Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

Task-general or specific: The alertness modulates post-error adjustment.

Previous studies have shown that alertness is closely related to executive control function, but its impact on components of post-error adjustment is unknown. This study applied the Attentional Networks Test and the Four-choice Flanker task with three response stimulus intervals (RSIs) to explore the correlation between alertness and post-error adjustment. The linear mixed-effects model of alertness and RSI on the post-error processing indicators showed a significant negative correlation between the alertness and post-error slowing (PES) under 200 ms RSI , as well as between alertness and post-error improvement in accuracy (PIA) under both 700 ms RSI and 1200 ms RSI. Participants with lower alertness showed larger post-error slowing in the early stages, while those with higher alertness had smaller PIA in later stages. This study revealed the effects of alertness on different processing components of post-error adjustment. The control strategies utilized by individuals with high and low levels of alertness differed in preparation for performance monitoring. Alertness improved post-error response speed in a task-unspecific manner, but not post-error adaptation.

Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges.

Viral infections have a major impact in human health. Ongoing viral transmission and escalating selective pressure have the potential to favor the emergence of vaccine- and antiviral drug-resistant viruses. Target-based approaches for the design of antiviral drugs can play a pivotal role in combating drug-resistant challenges. Drug design computational tools facilitate the discovery of novel drugs. This review provides a comprehensive overview of current drug design strategies employed in the field of antiviral drug resistance, illustrated through the description of a series of successful applications. These strategies include technologies that enhance compound-target affinity while minimizing interactions with mutated binding pockets. Furthermore, emerging approaches such as virtual screening, targeted protein/RNA degradation, and resistance analysis during drug design have been harnessed to curtail the emergence of drug resistance. Additionally, host targeting antiviral drugs offer a promising avenue for circumventing viral mutation. The widespread adoption of these refined drug design strategies will effectively address the prevailing challenge posed by antiviral drug resistance.

Cognitive and neural mechanisms of voluntary versus forced language switching in Chinese-English bilinguals: an fMRI study.

The ecological validity of bilingual code-switching has garnered increasing attention in recent years. Contrary to traditional studies that have focused on forced language switching, emerging theories posit that voluntary switching may not incur such a cost. To test these claims and understand differences between forced and voluntary switching, the present study conducted a systematic comparison through both behavioral and neural perspectives. Utilizing fMRI alongside picture-naming tasks, our findings diverge from prior work. Voluntary language switching not only demonstrated switching costs at the behavioral level but also significantly activated brain regions associated with inhibitory control. Direct comparisons of voluntary and forced language switching revealed no significant behavioral differences in switching costs, and both shared several common brain regions that were activated. On the other hand, a nuanced difference between the two types of language switching was revealed by whole-brain analysis: voluntary switching engaged fewer language control regions than forced switching. These findings offer a comprehensive view of the neural and behavioral dynamics involved in bilingual language switching, challenging prior claims that voluntary switching imposes no behavioral or neural costs, and thus providing behavioral and neuroimaging evidence for the involvement of inhibitory control in voluntary language switching.

Revolutionizing viral disease treatment: Phase separation and lysosome/exosome targeting as new areas and new paradigms for antiviral drug research.

With the advancement of globalization, our world is becoming increasingly interconnected. However, this interconnection means that once an infectious disease emerges, it can rapidly spread worldwide. Specifically, viral diseases pose a growing threat to human health. The COVID-19 pandemic has underscored the pressing need for expedited drug development to combat emerging viral diseases. Traditional drug discovery methods primarily rely on random screening and structure-based optimization, and new approaches are required to address more complex scenarios in drug discovery. Emerging antiviral strategies include phase separation and lysosome/exosome targeting. The widespread implementation of these innovative drug design strategies will contribute towards tackling existing viral infections and future outbreaks.

Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis.

Decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) is a promising target for treating tuberculosis (TB). Currently, most novel DprE1 inhibitors are discovered through high-throughput screening, while computer-aided drug design (CADD) strategies are expected to promote the discovery process. In this study, with the aid of structure-based virtual screening and computationally guided design, a series of novel scaffold N-(1-(6-oxo-1,6-dihydropyrimidine)-pyrazole) acetamide derivatives with significant antimycobacterial activities were identified. Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MICMtb values of 0.78-1.56 µM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MICMtb = 12.5 µM). LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications.

The D-SPECT SH reconstruction protocol: improved quantification of small left ventricle volumes.

BACKGROUND: Due to spatial resolution limitations, conventional NaI-SPECT typically overestimates the left ventricular (LV) ejection fraction (EF) in patients with small LV volumes. The purpose of this study was to explore the clinical application value of the small heart (SH) reconstruction protocol embedded in the postprocessing procedure of D-SPECT. METHODS: We retrospectively analyzed patients who undergo both D-SPECT and echocardiography (Echo) within one week. Patients with small LV volume were defined as those with a rest end-systolic volume (rESV) ≤ 25 mL and underwent reconstruction using the standard (SD) reconstruction protocol. The SH protocol was deemed successful in correcting the LVEF value if it decreased by 5% or more compared to the SD protocol. The ROC curve was used to calculate the optimal cutoff value of the SH protocol. LVEF, ESV and EDV were computed with SD and SH, respectively. Echo was performed as a reference, and Echo-LVEF, ESV, and EDV were calculated using the Teichholz formula. One-way ANOVA was used to compare these parameters among the three groups. RESULTS: The final study included 209 patients (73.21% female, age 67.34 ± 7.85 years). Compared with the SD protocol, the SH protocol significantly decreased LVEF (67.43 ± 7.38% vs. 71.30 ± 7.61%, p < 0.001). The optimal cutoff value for using the SH protocol was rESV > 17 mL (AUC = 0.651, sensitivity = 78.43%, specificity = 45.57%, p = 0.001). In the subgroup of rESV > 17 mL, there was no significant difference in LVEF (61.84 ± 4.67% vs. 62.83 ± 2.85%, p = 0.481) between the SH protocol and Echo, and no significant difference was observed in rESV (26.92 ± 3.25 mL vs. 27.94 ± 7.96 mL, p = 0.60) between the SH protocol and Echo. CONCLUSION: This pilot study demonstrated that the SH reconstruction protocol was able to effectively correct the overestimation of LVEF in patients with small LV volumes. Particularly, in the rESV > 17 mL subgroup, the time and computing power waste could be reduced while still ensuring the accuracy of the LVEF value and image quality.

Chemical Evolution and Biological Evaluation of Natural Products for Efficient Therapy of Acute Lung Injury.

Acute lung injury (ALI) is one of the most common complications in COVID-19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan-IIA) to achieve a piperidine-fused scaffold through a synthetic route of pre-activation, multi-component reaction, and post-modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti-inflammation and anti-oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product-inspired drug discovery.

The stranding of the ideography: A nonnegligible role of the spoken language.

Morin suggested that one of the reasons for the difficulty in standardizing graphic codes is that the production of spoken language reduces the need for graphic codes. Here we try to extend their claims from a psychological perspective, which allows us to conclude that the puzzle of ideography is perhaps related to human psychological traits and psychological evolution.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury.

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. (S)-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of (S)-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, (S)-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma.

The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC50 = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.

Brain mechanism of unfamiliar and familiar voice processing: an activation likelihood estimation meta-analysis.

Interpersonal communication through vocal information is very important for human society. During verbal interactions, our vocal cord vibrations convey important information regarding voice identity, which allows us to decide how to respond to speakers (e.g., neither greeting a stranger too warmly or speaking too coldly to a friend). Numerous neural studies have shown that identifying familiar and unfamiliar voices may rely on different neural bases. However, the mechanism underlying voice identification of individuals of varying familiarity has not been determined due to vague definitions, confusion of terms, and differences in task design. To address this issue, the present study first categorized three kinds of voice identity processing (perception, recognition and identification) from speakers with different degrees of familiarity. We defined voice identity perception as passively listening to a voice or determining if the voice was human, voice identity recognition as determining if the sound heard was acoustically familiar, and voice identity identification as ascertaining whether a voice is associated with a name or face. Of these, voice identity perception involves processing unfamiliar voices, and voice identity recognition and identification involves processing familiar voices. According to these three definitions, we performed activation likelihood estimation (ALE) on 32 studies and revealed different brain mechanisms underlying processing of unfamiliar and familiar voice identities. The results were as follows: (1) familiar voice recognition/identification was supported by a network involving most regions in the temporal lobe, some regions in the frontal lobe, subcortical structures and regions around the marginal lobes; (2) the bilateral superior temporal gyrus was recruited for voice identity perception of an unfamiliar voice; (3) voice identity recognition/identification of familiar voices was more likely to activate the right frontal lobe than voice identity perception of unfamiliar voices, while voice identity perception of an unfamiliar voice was more likely to activate the bilateral temporal lobe and left frontal lobe; and (4) the bilateral superior temporal gyrus served as a shared neural basis of unfamiliar voice identity perception and familiar voice identity recognition/identification. In general, the results of the current study address gaps in the literature, provide clear definitions of concepts, and indicate brain mechanisms for subsequent investigations.

Comprehensive Overview of Diamide Derivatives Acting as Ryanodine Receptor Activators.

The world's hunger is continuously rising due to conflicts, climate change, pandemics (such as the recent COVID-19), and crop pests and diseases. It is widely accepted that zero hunger is impossible without using agrochemicals to control crop pests and diseases. Diamide insecticides are one of the widely used green insecticides developed in recent years and play important roles in controlling lepidopteran pests. Currently, eight diamine insecticides have been commercialized, which target the insect ryanodine receptors. This review summarizes the development and optimization processes of diamide derivatives acting as ryanodine receptor activators. The review also discusses pest resistance to diamide derivatives and possible solutions to overcome the limitations posed by the resistance. Thus, with reference to structural biology, this study provides an impetus for designing and developing diamide insecticides with improved insecticidal activities.

The prognostic value of CZT SPECT myocardial blood flow (MBF) quantification in patients with ischemia and no obstructive coronary artery disease (INOCA): a pilot study.

BACKGROUND: Despite the demonstrated adverse outcome, it is difficult to early identify the risks for patients with ischemia and no obstructive coronary artery disease (INOCA). We aimed to explore the prognostic potential of CZT SPECT in INOCA patients. METHODS: The study population consisted of a retrospective cohort of 118 INOCA patients, all of whom underwent CZT SPECT imaging and invasive coronary angiography (ICA). Dynamic data were reconstructed, and MBF was quantified using net retention model. Major adverse cardiovascular events (MACEs) were defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure, late coronary revascularization, or hospitalization for unstable angina. RESULTS: During a median follow-up of 15 months (interquartile range (IQR) 11-20), 19 (16.1%) MACEs occurred; both stress myocardial blood flow (sMBF) ([Formula: see text]) and coronary flow reserve (CFR) ([Formula: see text]) were significantly lower in the MACE group. Optimal thresholds of sMBF<3.16 and CFR<2.52 were extracted from the ROC curves, and both impaired sMBF (HR: 15.08; 95% CI 2.95-77.07; [Formula: see text]) and CFR (HR: 6.51; 95% CI 1.43-29.65; [Formula: see text]) were identified as prognostic factors for MACEs. Only sMBF<3.16 (HR: 11.20; 95% CI 2.04-61.41; [Formula: see text]) remained a robust predictor when sMBF and CFR were integrated considered. Compared with CFR, sMBF provides better prognostic model discrimination and reclassification ability (C-index improvement = 0.06, [Formula: see text]; net reclassification improvement (NRI) = 0.19; integrated discrimination improvement (IDI) = 0.10). CONCLUSION: The preliminary results demonstrated that quantitative analysis on CZT SPECT provides prognostic value for INOCA patients, which may allow the stratification for early prevention and intervention.

A dummy molecularly imprinted ratiometric fluorescence nanosensor for the sensitive detection of guanidyl-microcystins in environmental water.

An effective strategy is proposed to construct a highly sensitive ratiometric fluorescence sensing platform for microcystins (MCs) based on a dummy molecularly imprinted polymer using metformin as a template. The imprinted nanohybrids of carbon dots (CDs) combined with fluorescein isothiocyanate (FITC) are synthesized (CDs-FITC-SiO2@MIP), in which the CDs and FITC serve as assisted response signals and reference enhancement signals, respectively. Metformin can be used as a dummy template for MCs due to its partially similar molecular fragments to MCs that can form a specific recognition site cavity. MCs can simultaneously induce an obvious fluorescence quenching effect for the CDs and a reference fluorescence enhancement for FITC-SiO2, enabling ratiometric fluorescence detection of MCs. Thus, CDs-FITC-SiO2@MIP used as a signal probe has favorable sensitivity, stability, and selectivity. More importantly, a good linear relationship between the fluorescence intensity ratio (I620/450) and the concentration of MCs in the range of 0.5-500 µg L-1 is obtained with a LOD of 0.013 µg L-1 and 0.022 µg L-1 for MC-RR and MC-LR, respectively, under the optimum conditions. This method has great application potential in water quality monitoring by using CDs-FITC-SiO2@MIP as a promising candidate for monitoring MCs in complex systems.

Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance.

As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

Molecular imprinted electrochemical sensor for ovalbumin detection based on boronate affinity and signal amplification approach.

Ovalbumin (OVA), a class of glycoproteins, is the main allergen in hen egg white that often causes allergies in humans, especially in babies. Therefore, it is pivotal to be able to detect and separate OVA. This work presents an ingenious sandwich-structured magnetic molecular imprinted electrochemical sensor for OVA detection by utilizing boronate affinity and signal amplification strategy. With anti-OVA antibody-modified gold nanoparticles (AuNPs) as amplifiers, the imprinted cavities in the probe could capture protein to form a sandwich structure. Due to its specific recognition of antibody and molecular imprinted polymers and the signal amplification of AuNPs, the sensor had good selectivity and sensitivity toward OVA and a low detection limit of 3.0 fg/mL. The sensor also had excellent stability and could satisfactorily detect OVA in real red wine samples.

Investigating cognitive flexibility deficit in schizophrenia using task-based whole-brain functional connectivity.

Background: Cognitive flexibility is a core cognitive control function supported by the brain networks of the whole-brain. Schizophrenic patients show deficits in cognitive flexibility in conditions such as task-switching. A large number of neuroimaging studies have revealed abnormalities in local brain activations associated with deficits in cognitive flexibility in schizophrenia, but the relationship between impaired cognitive flexibility and the whole-brain functional connectivity (FC) pattern is unclear. Method: We investigated the task-based functional connectivity of the whole-brain in patients with schizophrenia and healthy controls during task-switching. Multivariate pattern analysis (MVPA) was utilized to investigate whether the FC pattern can be used as a feature to discriminate schizophrenia patients from healthy controls. Graph theory analysis was further used to quantify the degrees of integration and segregation in the whole-brain networks to interpret the different reconfiguration patterns of brain networks in schizophrenia patients and healthy controls. Results: The results showed that the FC pattern classified schizophrenia patients and healthy controls with significant accuracy. Moreover, the altered whole-brain functional connectivity pattern was driven by a lower degree of network integration and segregation in schizophrenia, indicating that both global and local information transfers at the entire-network level were less efficient in schizophrenia patients than in healthy controls during task-switching processing. Conclusion: These results investigated the group differences in FC profiles during task-switching and not only elucidated that FC patterns are changed in schizophrenic patients, suggesting that task-based FC could be used as a potential neuromarker to discriminate schizophrenia patients from healthy controls in cognitive flexibility but also provide increased insight into the brain network organization that may contribute to impaired cognitive flexibility.

Task switching involves working memory: Evidence from neural representation.

It is generally assumed that task switching involves working memory, yet some behavioral studies question the relationship between working memory and task switching ability. This debate can be resolved by directly comparing the brain activity pattern in task switching and working memory processes. If the task switching involves working memory, the neural activity patterns evoked by such two tasks would exhibit higher similarity. Here, we employed the task switching task and working memory to investigate the characteristic of the neural representation in such two cognitive processes. A conjunction analysis showed that the bilateral superior parietal lobule (SPL), bilateral insula, bilateral middle frontal gyrus (MFG), bilateral dorsal lateral prefrontal cortex (DLPFC) and pre-supplementary motor area (pre-SMA) were commonly and significantly activated in both task switching and working memory task. Critically, we found that task switching and working memory processing elicited similar activity patterns in bilateral SPL, right insula, left MFG, left DLPFC and pre-SMA, consistent with common neural processes for both tasks. These results not only suggest that the task switching process involves working memory from the perspective of neural representation, but also provide major new insights into the neurocognitive links between task switching and working memory.

Investigating the Neural Bases of Risky Decision Making Using Multi-Voxel Pattern Analysis.

Choices between smaller certain reward and larger riskier reward are referred to as risky decision making. Numerous functional magnetic resonance imaging (fMRI) studies have investigated the neural substrates of risky decision making via conventional univariate analytical approaches, revealing dissociable activation of decisions involving certain rewards and risky rewards. However, it is still unclear how the patterns of brain activity predict the choice that the individual will make. With the help of multi-voxel pattern analyses, which is more sensitive for evaluating information encoded in spatially distributed patterns, we showed that fMRI activity patterns represent viable signatures of certain and risky choice and individual differences. Notably, the regions involved in representation of value and risk and cognitive control play prominent roles in differentiating certain and risky choices as well as individuals with distinct risk preference. These results deepen our understanding of the neural correlates of risky decision making as well as emphasize the important roles of regions involved in representation of value and risk cognitive control in predicting risky decision making and individual differences.