drug effects , Cell Survival/drug effects , Cells, Cultured , Dexamethasone/pharmacology , Femur Head/pathology , Femur Head/drug effects , Femur Head/blood supply , Femur Head/metabolism , Femur Head Necrosis/chemically induced , Femur Head Necrosis/pathology , Femur Head Necrosis/drug therapy , Femur Head Necrosis/metabolism , Glucocorticoids/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Neovascularization, Physiologic/drug effects , NF-kappa B/metabolism , Osteogenesis/drug effects , Signal Transduction/drug effects , Triterpenes/pharmacology
12.
Brief Bioinform ; 23(5)2022 09 20.
Article in English | MEDLINE | ID: mdl-35598334

ABSTRACT

The dynamics of complex diseases are not always smooth; they are occasionally abrupt, i.e. there is a critical state transition or tipping point at which the disease undergoes a sudden qualitative shift. There are generally a few significant differences in the critical state in terms of gene expressions or other static measurements, which may lead to the failure of traditional differential expression-based biomarkers to identify such a tipping point. In this study, we propose a computational method, the direct interaction network-based divergence, to detect the critical state of complex diseases by exploiting the dynamic changes in multivariable distributions inferred from observable samples and local biomolecular direct interaction networks. Such a method is model-free and applicable to both bulk and single-cell expression data. Our approach was validated by successfully identifying the tipping point just before the occurrence of a critical transition for both a simulated data set and seven real data sets, including those from The Cancer Genome Atlas and two single-cell RNA-sequencing data sets of cell differentiation. Functional and pathway enrichment analyses also validated the computational results from the perspectives of both molecules and networks.


Subject(s)
Neoplasms , Biomarkers/metabolism , Humans , Neoplasms/genetics , RNA
13.
Microb Pathog ; 194: 106829, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39084310

ABSTRACT

Goose astroviruses (GAstVs) are important pathogens which can cause gout in goslings leading to huge economic losses for the goose farming industry in China. In 2023, an infectious disease characterized by visceral gout broke out in commercial goose farms in Guangxi and Guangdong provinces of China. In this study, two GAstV strains of GXNN and GDCS were successfully isolated from these two disease-ridden goose farms. The complete genomic lengths of these two strains were 7166 bp, and phylogenetic analysis showed that they were both GAstV-2 subtypes. The 3-dimensional structures of the capsid protein were predicted and six characteristic mutation sites at amino acid positions 60, 61, 228, 229, 456 and 523 were found within the strong antigenic regions. A recombination event occurred at 6833-7070 nt between the GAstV TZ03 and Turkey astrovirus CA/00 and this was detected in both the GXNN and GDCS strains. Another recombinant event occurred at 63-2747 nt between the GAstV XT1 and GAstV SDPY and this was detected in the GDCS strain. When 1-day-old goslings were infected with the novel GXNN and GDCS strains, they showed severe visceral gout. This was accompanied by enlarged spleens, liver hemorrhages and urate deposits in the kidneys and ureters and their blood urea nitrogen levels were significantly elevated. The mortality rates of the GXNN- and GDCS-infected groups were pathogenically high at 80 % and 60 %, respectively. These results will promote our understanding of the evolution and epidemic potential of GAstVs in China.


Subject(s)
Astroviridae Infections , Capsid Proteins , Geese , Genome, Viral , Gout , Phylogeny , Poultry Diseases , Animals , Geese/virology , China , Astroviridae Infections/veterinary , Astroviridae Infections/virology , Poultry Diseases/virology , Poultry Diseases/pathology , Gout/virology , Gout/veterinary , Gout/pathology , Capsid Proteins/genetics , Avastrovirus/genetics , Avastrovirus/pathogenicity , Avastrovirus/isolation & purification , Avastrovirus/classification , Virulence , Astroviridae/genetics , Astroviridae/isolation & purification , Astroviridae/pathogenicity
14.
Virol J ; 21(1): 158, 2024 Jul 14.
Article in English | MEDLINE | ID: mdl-39004752

ABSTRACT

BACKGROUND: West Nile virus (WNV) is a rapidly spreading mosquito-borne virus accounted for neuroinvasive diseases. An insight into WNV-host factors interaction is necessary for development of therapeutic approaches against WNV infection. CD11b has key biological functions and been identified as a therapeutic target for several human diseases. The purpose of this study was to determine whether CD11b was implicated in WNV infection. METHODS: SH-SY5Y cells with and without MEK1/2 inhibitor U0126 or AKT inhibitor MK-2206 treatment were infected with WNV. CD11b mRNA levels were assessed by real-time PCR. WNV replication and expression of stress (ATF6 and CHOP), pro-inflammatory (TNF-α), and antiviral (IFN-α, IFN-ß, and IFN-γ) factors were evaluated in WNV-infected SH-SY5Y cells with CD11b siRNA transfection. Cell viability was determined by MTS assay. RESULTS: CD11b mRNA expression was remarkably up-regulated by WNV in a time-dependent manner. U0126 but not MK-2206 treatment reduced the CD11b induction by WNV. CD11b knockdown significantly decreased WNV replication and protected the infected cells. CD11b knockdown markedly increased TNF-α, IFN-α, IFN-ß, and IFN-γ mRNA expression induced by WNV. ATF6 mRNA expression was reduced upon CD11b knockdown following WNV infection. CONCLUSION: These results demonstrate that CD11b is involved in maintaining WNV replication and modulating inflammatory as well as antiviral immune response, highlighting the potential of CD11b as a target for therapeutics for WNV infection.


Subject(s)
CD11b Antigen , Virus Replication , West Nile virus , Humans , Virus Replication/drug effects , West Nile virus/physiology , West Nile virus/immunology , CD11b Antigen/genetics , CD11b Antigen/metabolism , Cell Line, Tumor , West Nile Fever/immunology , West Nile Fever/virology , Neuroblastoma/immunology , Neuroblastoma/virology , Host-Pathogen Interactions/immunology , Cell Survival/drug effects , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics
15.
J Theor Biol ; : 111974, 2024 Oct 22.
Article in English | MEDLINE | ID: mdl-39448025

ABSTRACT

PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) is a form of radiotherapy method where a patient is given a large dose or "pulse" of radiation a couple of weeks apart rather than daily small doses. The tumor response is then monitored to determine when the subsequent pulse should be given. Pre-clinical trials have shown better tumor response in mice that received immunotherapy along with pulses spaced 10 days apart. However, this was not the case when the pulses were 1 or 4 days apart. Therefore, a synergistic effect between immunotherapy and PULSAR is observed when the pulses are spaced out by a certain number of days. In our study, we aimed to develop a mathematical model that can capture the synergistic effect by considering a time-dependent weight function that takes into account the spacing between pulses. We determined feasible parameters by fitting murine tumor volume data of six treatment groups via simulated annealing algorithm. Applying these parameters to the model we simulated 4000 trials with varying sequencing of pulses. These simulations indicated that if pulses were spaced apart by at least 9 days the tumor volume was about 200 mm3 to 250 mm3 smaller when treated with PULSAR combined with immunotherapy. We successfully demonstrate that our model is simple to implement and can generate tumor volume data that is consistent with the pre-clinical trial data. Our model has the potential to aid in the development of clinical trials of PULSAR therapy.

16.
EMBO Rep ; 23(2): e53081, 2022 02 03.
Article in English | MEDLINE | ID: mdl-34866316

ABSTRACT

Mouse embryonic stem cells (mESCs) can self-renew indefinitely and maintain pluripotency. Inhibition of mechanistic target of rapamycin (mTOR) by the kinase inhibitor INK128 is known to induce paused pluripotency in mESCs cultured with traditional serum/LIF medium (SL), but the underlying mechanisms remain unclear. In this study, we demonstrate that mTOR complex 1 (mTORC1) but not complex 2 (mTORC2) mediates mTOR inhibition-induced paused pluripotency in cells grown in both SL and 2iL medium (GSK3 and MEK inhibitors and LIF). We also show that mTORC1 regulates self-renewal in both conditions mainly through eIF4F-mediated translation initiation that targets mRNAs of both cytosolic and mitochondrial ribosome subunits. Moreover, inhibition of mitochondrial translation is sufficient to induce paused pluripotency. Interestingly, eIF4F also regulates maintenance of pluripotency in an mTORC1-independent but MEK/ERK-dependent manner in SL, indicating that translation of pluripotency genes is controlled differently in SL and 2iL. Our study reveals a detailed picture of how mTOR governs self-renewal in mESCs and uncovers a context-dependent function of eIF4F in pluripotency regulation.


Subject(s)
Eukaryotic Initiation Factor-4F , Mechanistic Target of Rapamycin Complex 1 , Mouse Embryonic Stem Cells/cytology , Pluripotent Stem Cells/cytology , Animals , Eukaryotic Initiation Factor-4F/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 2 , Mice
17.
J Surg Res ; 296: 174-181, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38277954

ABSTRACT

INTRODUCTION: The Clavien-Dindo Classification (CDC) has been traditionally used for assessing postoperative complications. Recently, the Comprehensive Complication Index (CCI) has been introduced as a new tool. However, its prognostic significance in Gastric Cardia Adenocarcinoma (GCA) is yet to be determined. METHODS: The CCI and CDC of 203 patients who underwent radical surgery for GCA at Jinling Hospital from 2016 to 2023 were evaluated. Primary outcome variables included Hospital Length of Stay, duration of intensive care unit stay postoperatively, time to return to normal activities, and total hospitalization cost. The area under the curve was used to measure the correlation strength of the CCI and CDC for these outcomes. RESULTS: The CCI demonstrated superior association strength, indicated by higher area under the curve values for all primary outcome variables compared to the CDC: Hospital Length of Stay (0.956 versus 0.910), intensive care unit stay duration (0.969 versus 0.954), time to return to normal activities (0.983 versus 0.962), and total hospitalization cost (0.925 versus 0.911). CONCLUSIONS: The CCI showed a stronger positive association than the CDC with short-term postoperative complications in GCA. It has potential implications for improving postoperative patient management.


Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , Prognosis , Cardia/surgery , Severity of Illness Index , Adenocarcinoma/surgery , Adenocarcinoma/complications , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Stomach Neoplasms/surgery , Stomach Neoplasms/complications , Retrospective Studies
18.
J Chem Inf Model ; 64(8): 2933-2940, 2024 04 22.
Article in English | MEDLINE | ID: mdl-38530291

ABSTRACT

DeepKa is a deep-learning-based protein pKa predictor proposed in our previous work. In this study, a web server was developed that enables online protein pKa prediction driven by DeepKa. The web server provides a user-friendly interface where a single step of entering a valid PDB code or uploading a PDB format file is required to submit a job. Two case studies have been attached in order to explain how pKa's calculated by the web server could be utilized by users. Finally, combining the web server with post processing as described in case studies, this work suggests a quick workflow of investigating the relationship between protein structure and function that are pH dependent. The web server of DeepKa is freely available at http://www.computbiophys.com/DeepKa/main.


Subject(s)
Internet , Software , Deep Learning , Protein Conformation , Protein Kinases/chemistry , Protein Kinases/metabolism , User-Computer Interface , Hydrogen-Ion Concentration , Databases, Protein
19.
BMC Cardiovasc Disord ; 24(1): 182, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38532333

ABSTRACT

OBJECTIVE: To evaluate the early and mid-term outcomes of open repair in patients with thoracoabdominal aortic aneurysm (TAAA) after thoracic endovascular aortic repair (TEVAR). METHODS: This was a retrospective single center study. Data were retrospectively collected and analyzed for consecutive patients undergoing open TAAA repair (TAAAR) after TEVAR from November 2016 to June 2021. Indications for TAAAR included aneurysm progression due to endoleak, persisted false lumen perfusion, proximal/distal disease progression, and aorta rupture. The risk factor of operative mortality was analyzed by multivariable logistic regression model and the survival was evaluated by Kaplan-Meier. RESULTS: Sixty-three patients who met the inclusion criteria for the study were identified. The mean age at TAAAR was 41 ± 12 years and 43 (68.3%) were male. Marfan syndrome (MFS) was presented in 39 patients (61.9%). 60 (95.2%) patients presented with post-dissection aneurysm and 3 (4.8%) patients with degenerative aneurysm. The extent of TAAA was Crawford I in 9 (14.3%), II in 22 (34.9%), III in 23 (36.5%), and IV in 9 (14.3%). Emergent TAAAR was done in 10 (15.9%) patients, and deep hypothermic circulatory arrest was used in 22 (34.6%). Endograft was explanted in 31 (49.2%). Operative mortality was 11 (17.5%). Stroke, paraplegia, and acute kidney failure occurred in 5 (7.9%), 7 (11.1%), and 6 (9.5%) patients, respectively. Pulmonary complications occurred in 19 (30.2%) patients. The estimated survival was 74.8 ± 4.9% at 5 years. Late reoperations were performed in 2 patients at 2.5 years and 1.3 years, respectively. CONCLUSIONS: In this series of TAAA after TEVAR, TAAAR was related with a high risk of operative mortality and morbidity and the midterm outcomes represented a durable treatment and were respectable.


Subject(s)
Aortic Aneurysm, Thoracic , Aortic Aneurysm, Thoracoabdominal , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Humans , Male , Female , Endovascular Aneurysm Repair , Blood Vessel Prosthesis/adverse effects , Retrospective Studies , Blood Vessel Prosthesis Implantation/adverse effects , Treatment Outcome , Aortic Aneurysm, Thoracic/surgery , Risk Factors , Endovascular Procedures/adverse effects , Postoperative Complications
20.
MAGMA ; 37(2): 215-226, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38019377

ABSTRACT

OBJECTIVE: The study aims to propose an accurate labelling method of interscapular BAT (iBAT) in rats using dynamic MR fat fraction (FF) images with noradrenaline (NE) stimulation and then develop an automatic iBAT segmentation method using a U-Net model. MATERIALS AND METHODS: Thirty-four rats fed different diets or housed at different temperatures underwent successive MR scans before and after NE injection. The iBAT were labelled automatically by identifying the regions with obvious FF change in response to the NE stimulation. Further, these FF images along with the recognized iBAT mask images were used to develop a deep learning network to accomplish the robust segmentation of iBAT in various rat models, even without NE stimulation. The trained model was then validated in rats fed with high-fat diet (HFD) in comparison with normal diet (ND). RESULT: A total of 6510 FF images were collected using a clinical 3.0 T MR scanner. The dice similarity coefficient (DSC) between the automatic and manual labelled results was 0.895 ± 0.022. For the network training, the DSC, precision rate, and recall rate were found to be 0.897 ± 0.061, 0.901 ± 0.068 and 0.899 ± 0.086, respectively. The volumes and FF values of iBAT in HFD rats were higher than ND rats, while the FF decrease was larger in ND rats after NE injection. CONCLUSION: An automatic iBAT segmentation method for rats was successfully developed using the dynamic labelled FF images of activated BAT and deep learning network.


Subject(s)
Adipose Tissue, Brown , Deep Learning , Rats , Animals , Adipose Tissue, Brown/diagnostic imaging , Norepinephrine , Diet, High-Fat , Magnetic Resonance Spectroscopy , Magnetic Resonance Imaging/methods
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