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In the originally published version of this manuscript em dashes were inadvertently added in place of short dashes and spaces, particularly in the canonical name of the database being described. In addition to this changes have also been made to the formatting of Table 1 to aid understanding. No changes have been made to the content. These errors, for which the publisher apologizes, have been corrected.

N 6 -methyladenosine (m 6 A) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for m 6 A and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5. Herein, we designed and synthesized the ALKBH5 covalent inhibitor DDO-02267 by analyzing the protein structure of ALKBH5 and introducing salicylaldehyde warhead into noncovalent small molecule ligand. DDO-02267 specifically targeted Lys132 within ALKBH5, demonstrating significant selectivity for ALKBH5 in vitro. Additionally, DDO-02267 increased m 6 A levels and targeted the ALKBH5-AXL signaling axis in AML cells. The compound DDO-02267 can serve as a probe for investigating the biological function of mRNA demethylase and may inspire the development of future ALKBH5 inhibitors., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Whether working memory (WM) is encoded by persistent activity using attractors or by dynamic activity using transient trajectories has been debated for decades in both experimental and modeling studies, and a consensus has not been reached. Even though many recurrent neural networks (RNNs) have been proposed to simulate WM, most networks are designed to match respective experimental observations and show either transient or persistent activities. Those few which consider networks with both activity patterns have not attempted to directly compare their memory capabilities. In this study, we build transient-trajectory-based RNNs (TRNNs) and compare them to vanilla RNNs with more persistent activities. The TRNN incorporates biologically plausible modifications, including self-inhibition, sparse connection and hierarchical topology. Besides activity patterns resembling animal recordings and retained versatility to variable encoding time, TRNNs show better performance in delayed choice and spatial memory reinforcement learning tasks. Therefore, this study provides evidence supporting the transient activity theory to explain the WM mechanism from the model designing point of view., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Ketamine is a dissociative drug used for the treatment of depression. However, the neurofunctional mechanism underlying the antidepressant effect of ketamine remains unknown. According to previous research, low-dose ketamine affects large-scale brain networks, including default-mode and salient networks., Methods: A total of 43 patients with treatment-resistant depression (TRD) and suicidal ideation (SI) were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Depressive and suicidal symptoms were evaluated using the 17-item Hamilton Depression Rating Scale and the Columbia-Suicide Severity Rating Scale: Ideation Severity Subscale. Resting-state functional magnetic resonance imaging was performed at baseline and on day 3 after infusion. Graph theoretic metrics such as degree centrality and clustering coefficient were examined., Results: Relative to midazolam use, low-dose ketamine infusion reduced depressive (p = 0.001) and suicidal (p = 0.025) symptoms and improved the brain network integrity, including increased degree centrality and clustering coefficient in the angular gyrus and increased degree centrality in the right thalamus., Discussion: Neurofunctional changes in the thalamus and default-mode network (angular gyrus) may be associated with the antidepressant effect of ketamine on patients with TRD and SI., Clinical Trials Registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000033916., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2025. Published by Elsevier B.V.)

Recombinant adeno-associated virus (rAAV) has emerged as the vector of choice for in vivo gene delivery, with numerous clinical trials underway for the treatment of various human diseases. Utilizing rAAV in gene therapy requires a highly precise quantification method to determine the viral genome titer and further establish the optimal therapeutic dosage for a rAAV product. The conventional single-channel droplet digital PCR (1D ddPCR) method offers only partial information regarding the viral vector genome titer, lacking insights into its integrity. In our pursuit of further advancing rAAV analysis, we have developed a novel 3D ddPCR assay with advanced 3D linkage analysis. We have designed the three amplicon sites targeting both ends of the viral genome, as well as the center of key therapeutic gene of interest (GOI). This study aims to offer a more comprehensive and insightful assessment of rAAV products which includes not only quantity of viral genome titer but also the quality, distinguishing between partial ones and intact full-length viral genomes with the right GOI. Importantly, due to the random partitioning property of a digital PCR system, the 3D linkage analysis of rAAV viral genome requires a proper mathematical model to identify the true linked DNA molecules (full-length/intact DNA) from the population of false/unlinked DNA molecules (fragmented/partial DNA). We therefore have developed an AAV 3D linkage analysis workflow to characterize genomic integrity and intact titer for rAAV gene therapy products. In this study, we focus on evaluating our 3D linkage mathematical model by performing DNA mixing experiments and a case study using multiple rAAV samples. Particularly, we rigorously tested our algorithms by conducting experiments involving the mixing of seven DNA fragments to represent various AAV viral genome populations, including 3 single partials, 3 double partials, and 1 full-length genomes. Across all 37 tested scenarios, we validated the accuracy of our workflow's output for the percentages of 3D linkage by comparing to the known percentages of input DNA. Consequently, our comprehensive AAV analytical package not only offers insights into viral genome titer but also provides valuable information on its integrity and identity. This cost-effective approach, akin to the setup of traditional 1D or 2D dPCR, holds the potential to advance the application of rAAV in cell and gene therapy for the treatment of human diseases., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. Lonza Houston Inc., 2024.)

The application of temperature-compensated photonic device is hampered by poor accuracy and overly simplistic functions of propagation in photonic integrated circuits (PICs) field. Herein, we report a new library of donor-acceptor metal-organic framework (D-A MOF) with thermally activated delayed fluorescence (TADF) and the fabricating of temperature-compensated photonic device by virtue of the unique temperature response character of TADF emitters. Highly tunable through-space charge transfer (TSCT) of TADF was realized within the D-A MOFs through a novel strategy that synergistically combines the internal heavy atom effect (HAE) with an external HAE, induced by the incorporation of heavy atoms into different components, achieving the regulable photophysical indicators including adjustable PL wavelength (534 to 592 nm) and surging quantum yield (5.02 %-47.39 %). Further investigation of the impact of external HAE on TADF was conducted through crystal structures and Hirshfeld surface plots of four D-A regimes featuring substituent-based linkers. Notably, temperature-compensated photonic device based on heterocrystal was fabricated through integrating D-A MOFs with contrary temperature response. The emission signal output of the heterojunction remained nearly stable in 215 K to 295 K range, highlighting the promising potential application of TADF D-A MOF featuring sensitive temperature response in PICs field., (© 2025 Wiley-VCH GmbH.)

The Genomes OnLine Database (GOLD; https://gold.jgi.doe.gov/) at the Department of Energy Joint Genome Institute is a comprehensive online metadata repository designed to catalog and manage information related to (meta)genomic sequence projects. GOLD provides a centralized platform where researchers can access a wide array of metadata from its four organization levels namely Study, Organism/Biosample, Sequencing Project and Analysis Project. GOLD continues to serve as a valuable resource and has seen significant growth and expansion since its inception in 1997. With its expanded role as a collaborative platform, it not only actively imports data from other primary repositories like National Center for Biotechnology Information but also supports contributions from researchers worldwide. This collaborative approach has enriched the database with diverse datasets, creating a more integrated resource to enhance scientific insights. As genomic research becomes increasingly integral to various scientific disciplines, more researchers and institutions are turning to GOLD for their metadata needs. To meet this growing demand, GOLD has expanded by adding diverse metadata fields, intuitive features, advanced search capabilities and enhanced data visualization tools, making it easier for users to find and interpret relevant information. This manuscript provides an update and highlights the new features introduced over the last 2 years., (Published by Oxford University Press on behalf of Nucleic Acids Research 2024.)

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: This study was performed in accordance with the Declaration of Helsinki and was approved by the Taipei Veterans General Hospital Institutional Review Board. Informed consent was provided by all of the participants., (© 2024. The Author(s).)

Aim: Bipolar disorder (BD) and major depression have been associated with an increased risk of developing Parkinson's disease (PD); however, few studies have directly compared the risk of PD development between patients with BD and major depression while considering relevant risk factors and psychotropic medications., Methods: Using the Taiwan National Health Insurance Research Database, 21,186 patients with BD, 21,188 patients with major depression, and 42,374 controls were enrolled between 2001 and 2009, and followed until the end of 2011. Individuals who developed PD during the follow-up period were identified. Cox regression models were used to analyze the hazard ratio (HR) of developing PD, adjusting for demographic factors, comorbidities, and psychotropic medication usage., Results: Both patients with BD [HR 8.63, 95% confidence interval (CI) 6.35-11.72] and those with major depression (HR 5.68, 95% CI 4.15-7.78) had an elevated risk of subsequent PD compared to the controls. Patients with BD were associated with a 51% increased risk of subsequent PD compared with patients with major depression. Long-term treatment with antiepileptic mood stabilizers was associated with increased PD risk among patients with late-onset BD and high Charlson comorbidity index scores. Lithium was not associated with an increased PD risk., Conclusions: The study highlights an elevated PD risk in patients with BD and major depression compared to the controls, with BD patients at highest risk. Further research is needed to elucidate the complex interplay between psychotropic medications and neurodegenerative processes in BD, aiming to optimize therapeutic strategies and improve patient outcomes., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Low-grade inflammation (LGI) contributes to resistance against traditional antidepressants. However, whether the antidepressant and antisuicidal effects of ketamine on patients with treatment-resistant depression (TRD) differ between those with LGI and those without LGI remains unknown.This study included 167 patients with TRD, among whom 46 had LGI and 121 did not have LGI. The patients received a single infusion of either low-dose ketamine or a placebo. A C-reactive protein level of≥3 mg/L indicated LGI. Depressive symptoms were measured from baseline to day 3 by using the 17-item Hamilton Depression Rating Scale (HDRS) and the Montgomery-Asberg Depression Rating Scale (MADRS).Generalized estimating equation models revealed antidepressant effect of ketamine in patients with no LGI (HDRS scores: p <0.001; MADRS scores: p <0.001) but not in patients with LGI (all p >0.05). The antisuicidal effect of ketamine (indicated by the score on item 10 of the MADRS) was observed in both groups of patients with ( p =0.046) and without LGI ( p <0.001). However, ketamine was effective for TRD regardless of whether inflammation levels were high or low, while the placebo response was notably greater only in patients with LGI.This study suggests that among patients with TRD, only those without LGI respond to low-dose ketamine infusion. Whether the negative findings of the antidepressant effect of ketamine among patients with LGI may be because of the effect of the placebo infusion needs further investigation. Further randomized, placebo-controlled studies are needed to validate these findings., Competing Interests: The authors in this study had no conflict of interest to declare., (Thieme. All rights reserved.)

In the category of drugs approved by the U.S. FDA, pyrrolidine is the most frequently used core of five-membered nonaromatic heterocycles containing nitrogen. Herein, a Rh(II)/Pd(0) dual-catalyzed carbenoid N-H insertion/allylation cascade reaction has been developed. This protocol provide an efficient approach for the construction of diverse highly functionalized and polysubstituted pyrrolidines in high yields (up to 91%) with excellent chemoselectivities and high diastereoselectivities (>20:1) under mild reaction conditions.

Objective: Risk estimation of intracranial aneurysm rupture is critical in determining treatment strategy. There is a scarcity of multicenter studies on the predictive power of clinical-radiomics models for aneurysm rupture. This study aims to develop a clinical-radiomics model and explore its additional value in the discrimination of aneurysm rupture., Methods: A total of 516 aneurysms, including 273 (52.9%) with ruptured aneurysms, were retrospectively enrolled from four hospitals between January 2019 and August 2020. Relevant clinical features were collected, and radiomic characteristics associated with aneurysm were extracted. Subsequently, three models, including a clinical model, a radiomics model, and a clinical-radiomics model were constructed using multivariate logistic regression analysis to effectively classify aneurysm rupture. The performance of models was analyzed through operating characteristic curves, decision curve, and calibration curves analysis. Different models' comparison used DeLong tests. To offer an understandable and intuitive scoring system for assessing rupture risk, we developed a comprehensive nomogram based on the developed model., Results: Three clinical risk factors and fourteen radiomics features were explored to establish three models. The area under the receiver operating curve (AUC) for the radiomics model was 0.775 (95% CI,0.719-0.830), 0.752 (95% CI,0.663-0.841), 0.747 (95% CI,0.658-0.835) in the training, internal and external test datasets, respectively. The AUC for clinical model was 0.802 (95% CI, 0.749-0.854), 0.736 (95% CI, 0.644-0.828), 0.789 (95% CI, 0.709-0.870) in these three sets, respectively. The clinical-radiomics model showed an AUC of 0.880 (95% CI,0.840-0.920), 0.807 (95% CI,0.728-0.887), 0.815 (95% CI,0.740-0.891) in three datasets respectively. Compared with the radiomics and clinical models, the clinical-radiomics model demonstrated better diagnostic performance (DeLong' test P < 0.05)., Conclusion: The clinical-radiomics model represents a promising approach for predicting rupture of intracranial aneurysms., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Jia et al.)

Rainwater flowing along the ground, and from hard surface such as pavement and roofs, becomes surface water runoff, which flows to surface waters, and infiltrates into the ground to become groundwater. Surface water runoff can contain elevated levels of nitrates (NO 3 - ) from various sources including animal wastes and fertilizers. Reducing elevated levels of NO 3 - in surface water runoff can minimize and/or prevent groundwater and surface water contamination. Natural polyphenols in carpet grass, due to phenolic hydroxyl groups, can degrade aqueous NO 3 - . This study evaluated the potential for carpet grass to purify water by denitrifying NO 3 - as surface water flows through grass-covered land. The research investigated nitrate removal efficiency and reaction kinetics under various flow rates and doses of carpet grass, validating the feasibility of using natural polyphenols for water purification. A grass dose of 100 g and a retention time of 24 h, which produced approximately 20-80 mg/L as gallic acid equivalent (GAE) of polyphenol in simulated surface water runoff, were demonstrated to effectively degrade NO 3 - in aqueous solution (110 mg/L) and result in the denitrification of NO 3 - to nitrite (NO 2 - ) and eventually N 2 . The first-order reaction kinetic rate constants for NO 3 - degradation, NO 2 - formation, and subsequent degradation of NO 2 - are k obs (NO3-degradation) = 6.89 × 10 -2 h -1 , k 1(NO2-formation) = 5.11 × 10 -2 h -1 , and k 2(NO2-degradation) = 4.63 × 10 -2 h -1 , respectively, with a conversion rate (α) of NO 3 - to NO 2 - to be 0.74. Implementing natural vegetation, such as carpet grass, in water management practices offers an environmentally sustainable approach to reducing nitrate contamination in surface water runoff., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The synthetical methodology for the [Cu(dmp) 2 ] 2+/1+ (dmp = 2,9-dimethyl-1,10-phenanthroline; neocuproine) complexes has been systematically investigated by using various copper precursors, including CuCl 2 , Cu(NO 3 ) 2 , and Cu(ClO 4 ) 2 . After an anion exchange to trifluoromethanesulfonimide (TFSI), the tetra-coordinated Cu II (dmp) 2 (TFSI) 2 -Cu(ClO 4 ) 2 (7.43%) outperformed the penta-coordinated Cu II (dmp) 2 (TFSI)(NO 3 )-Cu(NO 3 ) 2 (4.30%) and Cu II (dmp) 2 (TFSI)(Cl)-CuCl 2 . Polymeric chalcogenides, including a conducting copolymeric electrode of PEDOT-PEDTT [PEDOT = poly(3,4-ethylenedioxythiophene); PEDTT = poly(3,4-ethylenedithiothiophene)] and a coordination polymeric electrode of silver bezeneselenolate ([Ag 2 (SePh) 2 ] n ; mithrene), are introduced as the electrocatalysts for [Cu(dmp) 2 ] 2+/1+ for the first time. After optimization, dye-sensitized solar cells (DSSCs) based on carbon cloth (CC)/AgSePh-30 (10.18%) showed superior electrocatalytic ability compared to the benchmark CC/Pt (7.43%) due to numerous active sites provided by electron-donating Se atoms, high film roughness, and bottom-up 2D charge transfer routes. The DSSC based on CC/PEDTT-50 (10.38%) also outperformed CC/Pt due to numerous active sites provided by electron-donating S atoms and proper energy band structure. This work sheds light on the future design and synthesis in Cu-complex mediators and functional polymeric chalcogenides for high-performance DSSCs.

Colorectal cancer (CRC) is a common cancer worldwide with an increasing annual incidence. Cancer stem cells (CSCs) play important roles in the occurrence, development, recurrence, and metastasis of CRC. The molecular mechanism regulating the development of colorectal CSCs remains unclear. The discovery of human induced pluripotent stem cells (hiPSCs) through somatic cell reprogramming has revolutionized the fields of stem cell biology and translational medicine. In the present study, we converted hiPSCs into cancer stem-like cells by culture with conditioned medium (CM) from CRC cells. These transformed cells, termed hiPSC-CSCs, displayed cancer stem-like properties, including a spheroid morphology and the expression of both pluripotency and CSC markers. HiPSC-CSCs showed tumorigenic and metastatic abilities in mouse models. The epithelial-mesenchymal transition phenotype was observed in hiPSC-CSCs, which promoted their migration and angiogenesis. Interestingly, upregulation of C-MYC was observed during the differentiation of hiPSC-CSCs. Mechanistically, CREB binding protein (CBP) bound to the C-MYC promoter, while histone deacetylase 1 and 3 (HDAC1/3) dissociated from the promoter, ultimately leading to an increase in histone acetylation and C-MYC transcriptional activation during the differentiation of hiPSC-CSCs. Pharmacological treatment with a CBP inhibitor or abrogation of CBP expression with a CRISPR/Cas9-based strategy reduced the stemness of hiPSC-CSCs. This study demonstrates for the first time that colorectal CSCs can be generated from hiPSCs. The upregulation of C-MYC via histone acetylation plays a crucial role during the conversion process. Inhibition of CBP is a potential strategy for attenuating the stemness of colorectal CSCs., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The authors declare that all methods were performed in accordance with the relevant guidelines and regulations. The procedures for collecting human blood samples were approved by the Institutional Review Board of the National Taiwan University Hospital. Signed informed consent was obtained from all participants. Additionally, the authors have obtained written informed consent for publication of the images., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Sarcomyxa edulis, a notable edible and medicinal mushroom indigenous to northeast China, is celebrated for its high nutritional value and delightful taste. In this study, white light as a control and examined the effects of red, green, and blue light on the agronomic traits, antioxidant capabilities, and nutritional composition of S. edulis. The results showed that different monochromatic light qualities affected the color of S. edulis pileus, with blue light demonstrating particular efficacy. Furthermore, blue light also regulated pileus length, whereas red light was instrumental in significantly increasing stalk length. Regarding antioxidant capacity, compared with red and green light, the activities of POD, SOD, and CAT were significantly improved by blue light irradiation, decreased MDA levels, and improved free radical scavenging potential. Additionally, blue light exposure led to an increase in the contents of 15 amino acids. Green light treatment reduced the crude fat content. For the first time, we found that light quality is a key factor in controlling the color of S. edulis. Blue light is an effective way to regulate the color and pileus size of S. edulis, and improve the antioxidant properties. The photobiological characteristics and the response of nutritional quality to light environment of S. edulis were clarified., (© 2024. The Author(s).)

Purpose: Mutations in ARID1A frequently occur in colorectal cancer (CRC) cells. However, there are currently no clinical treatment options specifically addressing this aberration. The preliminary in vitro experiments revealed a synthetic lethal interaction between ARID1A and Aurora kinase A (AURKA) in colorectal cancer (CRC) cells., Methods: We collected samples from 80 CRC patients and evaluated the efficacy of AURKA inhibitor (AURKAi) using the ATP-tumor chemosensitivity assay (ATP-TCA) on untreated ARID1A-proficient (ARID1A +) and ARID1A-deficient (ARID1A-) CRC patient samples. In addition, we validated this result by a clonogenic assay. Additionally, we examined the effects of AURKA inhibitors on cell cycle progression and apoptosis in ARID1A + and ARID1A- CRC patient samples using flow cytometry., Results: The results showed that AURKAi selectively inhibited the growth of ARID1A- CRC cells. Furthermore, AURKA inhibitors significantly increased G2/M arrest and induced apoptosis in ARID1A- cells., Conclusion: We believe that AURKAi hold promise as potential therapeutics for ARID1A mutation colorectal cancer patients., (© 2024. The Author(s).)

Study Objectives: This study aimed to explore the relationship between post-illumination pupillary response (PIPR) with sleep and circadian measures in a community sample of healthy older adults., Methods: Eligible participants were invited to complete a one-week sleep diary, actigraphy and provide an overnight urine sample to measure urinary 6-sulfatoxymelatonin (aMT6s). PIPR was defined as the as the pupil constriction at 6s post-stimulus (PIPR-6s), and ii) for 30s beginning 10s after stimulus (PIPR-30s) normalized as a percentage to the baseline pupil diameter, after 1s of blue and 1s of red-light stimulus, respectively. The Net-PIPRs were reported by subtracting the PIPR to red stimulus from the PIPR to blue stimulus. The relationship between PIPR metrics to aMT6s and actigraphic rest-activity rhythm parameters was examined by generalized linear models., Results: A total of 48 participants were recruited (Mean age: 62.6 ± 7.1 years, Male: 44%). Both Net PIPR-6s and Net PIPR-30s were significantly associated with actigraphic rest-activity amplitude (B=0.03, p=0.001 and B=0.03, p=0.01, respectively), and actigraphic rest-activity mesor (B=0.02, p=0.001 and B=0.03, p=0.004, respectively). Additionally, the Net PIPR-30s were positively associated with overnight aMT6s level (B=0.04, p=0.03), and negatively associated with actigraphic rest-activity acrophase (B=-0.01, p=0.004) in the fully adjusted models., Conclusion: Attenuated PIPR is associated with a reduced actigraphic amplitude and mesor. The reduced retinal light responsivity may be a potential pathway contributing to impaired photic input to the circadian clock and resulted in the age-related circadian changes in older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Thalamocortical connectivity is associated with cognitive and affective processing. The role of thalamocortical connectivity in the pathomechanism of treatment-resistant depression (TRD) remains unclear. This study included 48 patients with TRD and 48 healthy individuals. We investigated thalamocortical connectivity by performing resting-state functional MRI with the bilateral thalamus as the seed. In addition, patients with TRD were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS). Compared with the healthy individuals, the patients with TRD exhibited increased functional connectivity (FC) of the thalamus with the insula and superior temporal cortex and reduced the FC of the thalamus with the anterior paracingulate cortex and cerebellum crus II. Our study may support the crucial role of thalamocortical dysconnectivity in the TRD pathomechanism. However, the small sample size may limit the statistical power. A future study with a large sample size of patients with TRD would be required to validate our findings., (© 2024 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Background: The right inferior frontal gyrus (RIFG) is a potential beneficial brain stimulation target for autism. This randomized, double-blind, two-arm, parallel-group, sham-controlled clinical trial assessed the efficacy of intermittent theta burst stimulation (iTBS) over the RIFG in reducing autistic symptoms (NCT04987749)., Methods: Conducted at a single medical center, the trial enrolled 60 intellectually able autistic individuals (aged 8-30 years; 30 active iTBS). The intervention comprised 16 sessions (two stimulations per week for eight weeks) of neuro-navigated iTBS or sham over the RIFG. Fifty-seven participants (28 active) completed the intervention and assessments at Week 8 (the primary endpoint) and follow-up at Week 12., Results: Autistic symptoms (primary outcome) based on the Social Responsiveness Scale decreased in both groups (significant time effect), but there was no significant difference between groups (null time-by-treatment interaction). Likewise, there was no significant between-group difference in changes in repetitive behaviors and exploratory outcomes of adaptive function and emotion dysregulation. Changes in social cognition (secondary outcome) differed between groups in feeling scores on the Frith-Happe Animations (Week 8, p = 0.026; Week 12, p = 0.025). Post-hoc analysis showed that the active group improved better on this social cognition than the sham group. Dropout rates did not vary between groups; the most common adverse event in both groups was local pain. Notably, our findings would not survive stringent multiple comparison corrections., Conclusions: Our findings suggest that iTBS over the RIFG is not different from sham in reducing autistic symptoms and emotion dysregulation. Nonetheless, RIFG iTBS may improve social cognition of mentalizing others' feelings in autistic individuals.

Recent studies have identified a correlation between chronic viral hepatitis and cognitive impairment, yet the underlying mechanisms remain unclear. This study investigated the influence of TGFB1 genetic polymorphisms on cognitive function in individuals with and without hepatitis infections, hypothesizing that these polymorphisms and the viral hepatitis-induced inflammatory environment interact to affect cognitive abilities. Participants (173 with viral hepatitis and 258 healthy controls) were recruited. Genotyping of TGFB1 SNPs was performed using the C2-58 Axiom Genome-Wide TWB 2.0 Array Plate. Cognitive function was assessed using the MMSE and MoCA tests. Our results showed that healthy individuals carrying the C allele of rs2241715 displayed better performance in sentence writing (p = 0.020) and language tasks (p = 0.022). Notably, viral hepatitis was found to moderate the impact of the rs2241715 genotype on language function (p = 0.002). Similarly, those carrying the T allele of rs10417924 demonstrated superior orientation to time (p = 0.002), with viral hepatitis modifying the influence of the SNP on this particular cognitive function (p = 0.010). Our findings underscore the significant role of TGFβ1 in cognitive function and the moderating impact of viral hepatitis on TGFB1 SNP effects. These findings illuminate the potential of TGFB1 as a therapeutic target for cognitive impairment induced by viral hepatitis, thus broadening our understanding of TGFβ1 functionality in the pathogenesis of neurodegeneration., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Objectives: To establish the identification method of tumor tissue origin based on commonly used STR typing kits., Methods: ForenSeq TM DNA Signature Prep kit was used to detect the typing of 27 autosomal STR loci in 55 paired tumor tissue samples (tumor tissue paired with normal tissue of the same individual) and 75 unrelated individual whole blood samples. The genotyping data of full sibling pairs and parent-child pairs of 55 tumor tissues were simulated. The number of total identical alleles ( A n ) and identity by state (IBS) scores were calculated within the paired carcinoma (PC), the tumor-unrelated individual (UI), the tumor-simulated full sibling (FS) and the tumor-simulated parent-offspring (PO) groups. The tumor tissue origin identification and prediction models of 8 commonly used STR typing kits were established based on the statistical results obtained above, and an attempt was made to establish a specific model for tumor tissue origin identification. The accuracy, sensitivity and specificity were verified and evaluated using the additional 23 paired tumor tissue samples., Results: (1) In any kit, there was no statistically significant difference in the number of loci shared with 0 identical allele ( A 0 ) between the PC and PO groups. The number of loci shared with 1 identical allele ( A 1 ), 2 identical alleles ( A 2 ), and IBS scores were statistically significant different between the PC group and the UI, FS and PO groups. (2) The A n and IBS scores of different STRs varied in different groups. The A 2 levels of 13 STRs ( CSF1PO , D12S391 , D19S433 , D20S482 , D2S1338 , D3S1358 , D4S2408 , D7S820 , D8S1179 , FGA , TH01 , TPOX , vWA ) in PC group were higher than those of other STR loci. The A 2 levels of two STRs ( D6S1043 , Penta E ) in UI group were significantly lower than those of other STR loci. (3) The tumor tissue origin identification and prediction models of 8 commonly used STR typing kits and the identification model of tumor tissue origin with 15 STR loci (15-STRs) were successfully established, with sensitivity of 100%, specificity of 97.56%-99.88%, and accuracy of 97.59%-99.89%. Among them, the 15-STRs model had 100% sensitivity, 99.88% specificity, and 99.89% accuracy, which were higher than those of commonly used commercial kits., Conclusions: This study successfully establishes the tumor tissue origin identification methods with 8 commonly used STR typing kits, which expands the application of tumor tissue origin identification. In addition, the differences of different loci in the identification of tumor tissue origin were compared, and 15 STR loci which were particularly suitable for the identification of tumor tissue origin were selected, providing the data basis for the establishment of tumor origin tracing kits in future.

Background: Low-dose ketamine infusion has been demonstrated to exert antisuicidal effects on patients with treatment-resistant depression (TRD) and strong suicidal ideation. Although evidence suggests an association between hopelessness and suicidality, very few studies have investigated the antihopelessness effects of ketamine., Methods: This study included 84 patients with TRD and strong suicidal ideation. The diagnosis of depression was based on the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition, diagnostic criteria for major depressive disorder. They were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Hopelessness and suicidal symptoms were assessed at baseline, at 240 minutes postinfusion, and on Days 2, 3, 7, and 14 postinfusion. The assessments were performed using the self-report Beck Hopelessness Scale (BHS) and Positive and Negative Suicide Ideation Inventory (PANSI). The analysis focused on the positive and negative domains of the BHS and PANSI, respectively. The clinical trial was conducted between August 15, 2018, and November 30, 2021., Results: Statistical analyses performed using a generalized linear model revealed that the ketamine group had significantly higher PANSI-positive ( P = .008) and lower PANSI-negative ( P = .015) suicidal ideation scores on Day 2 postinfusion than did the midazolam group. At 240 minutes postinfusion, the ketamine group had significantly lower BHS-negative domain scores than did the midazolam group ( P = .031). Notably, the observed ketamine-induced reduction in hopelessness at 240 minutes postinfusion was associated with its antisuicidal effect on Day 2 postinfusion., Discussion: A single infusion of low-dose ketamine resulted in a brief (∼4 hours) yet significant reduction in hopelessness. Subjective antisuicidal effects of ketamine were noted on Day 2 postinfusion. Further studies are needed to elucidate the neuromechanisms underlying the antihopelessness and antisuicidal effects of ketamine., Trial Registration: UMIN Clinical Trials Registry identifiers: UMIN000033916 and UMIN000033760., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Introduction: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management., Methods: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason)., Results: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity., Conclusions: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms., Trial Registration: PROSPERO CRD42023391562., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes., Objective: To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data., Design, Setting, and Participants: This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship., Main Outcomes and Measures: Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality., Results: This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings., Conclusions and Relevance: To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

Objectives: To establish a rapid, accurate, and sensitive multiplex PCR detection method for the simultaneous identification of the six common edible meats (beef, lamp, chicken, pork, goose, duck), and to evaluate its application value in meat adulteration identification., Methods: Based on complete mitochondrial genomic sequences of six species in the GenBank database, DNA sequences (cattle： 16S rRNA ; sheep： COX-1 ; chickens： Cytb ; pig： COX-1 ; goose： NADH2 ; duck： 16S rRNA ) with intra-species conservation and inter-species specificity were screened, and species-specific primers were designed to construct a multiplex PCR detection system that can simultaneously detect the meat of six common species. The species specificity, sensitivity and reproducibility of the system were studied, and the simulated mixture sample detection was performed., Results: This study successfully constructed a multiplex PCR detection system that can detect the meats of six common species simultaneously. The system was not effective in DNA amplification of non-target species. When the DNA template sizes were 0.062 5-2 ng/μL, the amplified products of all six species could be detected. The duck component was still detected when the mixing ratio of duck and beef was as low as 0.5%., Conclusions: This study constructs and establishes a multiplex PCR detection system with strong specificity, high sensitivity, and good reproducibility. It can accurately identify the components of animal origin in common edible meats and provide a simple and practical method for identifying adulteration of common edible meats and meat products in China.

Time series forecasting is an essential tool across numerous domains, yet traditional models often falter when faced with unilateral boundary conditions, where data is systematically overestimated or underestimated. This paper introduces a novel approach to the task of unilateral boundary time series forecasting. Our research bridges the gap in existing methods by proposing a specialized framework to accurately forecast within these skewed datasets. The cornerstone of our approach is the unilateral mean square error (UMSE), an asymmetric loss function that strategically addresses underestimation biases in training data, improving the precision of forecasts. We further enhance model performance through the implementation of a dual model structure that processes underestimated and accurately estimated data points separately, allowing for a nuanced analysis of the data trends. Additionally, feature reconstruction is employed to recapture obscured dynamics, ensuring a comprehensive understanding of the data. We demonstrate the effectiveness of our methods through extensive experimentation with LightGBM and GRU models across diverse datasets, showcasing superior accuracy and robustness in comparison to traditional models and existing methods. Our findings not only validate the efficacy of our approach but also reveal its model-independence and broad applicability. This work lays the groundwork for future research in this domain, opening new avenues for sophisticated analytical models in various industries where precise time series forecasting is crucial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chang, Li and Lin.)

Purpose: Bone metastasis (BoM) has been closely associated with increased morbidity and poor survival outcomes in patients with non-small cell lung cancer (NSCLC). Given its significant implications, this study aimed to systematically compare the biological characteristics between advanced NSCLC patients with and without BoM. Methods: In this study, the genomic alterations from the tumor tissue DNA of 42 advanced NSCLC patients without BoM and 67 patients with BoM and were analyzed by a next-generation sequencing (NGS) panel. The serum concentrations of 18 heavy metals were detected by inductively coupled plasma emission spectrometry (ICP-MS). Results: A total of 157 somatic mutations across 18 mutated genes and 105 somatic mutations spanning 16 mutant genes were identified in 61 out of 67 (91.05%) patients with BoM and 37 of 42 (88.10%) patients without BoM, respectively. Among these mutated genes, NTRK1 , FGFR1 , ERBB4 , NTRK3 , and FGFR2 stood out exclusively in patients with BoM, whereas BRAF , GNAS , and AKT1 manifested solely in those without BoM. Moreover, both co-occurring sets of genes and mutually exclusive sets of genes in patients with BoM were different from those in patients without BoM. In addition, the serum concentrations of Cu and Sr in patients with BoM were significantly higher than in patients without BoM. One of our aims was to explore how these heavy metals associated with BoM interacted with other heavy metals, and significant positive correlations were observed between Cu and Co, between Cu and Cr, between Sr and Ba, and between Sr and Ni in patients with BoM. Given the significant impacts of molecular characteristics on patients' prognosis, we also observed a noteworthy negative correlation between EGFR mutations and Co, alongside a significant positive correlation between TP53 mutations and Cd. Conclusions: The genomic alterations, somatic interactions, key signaling pathways, functional biological information, and accumulations of serum heavy metals were markedly different between advanced NSCLC patients with and without BoM, and certain heavy metals (e.g., Cu, Sr) might have potentials to identify high-risk patients with BoM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

According to the theory of five movements and six climates, the innate constitution plays a crucial role in determining the underlyingpa thological mechanisms of diseases later in life. Previous studies have demonstrated a close association between the constitution, as defined by the theory of five movements and six climates, and the development of various types of tumors. Furt hermore,the tumorsubtype determined by the constitution has prognostic implications. This highlights the potential of utilizing the fivemovements and six climates theory to guide the implementation of precision medicine strategies in thefield of oncology. However, no resear ch has yet been conducted to investigate the use of this theory in guiding the development of tumor molecular classification and precisi onmedicine strategies. The objective of this research is to uncover the biological characteristics of each constitution within a pancanc ercohort and identify potential anti-tumor drugs that are applicable to patients with different constitutional types. By doing so, we aimto c ontribute to the establishment of a precision medicine strategy for tumors derived from the original concepts of traditional Chi nesemedicine(TCM). In this study, we obtainedpan-cancer Bulk RNA-Seq data from UCSC Xena, GWAS cohort data from the UKBiobank, and cis-eQTLs data from eQ TLGen and GTEx V8. We employed machine learning methods to screen for hub genes associated with each constitution. Subsequently, we utilized informatics tools to explore the biological characteristics of each constitut iondefined by the theory of five movements and six bioclimates. Further, potential anti-tumor drugs suitable for patients with differen tconstitutional types were identified through mendelian randomization, molecular docking, and drug-like prediction techniques. Withinthe pan-cancer cohort, significant differences were observed among different constitutions in terms of progression-free interval, biological f unctions, immune cell abundance, tumor drug sensitivity, and immunotherapy response. These findings suggest that the five movements and six climates theory can guide tumor molecular classification and the development of precision medicine strategies. Moreover,the biological characteristics inherent to each constitution partially shed light on the scientific implications of Chinese medicinetheories, offering a fresh perspective towards clinical cancer treatment. Through molecular docking and drug-like prediction, several po tential anti-tumor drugs such as 17-beta-estradiol, serotonin, trans-resveratrol, and linoleic acid were identified. Overall, the util izationof multi-omics approaches pro vides a powerful tool to unravel the scientific foundations of TCM theories. The elucidation of themu lti-omics features associated witheach constitution in tumors serves as the basis for applying the five movements and six climates theoryto tumor molecular classification and the development of precision medicine strategies.

The role of melancholic features on the antisuicidal effect of 0.5 mg/kg ketamine infusion has remained unclear in patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI). Whether ketamine diminishes suicidal ideation in patients with TRD-SI was also unknown. We enrolled 84 patients with TRD-SI, including 27 with melancholic features and 57 without, and then randomly administered a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) item 10, Columbia Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS), and self-reported Positive and Negative Suicide Ideation Inventory (PANSI) were used to assess suicidal symptoms from baseline to day 7. Generalized estimating equation models showed that only patients without melancholic features (MADRS item 10: infusion group effect, p = 0.017; CSSRS-ISS: infusion group × time effect, p = 0.008; PANSI-negative suicidal ideation: infusion group effect, p = 0.028) benefited from the antisuicidal effect of low-dose ketamine. The PANSI-positive ideation scores were higher in the ketamine group than in the midazolam group (p = 0.038) for patients with melancholic features. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Change of femoral neck ante-version angle postoperatively due to inadequate reduction could result in unsatisfying treatment outcome of intertrochanteric fracture. However, the influence of increased or decreased femoral neck ante-version on the biomechanical stability of the bone-implant complex has rarely been studied., Methods: A finite element model of a complete normal human femur with normal femoral neck ante-version as 13° was established accurately by scanning a 64 year old female femur. The models of 31-A1.1 intertrochanteric fractures with different femoral neck ante-version angles of 3°, 5.5°, 8°, 10.5°, 13°, 15.5°, 18°, 20.5°, 23° were created. They were assembled with a proximal femoral nail anti-rotation (PFNA) device. The biomechanical differences with varying femoral neck ante-version angles were compared using finite element analysis method., Results: As the femoral neck ante-version angle gradually increased from 13° to 23°with a gradient of 2.5°, the peak von Mises stress was gradually increased from 137.82 MPa to 276.02 MPa. Similarly, the peak von Mises stress was gradually increased from 137.82 MPa to 360.12 MPa with the femoral neck ante-version angle decreased from 13° to 3°. When decreased ante-version angle of 7.5° and increased ante-version angle of 10° will exceed the yield strength of femoral (240.32 MPa), the risk of femoral fracture will increase significantly. The maximum displacement of the femur was significantly reduced for increased ante-version models than for decreased ante-version models, whether the changes of ante-version angles were 2.5°, 5°, 7.5° or 10°. T he maximum stress of PFNA was found in the intersection of main nail and helical blade, and became greater gradually as the ante-version angle increased or decreased with a gradient of 2.5°. The maximum stress of PFNA was presented in the model 5.5° with the maximum stress of 724.42 MPa (near to the yield strength of titanium alloy of 700-1000 MPa), producing the breakage risk of PFNA. The maximum displacement of the PFNA was significantly reduced for increased ante-version models than for decreased ante-version models, whether the changes of ante-version angles were 2.5°, 5°, 7.5° or 10°., Conclusion: Based on the results of present study, it was demonstrated that the anatomical reduction of femoral neck ante-version was vital to secure the optimal stability. Abnormal femoral ante-version could increase the potential risk of failure for intertrochanteric fracture after PFNA. The stability of increased femoral ante-version (less than 10°) was superior to the stability of decreased ante-version (less than 5°) for the cases of difficulty to acquire anatomical reduction. The clinical implication of the finding was that increased femoral neck ante-version had an advantage of mechanical stability towards the decreased femoral neck ante-version for the cases of comminuted intertrochanteric fracture and failure of anatomical reduction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Developing a highly efficient atom-economic method for the preparation of 3-(1-heteroarylethyl)-indole scaffolds is of significant value in pharmaceutical and agricultural chemistry. Herein, a phosphoric acid-catalyzed N -addition reaction of 3-vinyl indoles with pyrazoles and C -addition reaction of 3-vinyl indoles with pyrazolones were developed. A series of pyrazole-substituted 3-(1-heteroarylethyl)-indole scaffolds were synthesized in excellent yields (up to 99% yield) under mild reaction conditions. A reasonable reaction mechanism was proposed to explain the experimental results.

A growing class of small RNAs, known as tRNA-derived RNAs (tdRs), tRNA-derived small RNAs or tRNA-derived fragments, have long been considered mere intermediates of tRNA degradation. These small RNAs have recently been implicated in an evolutionarily conserved repertoire of biological processes. In this Review, we discuss the biogenesis and molecular functions of tdRs in mammals, including tdR-mediated gene regulation in cell metabolism, immune responses, transgenerational inheritance, development and cancer. We also discuss the accumulation of tRNA-derived stress-induced RNAs as a distinct adaptive cellular response to pathophysiological conditions. Furthermore, we highlight new conceptual advances linking RNA modifications with tdR activities and discuss challenges in studying tdR biology in health and disease., (© 2024. Springer Nature Limited.)

Mesenchymal stem cells (MSCs) are one of the few stem cell types used in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair, due to their unique paracrine capacity, multiple differentiation potential, active components in exosomes, and effective mitochondria donation. At present, MSCs derived from tissues such as bone marrow and umbilical cord are widely applied in preclinical and clinical studies. Nevertheless, there remain challenges to the maintenance of consistently good quality MSCs derived from different donors or tissues, directly impacting their application as advanced therapy products. In this review, we discuss the promises, problems, and prospects associated with translation of MSC research into a pharmaceutical product. We review the hurdles encountered in translation of MSCs and MSC-exosomes from the research bench to an advanced therapy product compliant with good manufacturing practice (GMP). These difficulties include how to set up GMP-compliant protocols, what factors affect raw material selection, cell expansion to product formulation, establishment of quality control (QC) parameters, and quality assurance to comply with GMP standards. To avoid human error and reduce the risk of contamination, an automatic, closed system that allows real-time monitoring of QC should be considered. We also highlight potential advantages of pluripotent stem cells as an alternative source for MSC and exosomes generation and manufacture., (© 2023 Wiley Periodicals LLC.)

In the study of age estimation in living individuals, a lot of data needs to be analyzed by mathematical statistics, and reasonable medical statistical methods play an important role in data design and analysis. The selection of accurate and appropriate statistical methods is one of the key factors affecting the quality of research results. This paper reviews the principles and applicable principles of the commonly used medical statistical methods such as descriptive statistics, difference analysis, consistency test and multivariate statistical analysis, as well as machine learning methods such as shallow learning and deep learning in the age estimation research of living individuals, and summarizes the relevance and application prospects between medical statistical methods and machine learning methods. This paper aims to provide technical guidance for the age estimation research of living individuals to obtain more scientific and accurate results.

Objective: Asprosin, a newly identified adipokine, is pathologically increased in type 2 diabetes. The aim of this study is to see whether serum asprosin concentrations are linked to diabetes mellitus-induced erectile dysfunction (DMED)., Methods: 90 male patients with type 2 diabetes were included. According to the International Index of Erectile Function (IIEF-5) score, they were classified into two groups: 45 type 2 diabetes patients without erectile dysfunction (DM group) (IIEF-5 > 21),45 patients with diabetes induced erectile dysfunction (DMED group) (IIEF-5 ≤ 21)0.45 healthy male volunteers with normal blood glucose, IIEF-5 score > 21 points, and age matched with the DMED group were included as the control group. Anthropometric and biochemical variables were determined in all participants., Results: When compared to the controls, T2DM ( Type 2 Diabetes Mellitus)patients had higher serum asprosin levels. The DMED group had significantly higher serum asprosin than the T2DM groups(p < 0.001). After adjusting for multiple variables considered traditional risk factors for ED(erectile dysfunction), Asprosin can still be used as an independent risk factor for ED; The ROC(Receive Operating Characteristic Curve) indicates that asprosin has good sensitivity (97.8%) and specificity (62.2%) in predicting ED, with an area under the curve of 0.843.Correlation analysis shows that asprosin is negatively correlated with SOD(superoxide dismutase ) and positively correlated with MDA (malondialdehyde)., Conclusion: Serum asprosin concentrations are increased in patients with DMED. Also, asprosin is correlated with oxidative stress indexes (MDA, SOD)., (© 2024. The Author(s).)

Objective: To study the reversal effect of NVP-BEZ235 on doxorubicin resistance in Burkitt lymphoma RAJI cell line., Methods: The doxorubicin-resistant cell line was induced by treating RAJI cells with a concentration gradient of doxorubicin. The levels of Pgp, p-AKT, and p-mTOR in cells were detected by Western blot. Cell viability was detected by MTT assay. IC 50 was computed by SPSS., Results: The doxorubicin-resistant Burkitt lymphoma cell line, RAJI/DOX, was established successfully. The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin., Conclusion: The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Introduction: The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined., Objectives: To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP., Methods: A meta-analysis comprising 26 case-control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP., Results: Our meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (r G  = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein-protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained., Conclusion: With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

There is an emerging potential for digital assessment of depression. In this study, Chinese patients with major depressive disorder (MDD) and controls underwent a week of multimodal measurement including actigraphy and app-based measures (D-MOMO) to record rest-activity, facial expression, voice, and mood states. Seven machine-learning models (Random Forest [RF], Logistic regression [LR], Support vector machine [SVM], K-Nearest Neighbors [KNN], Decision tree [DT], Naive Bayes [NB], and Artificial Neural Networks [ANN]) with leave-one-out cross-validation were applied to detect lifetime diagnosis of MDD and non-remission status. Eighty MDD subjects and 76 age- and sex-matched controls completed the actigraphy, while 61 MDD subjects and 47 controls completed the app-based assessment. MDD subjects had lower mobile time (P = 0.006), later sleep midpoint (P = 0.047) and Acrophase (P = 0.024) than controls. For app measurement, MDD subjects had more frequent brow lowering (P = 0.023), less lip corner pulling (P = 0.007), higher pause variability (P = 0.046), more frequent self-reference (P = 0.024) and negative emotion words (P = 0.002), lower articulation rate (P < 0.001) and happiness level (P < 0.001) than controls. With the fusion of all digital modalities, the predictive performance (F1-score) of ANN for a lifetime diagnosis of MDD was 0.81 and 0.70 for non-remission status when combined with the HADS-D item score, respectively. Multimodal digital measurement is a feasible diagnostic tool for depression in Chinese. A combination of multimodal measurement and machine-learning approach has enhanced the performance of digital markers in phenotyping and diagnosis of MDD., (© 2024. The Author(s).)

Background: Malignant liver tumors seriously endanger human health. Among different therapeutic approaches, high-frequency irreversible electroporation (H-FIRE) is a recently emerging tumor ablation technique. The objective of this study was to evaluate the feasibility and safety of ultrasound-guided percutaneous H-FIRE using four electrode needles in porcine livers., Methods: Twelve experimental pigs underwent percutaneous H-FIRE ablation using a compound steep-pulse therapeutic device. Liver tissues adjacent to the gallbladder, blood vessels, and bile ducts were selected as the ablation targets. Pigs were randomly divided into three groups: (1) immediately after ablation (N = 4), (2) 2 days after ablation (N = 4), and (3) 7 days after ablation (N = 4). Blood routine, liver and kidney function, and myocardial enzyme levels were measured before and after ablation. Ultrasound, contrast-enhanced ultrasound (CEUS), contrast-enhanced magnetic resonance imaging (MRI), and hematoxylin-eosin staining were performed to evaluate the ablation performance., Results: Ultrasound-guided percutaneous H-FIRE ablations using four electrode needles were successfully performed in all 12 experimental pigs. The general conditions of the pigs, including postoperative activities and feeding behaviors, were normal, with no significant changes compared with the preoperative conditions. The imaging features of ultrasound, CEUS, and MRI demonstrated no significant changes in the gallbladder walls, bile ducts, or blood vessels close to the ablation areas. Laboratory tests showed that liver function indices and myocardial enzymes increased temporarily after H-FIRE ablation, but decreased to normal levels at 7 days after ablation. Histopathological examinations of porcine liver specimens showed that this technique could effectively ablate the target areas without damaging the surrounding or internal vascular systems and gallbladder., Conclusions: This study demonstrated the feasibility and safety of ultrasound-guided percutaneous H-FIRE ablation in porcine livers in vivo, and proposed a four-needle method to optimize its clinical application., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Short-term memory (STM) maintains information during a short delay period. How long-range and local connections interact to support STM encoding remains elusive. Here, we tackle the problem focusing on long-range projections from the medial prefrontal cortex (mPFC) to the anterior agranular insular cortex (aAIC) in head-fixed mice performing an olfactory delayed-response task. Optogenetic and electrophysiological experiments reveal the behavioral importance of the two regions in encoding STM information. Spike-correlogram analysis reveals strong local and cross-region functional coupling (FC) between memory neurons encoding the same information. Optogenetic suppression of mPFC-aAIC projections during the delay period reduces behavioral performance, the proportion of memory neurons, and memory-specific FC within the aAIC, whereas optogenetic excitation enhances all of them. mPFC-aAIC projections also bidirectionally modulate the efficacy of STM-information transfer, measured by the contribution of FC spiking pairs to the memory-coding ability of following neurons. Thus, prefrontal projections modulate insular neurons' functional connectivity and memory-coding ability to support STM., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To establish and forensically verify a 42 microhaplotypes (mircohaps, MHs) multiplex assay system based on next-generation sequencing (NGS), and to explore the application value of this system in the practice of forensic genetics., Methods: A total of 42 highly polymorphic MHs were selected from previous studies, and sequenced by the MiSeq FGx TM platform to verify the repeata-bility, sensitivity, specificity, stability, and mixture analysis ability of the detection system. Through population genetic investigation of 102 unrelated Chinese Han individuals in Liyang City, Jiangsu Province, China, the application value of this system in forensic genetics was evaluated., Results: The sequencing repeatability of the 42-plex MHs assay was 100% and the sensitivity was as low as 0.062 5 ng. The system had the ability to withstand the interference of indigo (≤2 500 ng/μL), humic acid (≤9 ng/μL), hemoglobin(≤20 μmol), and urea (≤200 ng/μL) and to detect mixtures of 2 people (1∶19), 3 people (1∶1∶9) and 4 people (1∶1∶1∶9). Based on 102 individual data, the combined power of discrimination and the combined power of exclusion were 1-3.45×10 -30 and 1-3.77×10 -11 , respectively, and the average effect value of alleles was 2.899., Conclusions: The 42-plex MHs assay was successfully established in this study and this system has high repeatability and sensitivity, good anti-jamming ability and mixture analysis ability. The 42 MHs are highly polymorphism and have good application value in individual identification and paternity testing.

Deciphering patterns of connectivity between neurons in the brain is a critical step toward understanding brain function. Imaging-based neuroanatomical tracing identifies area-to-area or sparse neuron-to-neuron connectivity patterns, but with limited throughput. Barcode-based connectomics maps large numbers of single-neuron projections, but remains a challenge for jointly analyzing single-cell transcriptomics. Here, we established a rAAV2-retro barcode-based multiplexed tracing method that simultaneously characterizes the projectome and transcriptome at the single neuron level. We uncovered dedicated and collateral projection patterns of ventromedial prefrontal cortex (vmPFC) neurons to five downstream targets and found that projection-defined vmPFC neurons are molecularly heterogeneous. We identified transcriptional signatures of projection-specific vmPFC neurons, and verified Pou3f1 as a marker gene enriched in neurons projecting to the lateral hypothalamus, denoting a distinct subset with collateral projections to both dorsomedial striatum and lateral hypothalamus. In summary, we have developed a new multiplexed technique whose paired connectome and gene expression data can help reveal organizational principles that form neural circuits and process information., Competing Interests: PX, JP, TY, ZC, HH, ZW, TL, XL, LW, LG, JY, WW, CL, ZL, YC No competing interests declared, (© 2024, Xu, Peng, Yuan et al.)

Three new griseofulvin derivatives, griseofulvinoside A-C ( 1 - 3 ), were isolated from the ethyl acetate extract of the solid fermentation product of Aureobasidium pullulans . Their structures were elucidated based on extensive spectroscopic data analysis of MS, 1D and 2D NMR. The antifungal activities of new compounds were evaluated against four phytopathogenic fungi in vitro , and all test compounds demonstrated inhibitory effects. Among them, compound 2 exhibited the most potent activities against the four selected phytopathogenic fungi with inhibitory rates ranging from 40.2 to 75.8% at 0.2 mg/mL.

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.