Protein Post-Translational Modifications Based on Proteomics: A Potential Regulatory Role in Animal Science.

Genomic studies in animal breeding have provided a wide range of references; however, it is important to note that genes and mRNA alone do not fully capture the complexity of living organisms. Protein post-translational modification, which involves covalent modifications regulated by genetic and environmental factors, serves as a fundamental epigenetic mechanism that modulates protein structure, activity, and function. In this review, we comprehensively summarize various phosphorylation and acylation modifications on metabolic enzymes relevant to energy metabolism in animals, including acetylation, succinylation, crotonylation, ß-hydroxybutylation, acetoacetylation, and lactylation. It is worth noting that research on animal energy metabolism and modification regulation lags behind the demands for growth and development in animal breeding compared to human studies. Therefore, this review provides a novel research perspective by exploring unreported types of modifications in livestock based on relevant findings from human or animal models.

Regional homogeneity alterations in multifrequency bands in patients with extracranial multi-organ tuberculosis: a prospective cross-sectional study.

Background: This study aimed to clarify the spontaneous neural activity in the conventional frequency band (0.01-0.08 Hz) and 2 subfrequency bands (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz) in patients with extracranial multi-organ tuberculosis (EMTB) through regional homogeneity (ReHo) analysis. Methods: In all, 32 patients with EMTB and 31 healthy controls (HCs) were assessed by resting-state functional magnetic resonance imaging (rs-fMRI) scans to clarify the abnormal spontaneous neural activity through ReHo analysis in the conventional frequency band and 2 subfrequency bands. Results: Compared with the HCs, the patients with EMTB exhibited decreased ReHo in the left postcentral gyrus [t=-4.79; 95% confidence interval (CI): -0.79 to -0.31] and the left superior cerebellum (t=-4.45; 95% CI: -0.54 to -0.21) in the conventional band. Conversely, increased ReHo was observed in the right middle occipital gyrus (t=3.94; 95% CI: 0.18-0.53). In the slow-4 band, patients with EMTB only exhibited decreased ReHo in the superior cerebellum (t=-4.69; 95% CI: -0.54 to -0.22); meanwhile, in the slow-5 band, these patients exhibited decreased ReHo in the right postcentral gyrus (t=-3.76; 95% CI: -0.74 to -0.21) and the left superior cerebellum (t=-5.20, 95% CI: -0.72 to -0.31). After Bonferroni correction, no significant correlation was observed between the ReHo values in clusters showing significant between-group differences and cognitive test scores. Conclusions: ReHo showed abnormal synchronous neural activity in patients with EMTB in different frequency bands, which provides a novel understanding of the pathological mechanism of EMTB.

2,5-Hexanedione Affects Ovarian Granulosa Cells in Swine by Regulating the CDKN1A Gene: A Transcriptome Analysis.

N-hexane, a common industrial organic solvent, causes multiple organ damage owing to its metabolite, 2,5-hexanedione (2,5-HD). To identify and evaluate the effects of 2,5-HD on sows' reproductive performance, we used porcine ovarian granulosa cells (pGCs) as a vehicle and carried out cell morphology and transcriptome analyses. 2,5-HD has the potential to inhibit the proliferation of pGCs and induce morphological changes and apoptosis depending on the dose. RNA-seq analyses identified 4817 differentially expressed genes (DEGs), with 2394 down-regulated and 2423 up-regulated following 2,5-HD exposure treatment. The DEG, cyclin-dependent kinase inhibitor 1A (CDKN1A), according to the Kyoto Encyclopedia of Genes and Genomes enrichment analysis, was significantly enriched in the p53 signaling pathway. Thus, we evaluated its function in pGC apoptosis in vitro. Then, we knocked down the CDKN1A gene in the pGCs to identify its effects on pGCs. Its knockdown decreased pGC apoptosis, with significantly fewer cells in the G1 phase (p < 0.05) and very significantly more cells in the S phase (p < 0.01). Herein, we revealed novel candidate genes that influence pGCs apoptosis and cell cycle and provided new insights into the role of CDKN1A in pGCs during apoptosis and cell cycle arrest.

Effect of a modified regimen on drug-sensitive retreated pulmonary tuberculosis: A multicenter study in China.

Background and objective: Retreatment pulmonary tuberculosis (PTB) still accounts for a large proportion of tuberculosis, and the treatment outcome is unfavorable. The recurrence of retreatment PTB based on long-term follow-up has not been well demonstrated. This study aimed to evaluate effect of a modified regimen on drug-sensitive retreated pulmonary tuberculosis. Methods: This multicenter cohort study was conducted in 29 hospitals from 23 regions of China from July 1, 2009, to December 31, 2020. Patients were divided into two treatment regimen groups including experimental group [modified regimen (4H-Rt2-E-Z-S(Lfx)/4H-Rt2-E)]and control group [standard regimen (2H-R-E-Z-S/6H-R-E or 3H-R-E-Z/6H-R-E)]. The patients enrolled were followed up of 56 months after successful treatment. We compared the treatment success rate, treatment failure rate, adverse reaction rate, and recurrence rate between two regimens. Multivariate Cox regression model was used to identify the potential risk factors for recurrence after successful treatment with proportional hazards assumptions tested for all variables. Results: A total of 381 patients with retreatment PTB were enrolled, including 244 (64.0%) in the experimental group and 137 (36.0%) in the control group. Overall, the treatment success rate was significant higher in the experimental group than control group (84.0 vs. 74.5%, P = 0.024); no difference was observed in adverse reactions between the two groups (25.8 vs. 21.2%, P > 0.05). A total of 307 patients completed the 56 months of follow-up, including 205 with the modified regimen and 102 with the standard regimen. Among these, 10 cases (3.3%) relapsed, including 3 in the experimental group and 7 in the control group (1.5% vs 6.9%, P = 0.035). Reduced risks of recurrence were observed in patients treated with the modified regimen compared with the standard regimen, and the adjusted hazard ratio was 0.19 (0.04-0.77). Conclusion: The modified retreatment regimen had more favorable treatment effects, including higher treatment success rate and lower recurrence rate in patients with retreated drug-sensitive PTB.

Copy Number Variation Analysis Revealed the Evolutionary Difference between Chinese Indigenous Pigs and Asian Wild Boars.

Copy number variation (CNV) has been widely used to study the evolution of different species. We first discovered different CNVs in 24 Anqingliubai pigs and 6 Asian wild boars using next-generation sequencing at the whole-genome level with 10× depth to understand the relationship between genetic evolution and production traits in wild boars and domestic pigs. A total of 97,489 CNVs were identified and divided into 10,429 copy number variation regions (CNVRs), occupying 32.06% of the porcine genome. Chromosome 1 had the most CNVRs, and chromosome 18 had the least. Ninety-six CNVRs were selected using VST 1% based on the signatures of all CNVRs, and sixty-five genes were identified in the selected regions. These genes were strongly correlated with traits distinguishing groups by enrichment in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways, such as growth (CD36), reproduction (CIT, RLN), detoxification (CYP3A29), and fatty acid metabolism (ELOVL6). The QTL overlapping regions were associated with meat traits, growth, and immunity, which was consistent with CNV analysis. Our findings increase the understanding of evolved genome structural variations between wild boars and domestic pigs, and provide new molecular biomarkers to guide breeding and the efficient use of available genetic resources.

Amplitude of low-frequency fluctuations in multiple-frequency bands in patients with intracranial tuberculosis: a prospective cross-sectional study.

Background: Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study brain functional alteration, but there have been no reports of research regarding the application of rs-fMRI in intracranial tuberculosis. The purpose of this prospective, cross-sectional study was to investigate spontaneous neural activity at different frequency bands in patients with intracranial tuberculosis using rs-fMRI with amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) methods. Methods: The rs-fMRI data of 31 patients with intracranial tuberculosis and 30 gender-, age-, and education-matched healthy controls (HCs) were included. The ALFF and fALFF values in the conventional frequency band (0.01-0.08 Hz) and 2 sub-frequency bands (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz) were calculated and compared between the groups. The resultant T-maps were corrected using the Gaussian random field (GRF) theory (voxel P<0.01, cluster P<0.05). Correlations between the ALFF and fALFF values and neurocognitive scores were assessed. Results: Compared with the HCs, patients with intracranial tuberculosis showed decreased ALFF in the right paracentral lobule (T=-4.69) in the conventional frequency band, in the right supplementary motor area (T=-4.85) in the slow-4 band, and in the left supplementary motor area (T=-3.76) in the slow-5 band. Compared to the slow-5 band, the voxels with decreased ALFF were spatially more extensive in the slow-4 band. Compared with HCs, patients with intracranial tuberculosis showed decreased fALFF in the opercular parts of the right inferior frontal gyrus (T=-4.50) and the left inferior parietal lobe (T=-4.86) and increased fALFF in the left inferior cerebellum (T=5.84) in the conventional frequency band. In the slow-4 band, fALFF decreased in the opercular parts of the right inferior frontal gyrus (T=-5.29) and right precuneus (T=-4.34). In the slow-5 band, fALFF decreased in the left middle occipital gyrus (T=-4.65) and right middle frontal gyrus (T=-5.05). Conclusions: Patients with intracranial tuberculosis showed abnormal intrinsic brain activity at different frequency bands, and ALFF abnormalities in different brain regions could be better detected in the slow-4 band. This preliminary study might provide new insights into understanding the pathophysiological mechanism in intracranial tuberculosis.

Single-nucleotide polymorphisms and activities of indoleamine 2,3-dioxygenase isoforms, IDO1 and IDO2, in tuberculosis patients.

PURPOSE: To explore the role and effects of the single-nucleotide polymorphisms (SNPs) of the two functionally related indoleamine 2,3-dioxygenase (IDO) isoforms on IDO activity in the Chinese Han ethnic population. METHODS: A total of 151 consecutive patients of Chinese Han ethnicity (99 men and 52 women; average age 51.92 ± 18.26 years) with pulmonary TB admitted to Beijing Chest Hospital between July 2016 and February 2017 were enrolled in the study. The serum levels of tryptophan (Trp) and its metabolites, IDO1 and IDO2 mRNA levels, and the relationship of IDO1 and IDO2 SNPs with the serum Kyn/Trp ratio in TB patients and healthy controls were examined by LC/ESI-MS/MS analysis. Genomic DNA was isolated from whole blood, and the PCR products were sequenced and analyzed. RESULTS: In Chinese Han participants, only IDO2 had SNPs R248W and Y359X that affected IDO activity, as determined by the serum Kyn/Trp ratio. IDO1 and IDO2 mRNA levels were inversely related in TB patients and healthy controls. CONCLUSIONS: IDO2 SNPs and the opposite expression pattern of IDO1 and IDO2 affected IDO activity in Chinese Han TB patients.

[Clinical effect of Senling Baizhu san on patients with sarcopenia].

OBJECTIVE: To observe the clinical effect of Senling Baizhu san (SLBZS) on patients with sarcopenia. METHODS: Eighty patients with spleen-stomach weakness sarcopenia admitted to the department of geriatrics of Hangzhou Third People's Hospital from January 2018 to March 2020 were enrolled. The patients were divided into control group and observation group by random number table method, 40 cases in each group. All patients were treated with conventional Western medicine, and the observation group was treated with SLBZS 100 mL, twice a day, on the basis of conventional Western medicine. The course of the treatments was 12 weeks. Grip strength and walking speed were recorded before and after treatment, and appendicular skeletal mass index (ASMI) was calculated. The serum levels of silence infor-mation regulator 1 (SIRT1), growth differentiation factor-8 (GDF-8) and insulin-like rowth factor-1 (IGF-1) were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression of AMP-activated protein kinase-α (AMPK-α) in serum was detected by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Compared with before treatment, grip strength, ASMI, IGF-1, SIRT1 and AMPK-α mRNA in both groups were significantly increased after treatment, while GDF-8 was significantly decreased. The changes of above indexes in the observation group were more significant than those in the control group after treatment [grip strength (kg): 20.00 (15.50, 21.00) vs. 18.20 (14.93, 19.50), ASMI (kg/m2): 5.80 (5.25, 6.00) vs. 5.30 (5.20, 5.50), IGF-1 (µg/L): 246.00 (229.00, 259.50) vs. 207.00 (187.00, 233.00), SIRT1 (ng/L): 649.2±38.3 vs. 624.6±38.6, AMPK-α mRNA (2-ΔΔCt): 0.30±0.03 vs. 0.27±0.03, GDF-8 (µg/L): 13.50 (12.00, 17.80) vs. 15.60 (14.08, 19.98), all P < 0.05]. There was no significant difference in walking speed between the two groups before and after treatment [0.56 (0.53, 0.62) m/s and 0.58 (0.55, 0.62) m/s in the control group before and after treatment, 0.58 (0.54, 0.64) m/s and 0.60 (0.56, 0.65) m/s in the observation group before and after treatment, both P > 0.05]. Spearman correlation analysis showed that IGF-1 was positively correlated with SIRT1 (r = 0.341, P = 0.002), IGF-1 was positively correlated with walking speed (r = 0.250, P = 0.026), and ASMI was positively correlated with grip strength (r = 0.367, P = 0.001). CONCLUSIONS: On the basis of conventional Western medicine, SLBZS has a remarkable effect on patients with sarcopenia of spleen-stomach weakness, which can provide a new idea of combining traditional Chinese and Western medicine for the treatment of sarcopenia.

Traditional Medicinal Plants as a Source of Antituberculosis Drugs: A System Review.

Medicinal plants are the chief components in the different oriental formulations in different traditional medical systems worldwide. As a thriving source of medicine, the medicinal plants with antituberculosis (TB) properties inspire the pharmacists to develop new drugs based on their active components or semimetabolites. In the present review, the anti-TB medicinal plants were screened from the scientific literatures, based on the botanical classification and the anti-TB activity. The obtained anti-TB medicinal plants were categorized into three different categories, viz., 159 plants critically examined with a total 335 isolated compounds, 131 plants with their crude extracts showing anti-TB activity, and 27 plants in literature with the prescribed formula by the traditional healers. Our systemic analysis on the medicinal plants can assist the discovery of novel and more efficacious anti-TB drugs.

Recent advances in functionalized upconversion nanoparticles for light-activated tumor therapy.

Upconversion nanoparticles (UCNPs) are a class of optical nanocrystals doped with lanthanide ions that offer great promise for applications in controllable tumor therapy. In recent years, UCNPs have become an important tool for studying the treatment of various malignant and nonmalignant cutaneous diseases. UCNPs convert near-infrared (NIR) radiation into shorter-wavelength visible and ultraviolet (UV) radiation, which is much better than conventional UV activated tumor therapy as strong UV-light can be damaging to healthy surrounding tissue. Moreover, UV light generally does not penetrate deeply into the skin, an issue that UCNPs can now address. However, the current studies are still in the early stage of research, with a long way to go before clinical implementation. In this paper, we systematically analysed recent advances in light-activated tumor therapy using functionalized UCNPs. We summarized the purpose and mechanism of UCNP-based photodynamic therapy (PDT), gene therapy, immunotherapy, chemo-therapy and integrated therapy. We believe the creation of functional materials based on UCNPs will offer superior performance and enable innovative applications, increasing the scope and opportunities for cancer therapy in the future.

Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents.

Decaprenylphosphoryl-ß-d-ribose 2'-oxidoreductase (DprE1) is a promising drug target for the development of novel anti-tubercular agents, and inhibitors of DprE1 are being investigated extensively. Among them, the 1,3-benzothiazinone compounds such as BTZ043, and its closer congener, PBTZ169, are undergoing clinical studies. It has been shown that both BTZ compounds are prodrugs, the nitro group is reduced to nitroso first, to which an adjacent Cys387 in the DprE1 binding pocket is covalently bound and results in suicide enzyme inhibition. We figured that replacement of the nitro with an electrophilic warhead would still achieve covalent interaction with nucleophilic Cys387, while the required reductive activation could be circumvented. To test this hypothesis, a number of covalent inhibitors of DprE1 were designed and prepared. The compounds inhibitory potency against DprE1 and anti-tubercular activity were investigated, their chemical reactivity, formation of covalent adduct between the warhead and the enzyme was demonstrated by mass spectrometry.

Nitrooxidoreductase Rv2466c-Dependent Fluorescent Probe for Mycobacterium tuberculosis Diagnosis and Drug Susceptibility Testing.

Firstly, this study demonstrated that natural product-inspired coumarin-based nitrofuranyl calanolides (NFCs) can form the Rv2466c-mycothiol (MSH)-NFC (RvMN) ternary complex via NFC binding to W21, N51, and Y61 of Rv2466c and be specifically reduced by Rv2466c, which is accompanied by the generation of a high level of fluorescence. Additionally, the results unveiled that the acetylated cysteine-glucosamine (AcCys-GlcN) motif of MSH is sufficient to interact with Rv2466c and adopt the active conformation that is essential for fully reducing NFCs. Further clinical translational investigation in this Article indicated that the novel fluorescent NFC probe can serve as a much needed high-throughput and low-cost detection method for detection of living Mycobacterium tuberculosis ( Mtb) and can precisely determine MIC values for a full range of available drugs. This method can greatly facilitate the development of phenotypic drug-susceptibility testing (pDST) that will allow the point-of-care treatment of tuberculosis (TB) within a week after diagnosis.

The Mono-Prep system increases the detection rate of sputum smear microscopy for diagnosing tuberculosis.

OBJECTIVE: Direct sputum smear microscopy (DSSM) has a low detection rate. This study investigated whether an alternative method called Mono-Prep smear microscopy (MPSM) can enhance the diagnosis of tuberculosis in tuberculosis laboratories that perform direct smear microscopy in China. METHODS: A total of 117 sputum samples were collected from outpatients who attended Beijing Chest Hospital. DSSM, MPSM, solid culture, and Xpert MTB/RIF were performed on the samples. RESULTS: The positive rates of DSSM, MPSM, solid culture, and Xpert MTB/RIF were 27.4% (32/117), 40.2% (47/117), 35.9% (42/117), and 52.1% (61/117), respectively. MPSM could detect 15 more cases of tuberculosis compared with DSSM (47 vs 32) among 117 sputum samples. This represented a significantly higher positive rate and sensitivity of MPSM compared with DSSM. However, MPSM appeared to have a lower specificity (81.3%) compared with DSSM (90.7%) with the solid culture used as a standard. CONCLUSION: Use of MPSM can increase the number of positive sputum samples, but it still needs improvement.

MGE-derived nNOS+ interneurons promote fear acquisition in nNOS-/- mice.

Neuronal nitric oxide synthase (nNOS) 1, mainly responsible for NO release in central nervous system (CNS) 2, plays a significant role in multiple physiological functions. However, the function of nNOS+ interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3-derived nNOS+ interneurons in fear learning. To determine the origin of nNOS+ interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4, caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6. The results showed that MGE contained the most abundant precursors of nNOS+ interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS+ interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS+ interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS-/-) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS-/- but not the wild-type mice, suggesting the importance of nNOS+ neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS-/- mice or wild-type mice into DG of the nNOS-/- mice and found that only MGE cells from wild-type mice but not the nNOS-/- mice rescued the deficit in acquisition of the nNOS-/- mice, further confirming the positive role of nNOS+ neurons in fear learning.

Crystal structure of di-chlorido-(2,2':6',2''-terpyridine-κ(3) N,N',N'')zinc: a redeter-min-ation.

The crystal structure of the title compound, [ZnCl2(C15H11N3)], was redetermined based on modern CCD data. In comparison with the previous determination from photographic film data [Corbridge & Cox (1956 ▶). J. Chem. Soc. 159, 594-603; Einstein & Penfold (1966 ▶). Acta Cryst. 20, 924-926], all non-H atoms were refined with anisotropic displacement parameters, leading to a much higher precision in terms of bond lengths and angles [e.g. Zn-Cl = 2.2684 (8) and 2.2883 (11) compared to 2.25 (1) and 2.27 (1) Å]. In the title mol-ecule, the Zn(II) atom is five-coordinated in a distorted square-pyramidal mode by two Cl atoms and by the three N atoms from the 2,2':6',2''-terpyridine ligand. The latter is not planar and shows dihedral angles between the least-squares planes of the central pyridine ring and the terminal rings of 3.18 (8) and 6.36 (9)°. The mol-ecules in the crystal structure pack with π-π inter-actions [centroid-centroid distance = 3.655 (2) Å] between pyridine rings of neighbouring terpyridine moieties. These, together with inter-molecular C-H⋯Cl inter-actions, stablize the three-dimensional structure.