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1.
PhytoKeys ; 243: 105-112, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947550

RESUMO

Lappulaeffusa D.H.Liu & W.J.Li, a new species of Boraginaceae from Xinjiang, China, is described and illustrated in this study. The new species is morphologically similar to Lappulahimalayensis and L.tadshikorum. However, it can be distinguished from the compared species by several characteristics, such as: stem single, erect, frequently branched at middle and above, densely spreading hispid, hairs discoid at base; corolla white or blue; fruit compressed, heteromorphic nutlets with two rows of marginal glochids, nutlets acute ovoid, disc narrowly ovate-triangular. The diagnosis of the new species is supported with comprehensive investigation including photographs, detailed description, notes on etymology, distribution and habitat, conservation status, as well as comparisons with morphologically similar species.

2.
Front Bioeng Biotechnol ; 12: 1410203, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994125

RESUMO

Intensive agricultural activities could cause lead (Pb) bioaccumulation, threatening human health. Although the enzyme-induced carbonate precipitation (EICP) technology has been applied to tackle the aforesaid problem, the urease may denature or even lose its activity when subjected to a significant Pb2+ toxicity effect. To this end, the nano-hydroxyapatite (nHAP)-assisted EICP was proposed to reduce the mobility of Pb2+. Results indicated that a below 30% immobilization efficiency at 60 mM Pb2+ was attained under EICP. nHAP adsorbed the majority of Pb2+, preventing Pb2+ attachment to urease. Further, hydroxylphosphohedyphane or hydroxylpyromorphite was formed at 60 mM Pb2+, followed by the formation of cerussite, allowing hydroxylphosphohedyphane or hydroxylpyromorphite to be wrapped by cerussite. By contrast, carbonate-bearing hydroxylpyromorphite of higher stability (Pb10(PO4)6CO3) was developed at 20 mM Pb2+ as CO3 2- substituted the hydroxyl group in hydroxylpyromorphite. Moreover, nHAP helped EICP to form nucleated minerals. As a result, the EICP-nHAP technology raised the immobilization efficiency at 60 mM Pb2+ up to 70%. The findings highlight the potential of applying the EICP-nHAP technology to Pb-containing water bodies remediation.

3.
Neurosurg Rev ; 47(1): 331, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39008189

RESUMO

To determine a rapid and accurate method for locating the keypoint and "keyhole" in the suboccipital retrosigmoid keyhole approach. (1) Twelve adult skull specimens were selected to locate the anatomical landmarks on the external surface of the skull.The line between the infraorbital margin and superior margin of the external acoustic meatus was named the baseline. A coordinate system was established using the baseline and its perpendicular line through the top point of diagastric groove.The perpendicular distance (x), and the horizontal distance (y) between the central point of the "keyhole" and the top point of the digastric groove in that coordinate system were measured. The method was applied to fresh cadaveric specimens and 53 clinical cases to evaluate its application value. (1) x and y were 14.20 ± 2.63 mm and 6.54 ± 1.83 mm, respectively (left) and 14.95 ± 2.53 mm and 6.65 ± 1.61 mm, respectively (right). There was no significant difference between the left and right sides of the skull (P > 0.05). (2) The operative area was satisfactorily exposed in the fresh cadaveric specimens, and no venous sinus injury was observed. (3) In clinical practice, drilling did not cause injury to venous sinuses, the mean diameter of the bone windows was 2.0-2.5 cm, the mean craniotomy time was 26.01 ± 3.46 min, and the transverse and sigmoid sinuses of 47 patients were well-exposed. We propose a "one point, two lines, and two distances" for "keyhole" localization theory, that is we use the baseline between the infraorbital margin and superior margin of the external acoustic meatus and the perpendicular line to the baseline through the top point of the digastric groove to establish a coordinate system. And the drilling point was 14.0 mm above and 6.5 mm behind the top point of the digastric groove in the coordinate system.


Assuntos
Cadáver , Cavidades Cranianas , Craniotomia , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Cavidades Cranianas/anatomia & histologia , Cavidades Cranianas/cirurgia , Craniotomia/métodos , Procedimentos Neurocirúrgicos/métodos , Idoso , Adulto Jovem , Seios Transversos/anatomia & histologia , Seios Transversos/cirurgia , Crânio/anatomia & histologia , Crânio/cirurgia
4.
Polymers (Basel) ; 16(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-39000641

RESUMO

Facial lifting with polydioxanone barbed threads has been widely used in aesthetic treatment for years. However, gravity resists the thread and continuously pulls the face downward. This study aims to determine methods to lift the skin more efficiently with longer longevity. The quality of the thread is important and is defined by the pulling and pullout strengths. Moreover, the method of using threads is also important. We compared five thread-implantation techniques and six angles for the V-shaped implantation methods using a polydimethylsiloxane model to simulate thread migration in tissues. The results of the simulated thread-lift techniques can provide valuable information for physicians, enabling a more precise design of facelift surgery techniques.

5.
Sci Data ; 11(1): 770, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997281

RESUMO

Theretra japonica is an important pollinator and agricultural pest in the family Sphingidae with a wide range of host plants. High-quality genomic resources facilitate investigations into behavioral ecology, morphological and physiological adaptations, and the evolution of genomic architecture. However, chromosome-level genome of T. japonica is still lacking. Here we sequenced and assembled the high-quality genome of T. japonica by combining PacBio long reads, Illumina short reads, and Hi-C data. The genome was contained in 95 scaffolds with an accumulated length of 409.55 Mb (BUSCO calculated a genome completeness of 99.2%). The 29 pseudochromosomes had a combined length of 403.77 Mb, with a mapping rate of 98.59%. The genomic characterisation of T. japonica will contribute to further studies for Sphingidae and Lepidoptera.


Assuntos
Genoma de Inseto , Animais , Mariposas/genética , Cromossomos de Insetos/genética , Lepidópteros/genética
6.
BMC Public Health ; 24(1): 1858, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992645

RESUMO

BACKGROUND: Spontaneous abortion is a common complication of pregnancy that can lead to adverse physical and psychological outcomes for women. Vitamin D is reported to be associated with reproductive functions, whereas its casual effects on abortion remains unclear. MATERIALS AND METHODS: In this study, a two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between serum 25 hydroxyvitamin D [25(OH)D] concentration and the risk of spontaneous abortion. GWAS summary data of 25(OH)D were used as exposure, and data of spontaneous abortion was considered as outcome. A retrospective study was additionally conducted to verify the MR results. RESULTS: MR estimates showed that a higher 25(OH)D level was potentially associated with decreased risk of spontaneous abortion (IVW, OR = 0.98, 95%CI = 0.90-1.06; MR Egger, OR = 0.94, 95%CI = 0.84-1.05; Weighted median, OR = 0.93, 95%CI = 0.82-1.06; Weighted mode, OR = 0.93, 95%CI = 0.84-1.03), though the P-value was not statistically significant. The retrospective study also produced consistent result of Vitamin D's protective role to spontaneous abortion. The P-value was very close to statistical significance (P = 0.053). CONCLUSIONS: This study reports the potential protective role of serum 25(OH)D concentration to spontaneous abortion, suggesting that increased vitamin D levels may decrease the risk of abortion. Further larger prospective studies and/or even randomized controlled trials are needed to confirm causal relationship between vitamin D and abortion.


Assuntos
Aborto Espontâneo , Análise da Randomização Mendeliana , Vitamina D , Humanos , Feminino , Aborto Espontâneo/epidemiologia , Vitamina D/sangue , Vitamina D/análogos & derivados , Estudos Retrospectivos , Gravidez , Adulto , Estudo de Associação Genômica Ampla
7.
Heliyon ; 10(12): e32789, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38975065

RESUMO

Huoxiang Zhengqi San (HXZQS), a traditional Chinese herbal formula, enjoys widespread use in Chinese medicine to treat diarrhea with cold-dampness trapped spleen syndrome (CDSS), which is induced by exposure to cold and high humidity stress. This study aimed to explore its therapeutic mechanisms in mice, particularly focusing on the intestinal microbiota. Forty male SPF-grade KM mice were allocated into two groups: the normal control group (H-Cc, n = 10) and the CDSS group (H-Mc, n = 30). After modeling, H-Mc was subdivided into H-Mc (n = 15) and HXZQS treatment (H-Tc, n = 15) groups. Intestinal samples were analyzed for enzyme activity and microbiota composition. Our findings demonstrated a notable reduction in intestinal lactase activity post-HXZQS treatment (P < 0.05). Lactobacillus johnsonii, Lactobacillus reuteri, and Lactobacillus murinus emerged as the main dominant species across most groups. However, in the H-Mc group, Clostridium sensu stricto 1 was identified as the exclusive dominant bacteria. LEfSe analysis highlighted Clostridiales vadinBB60 group and Corynebacterium as differential bacteria in the H-Tc group, and Cyanobacteria unidentified specie in the H-Mc group. Predicted microbiota functions aligned with changes in abundance, notably in cofactors and vitamins metabolism. The collinear results of the intestinal microbiota interaction network showed that HXZQS restored cooperative interactions among rare bacteria by mitigating their mutual promotion. The HXZQS decoction effectively alleviates diarrhea with CDSS by regulating intestinal microbiota, digestive enzyme activity, and microbiota interaction. Notably, it enhances Clostridium vadinBB60 and suppresses Cyanobacteria unidentified specie, warranting further study.

8.
Eur J Med Chem ; 275: 116626, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38944934

RESUMO

The global microbial resistance is a serious threat to human health, and multitargeting compounds are considered to be promising to combat microbial resistance. In this work, a series of new thiazolylquinolones with multitargeting antimicrobial potential were developed through multi-step reactions using triethoxymethane and substituted anilines as start materials. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Antimicrobial evaluation revealed that some of the target compounds could effectively inhibit microbial growth. Especially, carbothioamido hydrazonyl aminothiazolyl quinolone 8a showed strong inhibitory activity toward drug-resistant Staphylococcus aureus with MIC value of 0.0047 mM, which was 5-fold more active than that of norfloxacin. The highly active compound 8a exhibited negligible hemolysis, no significant toxicity in vitro and in vivo, low drug resistance, as well as rapidly bactericidal effects, which suggested its favorable druggability. Furthermore, compound 8a was able to effectively disrupt the integrity of the bacterial membrane, intercalate into DNA and inhibit the activity of topoisomerase IV, suggesting multitargeting mechanism of action. Compound 8a could form hydrogen bonds and hydrophobic interactions with DNA-topoisomerase IV complex, indicating the insertion of aminothiazolyl moiety was beneficial to improve antibacterial efficiency. These findings indicated that the active carbothioamido hydrazonyl aminothiazolyl quinolone 8a as a chemical therapeutic candidate demonstrated immense potential to tackle drug-resistant bacterial infections.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Quinolonas , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Quinolonas/farmacologia , Quinolonas/química , Quinolonas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Humanos , Relação Dose-Resposta a Droga , Staphylococcus aureus/efeitos dos fármacos , Animais
9.
World J Gastroenterol ; 30(20): 2638-2656, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38855150

RESUMO

As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.


Assuntos
Biomarcadores Tumorais , Detecção Precoce de Câncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/epidemiologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Prognóstico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , China/epidemiologia , Incidência , Fatores de Risco
10.
JAMA Oncol ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38869865

RESUMO

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. Design, Setting, and Participants: This prospective nonrandomized trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. Conclusions and Relevance: The findings of this nonrandomized trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.

11.
Opt Express ; 32(11): 19449-19457, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38859079

RESUMO

Germanium-on-Silicon (Ge-on-Si) avalanche photodiodes (APDs) are of considerable interest as low intensity light detectors for emerging applications. The Ge absorption layer detects light at wavelengths up to ≈ 1600 nm with the Si acting as an avalanche medium, providing high gain with low excess avalanche noise. Such APDs are typically used in waveguide configurations as growing a sufficiently thick Ge absorbing layer is challenging. Here, we report on a new vertically illuminated pseudo-planar Ge-on-Si APD design utilizing a 2 µm thick Ge absorber and a 1.4 µm thick Si multiplication region. At a wavelength of 1550 nm, 50 µm diameter devices show a responsivity of 0.41 A/W at unity gain, a maximum avalanche gain of 101 and an excess noise factor of 3.1 at a gain of 20. This excess noise factor represents a record low noise for all configurations of Ge-on-Si APDs. These APDs can be inexpensively manufactured and have potential integration in silicon photonic platforms allowing use in a variety of applications requiring high-sensitivity detectors at wavelengths around 1550 nm.

12.
Fundam Res ; 4(1): 188-198, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38933843

RESUMO

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

13.
Ann Acad Med Singap ; 53(3): 170-186, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38920244

RESUMO

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.


Assuntos
Antituberculosos , Técnica Delphi , Tuberculose Pulmonar , Tuberculose , Humanos , Singapura , Antituberculosos/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/diagnóstico , Consenso
14.
Micromachines (Basel) ; 15(6)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38930726

RESUMO

As one of the most significant research topics in robotics, microrobots hold great promise in biomedicine for applications such as targeted diagnosis, targeted drug delivery, and minimally invasive treatment. This paper proposes an enhanced YOLOv5 (You Only Look Once version 5) microrobot detection and tracking system (MDTS), incorporating a visual tracking algorithm to elevate the precision of small-target detection and tracking. The improved YOLOv5 network structure is used to take magnetic bodies with sizes of 3 mm and 1 mm and a magnetic microrobot with a length of 2 mm as the pretraining targets, and the training weight model is used to obtain the position information and motion information of the microrobot in real time. The experimental results show that the accuracy of the improved network model for magnetic bodies with a size of 3 mm is 95.81%, representing an increase of 2.1%; for magnetic bodies with a size of 1 mm, the accuracy is 91.03%, representing an increase of 1.33%; and for microrobots with a length of 2 mm, the accuracy is 91.7%, representing an increase of 1.5%. The combination of the improved YOLOv5 network model and the vision algorithm can effectively realize the real-time detection and tracking of magnetically controlled microrobots. Finally, 2D and 3D detection and tracking experiments relating to microrobots are designed to verify the robustness and effectiveness of the system, which provides strong support for the operation and control of microrobots in an in vivo environment.

15.
Nat Commun ; 15(1): 5310, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906867

RESUMO

Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials.


Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Glicoproteínas , Herpesvirus Humano 4 , Animais , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Infecções por Vírus Epstein-Barr/virologia , Anticorpos Neutralizantes/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Feminino , Camundongos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Glicoproteínas/imunologia , Glicoproteínas/administração & dosagem , Nanopartículas/administração & dosagem , Nanopartículas/química , Adjuvantes Imunológicos/administração & dosagem , Linfoma/imunologia , Linfoma/virologia , Nanovacinas
16.
Org Lett ; 26(25): 5318-5322, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38888237

RESUMO

Herein we report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs). This bench-stable compound was found to be a versatile electrophile in a ring-opening reaction with various types of nucleophiles. Its utility as a versatile medicinal chemistry building block is further demonstrated in the synthesis of an LDD compound targeting degradation of the androgen receptor.


Assuntos
Compostos Azabicíclicos , Piperazinas , Estrutura Molecular , Piperazinas/química , Piperazinas/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/síntese química , Química Farmacêutica , Ligantes , Sais/química
17.
J Phys Chem B ; 128(25): 6123-6133, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38875519

RESUMO

The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.


Assuntos
Proliferação de Células , Isatina , Isatina/química , Isatina/farmacologia , Isatina/síntese química , Humanos , Células HeLa , Proliferação de Células/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Linhagem Celular Tumoral , Fluorescência
18.
Cell Rep ; 43(6): 114290, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38823012

RESUMO

Coexpressing multiple identical single guide RNAs (sgRNAs) in CRISPR-dependent engineering triggers genetic instability and phenotype loss. To provide sgRNA derivatives for efficient DNA digestion, we design a high-throughput digestion-activity-dependent positive screening strategy and astonishingly obtain functional nonrepetitive sgRNA mutants with up to 48 out of the 61 nucleotides mutated, and these nonrepetitive mutants completely lose canonical secondary sgRNA structure in simulation. Cas9-sgRNA complexes containing these noncanonical sgRNAs maintain wild-type level of digestion activities in vivo, indicating that the Cas9 protein is compatible with or is able to adjust the secondary structure of sgRNAs. Using these noncanonical sgRNAs, we achieve multiplex genetic engineering for gene knockout and base editing in microbial cell factories. Libraries of strains with rewired metabolism are constructed, and overproducers of isobutanol or 1,3-propanediol are identified by biosensor-based fluorescence-activated cell sorting (FACS). This work sheds light on the remarkable flexibility of the secondary structure of functional sgRNA.


Assuntos
Citometria de Fluxo , RNA Guia de Sistemas CRISPR-Cas , RNA Guia de Sistemas CRISPR-Cas/metabolismo , RNA Guia de Sistemas CRISPR-Cas/genética , Citometria de Fluxo/métodos , Sistemas CRISPR-Cas/genética , Mutação/genética , Conformação de Ácido Nucleico , Ensaios de Triagem em Larga Escala/métodos , Butanóis/metabolismo , Edição de Genes/métodos , Proteína 9 Associada à CRISPR/metabolismo , Proteína 9 Associada à CRISPR/genética
19.
Virology ; 597: 110150, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38917690

RESUMO

Coronaviruses (CoVs) comprise a group of important human and animal pathogens that threaten public health because of their interspecies transmission potential to humans. However, virus-like particles (VLPs) constitute versatile tools in CoVs vaccine development due to their favorable immunological characteristics. Here, we engineered the VLPs composed of the spike (S), membrane (M), and envelope (E) structural proteins of the Porcine deltacoronavirus (PDCoV) and examined their immune responses in mice. Neutralization assays and flow Cytometry demonstrated that PDCoV VLPs induced highly robust neutralizing antibodies (NAbs) and elicited cellular immunity. To assess the protective efficacy of VLPs in newborn piglets, pregnant sows received vaccinations with either a PDCoV-inactivated vaccine or VLPs at 40 and 20 days before delivery. Five days post-farrowing, piglets were orally challenged with the PDCoV strain. Severe diarrhea, high viral RNA copies, and substantial intestinal villus atrophy were detected in piglets born to unimmunized sows. However, piglets from sows immunized with VLPs exhibited high NAbs titers and markedly reduced microscopic damage to the intestinal tissues, with no piglet showing diarrhea. Hence, the results indicate that the VLPs are a potential clinical candidate for PDCoV vaccination, while the strategy may serve as a platform for developing other coronavirus vaccines.

20.
J Hazard Mater ; 474: 134744, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38850933

RESUMO

Compared to traditional lead-remediating materials, natural-occurring paleosol is ubiquitous and could be a promising alternative due to its rich content in calcite, a substance known for its lead-removal ability via carbonate dissolution-PbCO3 precipitation process. Yet, the capability of paleosol to remediate aqueous solutions polluted with heavy metals, lead included, has rarely been assessed. To fill this gap, a series of column permeation experiments with influent Pb2+ concentrations of 2000, 200, and 20 mg/L were conducted and monitored by the spectral induced polarization technique. Meanwhile, the SEM-EDS, XRD, XPS, FTIR and MIP tests were carried out to unveil the underlying remediation mechanisms. The Pb-retention capacity of paleosol was 1.03 mmol/g. The increasing abundance of Pb in the newly-formed crystals was confirmed to be PbCO3 by XRD, SEM-EDS and XPS. Concurrently, after Pb2+ permeation, the decreasing calcite content in paleosol sample from XRD test, and the appearance of Ca2+ in the effluent confirmed that the dissolution of CaCO3 followed by the precipitation of PbCO3 was the major mechanism. The accumulated Pb (i.e., the diminished Ca) in paleosol was inversely proportional (R2 >0.82) to the normalized chargeability (mn), an SIP parameter denoting the quantity of polarizable units (primarily calcite).

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