Spontaneous Degradation of the "Forever Chemicals" Perfluoroalkyl and Polyfluoroalkyl Substances (PFASs) on Water Droplet Surfaces.

Because of their innate chemical stability, the ubiquitous perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been dubbed "forever chemicals" and have attracted considerable attention. However, their stability under environmental conditions has not been widely verified. Herein, perfluorooctanoic acid (PFOA), a widely used and detected PFAS, was found to be spontaneously degraded in aqueous microdroplets under room temperature and atmospheric pressure conditions. This unexpected fast degradation occurred via a unique multicycle redox reaction of PFOA with interfacial reactive species on the droplet surface. Similar degradation was observed for other PFASs. This study extends the current understanding of the environmental fate and chemistry of PFASs and provides insight into aid in the development of effective methods for removing PFASs.

Neurovascular coupling alteration in drug-naïve Parkinson's disease: The underlying molecular mechanisms and levodopa's restoration effects.

BACKGROUND: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. MATERIAL AND METHODS: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. RESULTS: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value <0.0006). The distribution of NVC differences correlated with the density of dopaminergic, serotonin, MU-opioid, and cholinergic receptors/transporters. Additionally, levodopa ameliorated abnormal NVC in most of these regions, where there were primarily ALFF changes with limited CBF modifications. CONCLUSION: Patients exhibited NVC dysfunction primarily in the striato-thalamo-cortical circuit and motor control regions, which could be driven by dopaminergic and nondopaminergic systems, and levodopa therapy mainly restored abnormal NVC by modulating neuronal activity.

Microstructural alterations of the hypothalamus in Parkinson's disease and probable REM sleep behavior disorder.

BACKGROUND: Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. OBJECTIVES: We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. METHODS: This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. RESULTS: PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. CONCLUSIONS: Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity.

BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease worldwide and has emerged as a serious public health issue with no approved treatment. The development of NAFLD is strongly associated with hepatic lipid content, and patients with NAFLD have significantly higher rates of hepatic de novo lipogenesis (DNL) than lean individuals. Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is dramatically increased in obesity and plays important role in proinflammatory cytokine production and insulin resistance. But the role of liver LTB4/LTB4 receptor 1 (Ltb4r1) in lipid metabolism is unclear. APPROACH AND RESULTS: Hepatocyte-specific knockout (HKO) of Ltb4r1 improved hepatic steatosis and systemic insulin resistance in both diet-induced and genetically induced obese mice. The mRNA level of key enzymes involved in DNL and fatty acid esterification decreased in Ltb4r1 HKO obese mice. LTB4/Ltb4r1 directly promoted lipogenesis in HepG2 cells and primary hepatocytes. Mechanically, LTB4/Ltb4r1 promoted lipogenesis by activating the cAMP-protein kinase A (PKA)-inositol-requiring enzyme 1α (IRE1α)-spliced X-box-binding protein 1 (XBP1s) axis in hepatocytes, which in turn promoted the expression of lipogenesis genes regulated by XBP1s. In addition, Ltb4r1 suppression through the Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery alleviated the fatty liver phenotype in obese mice. CONCLUSIONS: LTB4/Ltb4r1 promotes hepatocyte lipogenesis directly by activating PKA-IRE1α-XBP1s to promote lipogenic gene expression. Inhibition of hepatocyte Ltb4r1 improved hepatic steatosis and insulin resistance. Ltb4r1 is a potential therapeutic target for NAFLD.

Cholinergic basal forebrain system degeneration underlies postural instability/gait difficulty and attention impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: The specific pathophysiological mechanisms underlying postural instability/gait difficulty (PIGD) and cognitive function in Parkinson's disease (PD) remain unclear. Both postural and gait control, as well as cognitive function, are associated with the cholinergic basal forebrain (cBF) system. METHODS: A total of 84 PD patients and 82 normal controls were enrolled. Each participant underwent motor and cognitive assessments. Diffusion tensor imaging was used to detect structural abnormalities in the cBF system. The cBF was segmented using FreeSurfer, and its fiber tract was traced using probabilistic tractography. To provide information on extracellular water accumulation, free-water fraction (FWf) was quantified. FWf in the cBF and its fiber tract, as well as cortical projection density, were extracted for statistical analyses. RESULTS: Patients had significantly higher FWf in the cBF (p < 0.001) and fiber tract (p = 0.021) than normal controls, as well as significantly lower cBF projection in the occipital (p < 0.001), parietal (p < 0.001) and prefrontal cortex (p = 0.005). In patients, a higher FWf in the cBF correlated with worse PIGD score (r = 0.306, p = 0.006) and longer Trail Making Test A time (r = 0.303, p = 0.007). Attentional function (Trail Making Test A) partially mediated the association between FWf in the cBF and PIGD score (indirect effect, a*b = 0.071; total effect, c = 0.256; p = 0.006). CONCLUSIONS: Our findings suggest that degeneration of the cBF system in PD, from the cBF to its fiber tract and cortical projection, plays an important role in cognitive-motor interaction.

Lighting up endogenous H2O2 in the tumor microenvironment using a dual-mode nanoprobe for long afterglow and MR bioimaging.

Persistent luminescent nanoparticles (PLNPs) are excellent luminescent materials, and near-infrared PLNPs are efficiently applied for biosensing and bioimaging due to their advantages of no excitation, excellent light stability and long afterglow. However, due to interference from the complex environment within organisms, single-mode imaging methods often face limitations in selectivity, sensitivity, and accuracy. Therefore, it is desirable to construct a dual-mode imaging probe strategy with higher specificity and sensitivity for bioimaging. Magnetic resonance imaging (MRI) has been widely used in the field of bioimaging due to its advantages of high resolution, non-radiation and non-invasiveness. Here, by combining near-infrared PLNPs and manganese dioxide (MnO2) nanosheets, a sensitive and convenient dual-mode "turn on" bioimaging nanoprobe ZGC@MnO2 has been developed for long afterglow imaging and MRI of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment (TME). The monitoring of H2O2 has garnered significant attention due to its crucial role in human pathologies. For the dual-mode "turn on" bioimaging nanoprobe, the near-infrared PLNPs of quasi-spherical ZnGa2O4:Cr (ZGC) nanoparticles were synthesized as luminophores, and MnO2 nanosheets were utilized as a fluorescence quencher, carrier and H2O2 recognizer. H2O2 in the TME could reduce MnO2 nanosheets to Mn2+ for MRI, and ZGC nanoparticles were released for long afterglow imaging. Finally, the ZGC@MnO2 nanoprobe exhibited a rapid response, an excellent signal-to-noise ratio and a limit of detection of 3.67 nM for endogenous H2O2 in the TME. This dual-mode approach enhances the detection sensitivity for endogenous H2O2, thereby facilitating the research of endogenous H2O2-associated diseases and clinical diagnostics.

A DNA octahedral amplifier for endogenous circRNA detection and bioimaging in living cells and its biomarker study.

The discovery of reliable biomarkers is essential for early diagnosis, treatment, and prognosis assessment of diseases. Many research studies have shown that circRNA is a potential biomarker for diagnosis and prognosis of diseases. However, in situ monitoring circRNA in live cells is still a challenge at present, which brings a major limitation to the development and verification of circRNA as a disease biomarker. In this study, a catalytic hairpin assembly (CHA) reaction-based DNA octahedral amplifier (DOA) was developed for fluorescence resonance energy transfer (FRET) detection and bioimaging of circRNA in living cells. The DOA was first produced by self-assembling a DNA octahedron with six customized single-stranded DNAs, and two hairpins H1 (Cy3) and H2 (Cy5) were then hybridized to four vertices of the DNA octahedron. Idiopathic pulmonary fibrosis (IPF)-related circHIPK3 was used as the target. Once the CHA reaction from H1 and H2 on DOA was activated by a sequence-specific back-splice junction (BSJ) of circHIPK3, a significant FRET signal can be obtained from Cy3 to Cy5. The circHIPK3 was subsequently released to cause the next CHA reaction. Because the DOA has the advantages of the spatial-confinement effect, resistance to nuclease degradation and easy penetration into cells, rapid and excellent signal amplification FRET detection and bioimaging of endogenous circHIPK3 can be achieved in various cells. This study provides a high-precision assay platform to explore the possibility of using circRNA as a biomarker, and it is valuable for circRNA-related early diagnosis and treatment of diseases.

Multimodal Model to Predict Tissue-to-Blood Partition Coefficients of Chemicals in Mammals and Fish.

Tissue-to-blood partition coefficients (Ptb) are key parameters for assessing toxicokinetics of xenobiotics in organisms, yet their experimental data were lacking. Experimental methods for measuring Ptb values are inefficient, underscoring the urgent need for prediction models. However, most existing models failed to fully exploit Ptb data from diverse sources, and their applicability domain (AD) was limited. The current study developed a multimodal model capable of processing and integrating textual (categorical features) and numerical information (molecular descriptors/fingerprints) to simultaneously predict Ptb values across various species, tissues, blood matrices, and measurement methods. Artificial neural network algorithms with embedding layers were used for the multimodal modeling. The corresponding unimodal models were developed for comparison. Results showed that the multimodal model outperformed unimodal models. To enhance the reliability of the model, a method considering categorical features, weighted molecular similarity density, and weighted inconsistency in molecular activities of structure-activity landscapes was used to characterize the AD. The model constrained by the AD exhibited better prediction accuracy for the validation set, with the determination coefficient, root mean-square error, and mean absolute error being 0.843, 0.276, and 0.213 log units, respectively. The multimodal model coupled with the AD characterization can serve as an efficient tool for internal exposure assessment of chemicals.

HIO3-HIO2-Driven Three-Component Nucleation: Screening Model and Cluster Formation Mechanism.

Iodine oxoacids (HIO3 and HIO2)-driven nucleation has been suggested to efficiently contribute to new particle formation (NPF) in marine atmospheres. Abundant atmospheric nucleation precursors may further enhance HIO3-HIO2-driven nucleation through various multicomponent nucleation mechanisms. However, the specific enhancing potential (EP) of different precursors remains largely unknown. Herein, the EP-based screening model of precursors and enhancing mechanism of the precursor with the highest EP on HIO3-HIO2 nucleation were investigated. The formation free energies (ΔG), as critical parameters for evaluating EP, were calculated for the dimers of 63 selected precursors with HIO2. Based on the ΔG values, (1) a quantitative structure-activity relationship model was developed for evaluating ΔG of other precursors and (2) atmospheric concentrations of 63 (precursor)1(HIO2)1 dimer clusters were assessed to identify the precursors with the highest EP for HIO3-HIO2-driven nucleation by combining with earlier results for the nucleation with HIO3 as the partner. Methanesulfonic acid (MSA) was found to be one of the precursors with the highest EP. Finally, we found that MSA can effectively enhance HIO3-HIO2 nucleation at atmospheric conditions by studying larger MSA-HIO3-HIO2 clusters. These results augment our current understanding of HIO3-HIO2 and MSA-driven nucleation and may suggest a larger impact of HIO2 in atmospheric aerosol nucleation.

High mobility group AT-hook 1 (HMGA1) is an important positive regulator of hepatitis B virus (HBV) that is reciprocally upregulated by HBV X protein.

Chronic infection with hepatitis B virus (HBV) is associated with liver cirrhosis and hepatocellular carcinoma. Upon infection of hepatocytes, HBV covalently closed circular DNA (cccDNA) exists as histone-bound mini-chromosome, subjected to transcriptional regulation similar to chromosomal DNA. Here we identify high mobility group AT-hook 1 (HMGA1) protein as a positive regulator of HBV transcription that binds to a conserved ATTGG site within enhancer II/core promoter (EII/Cp) and recruits transcription factors FOXO3α and PGC1α. HMGA1-mediated upregulation of EII/Cp results in enhanced viral gene expression and genome replication. Notably, expression of endogenous HMGA1 was also demonstrated to be upregulated by HBV, which involves HBV X protein (HBx) interacting with SP1 transcription factor to activate HMGA1 promoter. Consistent with these in vitro results, chronic hepatitis B patients in immune tolerant phase display both higher intrahepatic HMGA1 protein levels and higher serum HBV markers compared to patients in inactive carrier phase. Finally, using a mouse model of HBV persistence, we show that targeting endogenous HMGA1 through RNA interference facilitated HBV clearance. These data establish HMGA1 as an important positive regulator of HBV that is reciprocally upregulated by HBV via HBx and also suggest the HMGA1-HBV positive feedback loop as a potential therapeutic target.

Comparison of lung lesion assessment using free-breathing dynamic contrast-enhanced 1.5-T MRI with a golden-angle radial stack-of-stars VIBE sequence and CT.

BACKGROUND: Few studies have investigated the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a free-breathing golden-angle radial stack-of-stars volume-interpolated breath-hold examination (FB radial VIBE) sequence in the lung. PURPOSE: To investigate whether DCE-MRI using the FB radial VIBE sequence can assess morphological and kinetic parameters in patients with pulmonary lesions, with computed tomography (CT) as the reference. MATERIAL AND METHODS: In total, 43 patients (30 men; mean age = 64 years) with one lesion each were prospectively enrolled. Morphological and kinetic features on MRI were calculated. The diagnostic performance of morphological MR features was evaluated using a receiver operating characteristic (ROC) curve. Kinetic features were compared among subgroups based on histopathological subtype, lesion size, and lymph node metastasis. RESULTS: The maximum diameter was not significantly different between CT and MRI (3.66 ± 1.62 cm vs. 3.64 ± 1.72 cm; P = 0.663). Spiculation, lobulation, cavitation or bubble-like areas of low attenuation, and lymph node enlargement had an area under the ROC curve (AUC) >0.9, while pleural indentation yielded an AUC of 0.788. The lung cancer group had significantly lower Ktrans, Ve, and initial AUC values than the other cause inflammation group (0.203, 0.158, and 0.589 vs. 0.597, 0.385, and 1.626; P < 0.05) but significantly higher values than the tuberculosis group (P < 0.05). CONCLUSION: Morphology features derived from FB radial VIBE have high correlations with CT, and kinetic analyses show significant differences between benign and malignant lesions. DCE-MRI with FB radial VIBE could serve as a complementary quantification tool to CT for radiation-free assessments of lung lesions.

Synthesis of Bispecific Antibody Conjugates Using Functionalized Poly-ADP-ribose Polymers.

Poly-ADP-ribose (PAR) is a natural type of polymer derived from enzymatic reactions catalyzed by cellular poly(ADP-ribose) polymerases (PARPs). Given its notable solubility and biocompatibility, the PAR polymer may function as effective carriers for therapeutics in addition to modulating biomolecular interactions in cells. To explore its therapeutic potential, we herein developed a PAR polymer-based bispecific antibody targeting both human epidermal growth factor receptor 2 (HER2) and T-cell CD3 antigens. This was accomplished by conjugating anti-HER2 and anti-CD3 monoclonal antibodies to azido-functionalized PAR polymers through click chemistry. The generated PAR polymer-anti-HER2/anti-CD3 antibody conjugate could not only bind specifically to both HER2- and CD3-expressing target cells but also display potent cytotoxicity against HER2-positive breast cancer cells in the presence of non-activated human peripheral blood mononuclear cells (PBMCs). Functionalized PAR polymers provide a new strategy for synthesizing bispecific antibodies and may enable generation of PAR polymer-based conjugates with unique pharmacological activities for biomedical applications.

Counterintuitive Oxidation of Alcohols at Air-Water Interfaces.

This study shows that the oxidation of alcohols can rapidly occur at air-water interfaces. It was found that methanediols (HOCH2OH) orient at air-water interfaces with a H atom of the -CH2- group pointing toward the gaseous phase. Counterintuitively, gaseous hydroxyl radicals do not prefer to attack the exposed -CH2- group but the -OH group that forms hydrogen bonds with water molecules at the surface via a water-promoted mechanism, leading to the formation of formic acids. Compared with gaseous oxidation, the water-promoted mechanism at the air-water interface significantly lowers free-energy barriers from ∼10.7 to ∼4.3 kcal·mol-1 and therefore accelerates the formation of formic acids. The study unveils a previously overlooked source of environmental organic acids that are bound up with aerosol formation and water acidity.

Functional connectome predicting individual gait function and its relationship with molecular architecture in Parkinson's disease.

Gait impairment is a common symptom of Parkinson's disease (PD), but its neural signature remains unclear due to the interindividual variability of gait performance. Identifying a robust gait-brain correlation at the individual level would provide insight into a generalizable neural basis of gait impairment. In this context, this study aimed to detect connectome that can predict individual gait function of PD, and follow-up analyses assess the molecular architecture underlying the connectome by relating it to the neurotransmitter-receptor/transporter density maps. Resting-state functional magnetic resonance imaging was used to detect the functional connectome, and gait function was assessed via a 10 m-walking test. The functional connectome was first detected within drug-naive patients (N = 48) by using connectome-based predictive modeling following cross-validation and then successfully validated within drug-managed patients (N = 30). The results showed that the motor, subcortical, and visual networks played an important role in predicting gait function. The connectome generated from patients failed to predict the gait function of 33 normal controls (NCs) and had distinct connection patterns compared to NCs. The negative connections (connection negatively correlated with 10 m-walking-time) pattern of the PD connectome was associated with the density of the D2 receptor and VAChT transporter. These findings suggested that gait-associated functional alteration induced by PD pathology differed from that induced by aging degeneration. The brain dysfunction related to gait impairment was more commonly found in regions expressing more dopaminergic and cholinergic neurotransmitters, which may aid in developing targeted treatments.

Presence but not the timing of onset of REM sleep behavior disorder distinguishes evolution patterns in Parkinson's disease.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) could develop preceding or come after motor symptoms during Parkinson's disease (PD). It remains unknown that whether PD with different timing of RBD onset relative to motor symptoms suggests different spatiotemporal sequence of neurodegeneration. This study aimed to explore the sequence of disease progression in crucially involved brain regions in PD with different timing of RBD onset. METHOD: We recruited 157 PD, 16 isolated RBD (iRBD), and 78 healthy controls. PD patients were identified as (1) PD with RBD preceding motor symptoms (PD-preRBD, n = 50), (2) PD with RBD posterior to motor symptoms (PD-postRBD, n = 31), (3) PD without RBD (PD-nonRBD, n = 75). The volumes of crucial brain regions, including the basal ganglia and limbic structures in T1-weighted imaging, and the contrast-noise-ratios of locus coeruleus (LC) and substantia nigra (SN) in neuromelanin-sensitive magnetic resonance imaging, were extracted. To simulate the sequence of disease progression for cross-sectional data, an event-based model was introduced to estimate the maximum likelihood sequence of regions' involvement for each group. Then, a statistical parameter, the Bhattacharya coefficient (BC), was used to evaluate the similarity of the sequence. RESULTS: The model predicted that SN occupied the highest likelihood in the maximum likelihood sequence of disease progression in the all PD subgroups, while LC was specifically positioned earlier to SN in iRBD, a prodromal phase of PD. Subsequent early involvement of LC was observed in the both PD-preRBD and PD-postRBD. In contrast, atrophy in the para-hippocampal gyrus but relatively intact LC in the early stage was demonstrated in PD-nonRBD. Then, the similarity comparisons indicated higher BC between PD-postRBD and PD-preRBD (BC = 0.76) but lower BC between PD-postRBD and PD-nonRBD group (BC = 0.41). iRBD had higher BC against PD-preRBD (BC = 0.66) and PD-postRBD (BC = 0.63) but lower BC against PD- nonRBD (BC = 0.48). CONCLUSION: The spatiotemporal sequence of neurodegeneration between PD-pre and PD-post were similar but distinct from PD-nonRBD. The presence of RBD may be the essential factor for differentiating the degeneration patterns of PD, but the timing of RBD onset has currently proved to be not.

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease.

Dopamine replacement therapy (DRT) represents the standard treatment for Parkinson's disease (PD), however, instant and long-term medication influence on patients' brain function have not been delineated. Here, a total of 97 drug-naïve patients, 43 patients under long-term DRT, and 94 normal control (NC) were, retrospectively, enrolled. Resting-state functional magnetic resonance imaging data and motor symptom assessments were conducted before and after levodopa challenge test. Whole-brain functional connectivity (FC) matrices were constructed. Network-based statistics were performed to assess FC difference between drug-naïve patients and NC, and these significant FCs were defined as disease-related connectomes, which were used for further statistical analyses. Patients showed better motor performances after both long-term DRT and levodopa challenge test. Two disease-related connectomes were observed with distinct patterns. The FC of the increased connectome, which mainly consisted of the motor, visual, subcortical, and cerebellum networks, was higher in drug-naïve patients than that in NC and was normalized after long-term DRT (p-value <.050). The decreased connectome was mainly composed of the motor, medial frontal, and salience networks and showed significantly lower FC in all patients than NC (p-value <.050). The global FC of both increased and decreased connectome was significantly enhanced after levodopa challenge test (q-value <0.050, false discovery rate-corrected). The global FC of increased connectome in ON-state was negatively associated with levodopa equivalency dose (r = -.496, q-value = 0.007). Higher global FC of the decreased connectome was related to better motor performances (r = -.310, q-value = 0.022). Our findings provided insights into brain functional alterations under dopaminergic medication and its benefit on motor symptoms.

Experimental and molecular support for Cfap70 as a causative gene of 'multiple morphological abnormalities of the flagella' with male infertility†.

Multiple morphological abnormalities of the flagella, a severe form of asthenozoospermia, can lead to male infertility. Recent studies have implicated an association between human CFAP70 deficiency and multiple morphological abnormalities of the flagella; however, the underlying biological mechanism and supporting experimental evidence in animal models remain unclear. To address this gap, we used CRISPR/Cas9 technology to generate Cfap70-deficient mice to investigate the relationship between Cfap70 deficiency and multiple morphological abnormalities of the flagella. Our findings show that the loss of CFAP70 leads to multiple morphological abnormalities of the flagella and spermiogenesis defects. Specifically, the lack of CFAP70 impairs sperm flagellum biogenesis and head shaping during spermiogenesis. Late-step spermatids from Cfap70-deficient mouse testis exhibited club-shaped sperm heads and abnormal disassembly of the manchette. Furthermore, we found that CFAP70 interacts with DNAI1 and DNAI2; Cfap70 deficiency also reduces the level of AKAP3 in sperm flagella, indicating that CFAP70 may participate in the flagellum assembly and transport of flagellar components. These findings provide compelling evidence implicating Cfap70 as a causative gene of multiple morphological abnormalities of the flagella and highlight the consequences of CFAP70 loss on flagellum biogenesis.

Machine Learning Model for Screening Thyroid Stimulating Hormone Receptor Agonists Based on Updated Datasets and Improved Applicability Domain Metrics.

Machine learning (ML) models for screening endocrine-disrupting chemicals (EDCs), such as thyroid stimulating hormone receptor (TSHR) agonists, are essential for sound management of chemicals. Previous models for screening TSHR agonists were built on imbalanced datasets and lacked applicability domain (AD) characterization essential for regulatory application. Herein, an updated TSHR agonist dataset was built, for which the ratio of active to inactive compounds greatly increased to 1:2.6, and chemical spaces of structure-activity landscapes (SALs) were enhanced. Resulting models based on 7 molecular representations and 4 ML algorithms were proven to outperform previous ones. Weighted similarity density (ρs) and weighted inconsistency of activities (IA) were proposed to characterize the SALs, and a state-of-the-art AD characterization methodology ADSAL{ρs, IA} was established. An optimal classifier developed with PubChem fingerprints and the random forest algorithm, coupled with ADSAL{ρs ≥ 0.15, IA ≤ 0.65}, exhibited good performance on the validation set with the area under the receiver operating characteristic curve being 0.984 and balanced accuracy being 0.941 and identified 90 TSHR agonist classes that could not be found previously. The classifier together with the ADSAL{ρs, IA} may serve as efficient tools for screening EDCs, and the AD characterization methodology may be applied to other ML models.

Peritumoral and Intratumoral Texture Features Based on Multiparametric MRI and Multiple Machine Learning Methods to Preoperatively Evaluate the Pathological Outcomes of Pancreatic Cancer.

BACKGROUND: Radiomics-based preoperative evaluation of lymph node metastasis (LNM) and histological grade (HG) might facilitate the decision-making for pancreatic cancer and further efforts are needed to develop effective models. PURPOSE: To develop multiparametric MRI (MP-MRI)-based radiomics models to evaluate LNM and HG. STUDY TYPE: Retrospective. POPULATION: The pancreatic cancer patients from the main center (n = 126) were assigned to the training and validation sets at a 4:1 ratio. The patients from the other center (n = 40) served as external test sets. FIELD STRENGTH/SEQUENCE: A 3.0 T and 1.5 T/T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast enhancement T1-weighted imaging. ASSESSMENT: A total of 10,686 peritumoral and intratumoral radiomics features were extracted which contained first-order, shape-based, and texture features. The following three-step method was applied to reduce the feature dimensionality: SelectKBest (a function from scikit-learn package), least absolute shrinkage and selection operator (LASSO), and recursive feature elimination based on random forest (RFE-RF). Six classifiers (random forest, logistic regression, support vector machine, K-nearest neighbor, decision tree, and XGBOOST) were trained and selected based on their performance to construct the clinical, radiomics, and combination models. STATISTICAL TESTS: Delong's test was used to compare the models' performance. P value less than 0.05 was considered significant. RESULTS: Twelve significant features for LNM and 11 features for HG were obtained. Random forest and logistic regression performed better than the other classifiers in evaluating LNM and HG, respectively, according to the surgical pathological results. The best performance was obtained with the models that combined peritumoral and intratumoral features with area under curve (AUC) values of 0.944 and 0.892 in the validation and external test sets for HG and 0.924 and 0.875 for LNM. DATA CONCLUSION: Radiomics holds the potential to evaluate LNM and HG of pancreatic cancer. The combination of peritumoral and intratumoral features will make models more accurate. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Occurrence and Health Risks of Organic Micropollutants in Tap Water in Dalian.

Organic micropollutants (OMPs) in tap water may pose risks to human health. Previous studies on the potential health risks of OMPs in tap water may have underestimated the potential health risks of OMPs due to their limited coverage in target pollutants and incomplete toxicity data. In this study, tap water samples were collected in 37 sampling sites in Dalian, China. More than 1,200 target pollutants were screened by combining screening analysis and target analysis. A total of 93 OMPs were detected, with concentration summation ranging from 157 to 1.7 × 104 ng/L among different sampling sites. A total of 17 OMPs (12 agrochemicals, 3 pharmaceuticals and personal care products, and 2 other compounds) were detected in over 80% of the sampling sites. Especially, imidacloprid, tebuconazole, and atrazine-desethyl were found in all the sampling sites. Computational toxicology models were adopted to predict the missing toxicity threshold values of the identified chemicals. Noncarcinogenic risks were estimated to be negligible among all the sampling sites, while carcinogenic risks at six sites were above 10-6 but below 10-4, indicating non-negligible risks. Griseofulvin contributed the most to the carcinogenic risk. This study offers valuable insights that can guide future initiatives to safeguard tap water safety.