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关键词： Neolithic   Coprolite   Diet   X-ray computed tomography   Mass spectrometry   Scanning electron microscopy  

摘要： Coprolites (fossilized faeces) can provide valuable insights into species' diet and related habits. In archaeozoological contexts, they are a potential source of information on human-animal interactions as well as human and animal subsistence. However, despite a broad discussion on coprolites in archaeology, such finds are rarely subject to detailed examination by researchers, perhaps due to the destructive nature of traditional analytical methods. Here, we have examined coprolitic remains from the Neolithic (third millennium BCE) settlement at Skara Brae, Orkney, using a range of modern methods: X-ray computed tomography, scanning electron microscopy, lipid and protein analysis (shotgun proteomics of the coprolite matrix as well as collagen peptide mass fingerprinting of isolated bone fragments). This combined approach minimised destructiveness of sampling, leaving sufficient material for subsequent study, while providing more information than traditional morphological examination alone. Based on gross visual examination, coprolites were predominantly attributed to domestic dogs (Canis familiaris), with morphologically identified bone inclusions derived from domestic sheep (Ovis aries) and common voles (Microtus arvalis). Partial dissection of a coprolite provided bone samples containing protein markers akin to those of domestic sheep. Considering the predominance of vertebral and distal limb bone fragments, Skara Brae dogs were probably consuming human butchery or meal refuse, either routinely fed to them or scavenged. The presumably opportunistic consumption of rodents may also have played a role in pest control.

关键词： bioanalytical chemistry   CRISPR   electrochemistry   genetic circuits   primer exchange reaction  

摘要： Modular construction of an autonomous and programmable multi-functional heterogeneous biochemical circuit that can identify, transform, translate, and amplify biological signals into physicochemical signals based on logic design principles can be a powerful means for the development of a variety of biotechnologies. To explore the conceptual validity, we design a CRISPR-array-mediated primer-exchange-reaction-based biochemical circuit cascade, which probes a specific biomolecular input, transform the input into a structurally accessible form for circuit wiring, translate the input information into an arbitrary sequence, and finally amplify the prescribed sequence through autonomous formation of a signaling concatemer. This upstream biochemical circuit is further wired with a downstream electrochemical interface, delivering an integrated bioanalytical platform. We program this platform to directly analyze the genome of SARS-CoV-2 in human cell lysate, demonstrating the capability and the utility of this unique integrated system.

关键词： single-domain antibody (SdAb)   protein chemistry   antibody engineering   cell signaling   synthetic biology  

摘要： Reagents that bind tightly and specifically to biomolecules of interest remain essential in the exploration of biology and in their ultimate application to medicine. Besides ligands for receptors of known specificity, agents commonly used for this purpose are monoclonal antibodies derived from mice, rabbits, and other animals. However, such antibodies can be expensive to produce, challenging to engineer, and are not necessarily stable in the context of the cellular cytoplasm, a reducing environment. Heavy chain-only antibodies, discovered in camelids, have been truncated to yield single-domain antibody fragments (VHHs or nanobodies) that overcome many of these shortcomings. Whereas they are known as crystallization chaperones for membrane proteins or as simple alternatives to conventional antibodies, nanobodies have been applied in settings where the use of standard antibodies or their derivatives would be impractical or impossible. We review recent examples in which the unique properties of nanobodies have been combined with complementary methods, such as chemical functionalization, to provide tools with unique and useful properties.

摘要： Background: Myeloma remains an incurable disease and most patients will relapse. The optimal timing of salvage initiation remains uncertain although there is a trend to treating early biochemical relapse. In the current COVID-19 pandemic, delaying therapy of asymptomatic relapsed patients is also desirable, but avoidance of renal failure and symptomatic bony disease is important. Whole body STIR MRI with diffusion weighted imaging (DWI) has the potential to diagnose bone involvement at a very early, pre-symptomatic stage, before cortical destruction occurs. It may be a useful tool to assess the ability to defer therapy in myeloma patients with asymptomatic biochemical relapse. Methods: We performed a retrospective audit of newly diagnosed patients with symptomatic myeloma, diagnosed between April 2012 and Oct 2019. We studied only patients in first relapse who had achieved PR or better to first-line therapy. Patients were typically monitored with monthly serum protein electrophoresis and free light chain assessments. The preferred imaging modality during the study period was whole body STIR MRI with DWI analysis and additional dedicated spinal sequences. Response and relapse criteria were as defined by the IMWG with the exception that regular urine BJP monitoring was not performed. Rapid biochemical relapse was defined as per Sonneveld (ASH Education Book 2017). The decision to initiate therapy for relapse was at the discretion of the treating hematologist. Results: 125 patients with newly diagnosed symptomatic myeloma who achieved PR or better to first line therapy were identified. Median age at diagnosis was 64yrs (range, 32 to 89yrs) and 72% were male. Immunoglobulin type was IgG (54%), IgA (23%), light chain (22%) and IgD (1%). ISS stage was I (19%), II (60%) and III (21%) and 21% were high risk as defined by the presence of t(4;14), t(14;16) or del17p by bone marrow FISH. Half received autologous stem cell transplantation with bortezomib-based therapy being the

关键词： Biosynthesis   Palladium nanoparticles   Chemical fixatives   Catalytic performance  

摘要： Palladium nanoparticles (PdNPs) can catalyse a range of reductive chemical reactions transforming both organic and inorganic environmental pollutants. PdNPs that ranged from < 2 to 2-40 nm were synthesized using chemical methods, and bacterial biomass with/without chemical fixatives. PdNP formation was enhanced by adsorption of Pd(II) to bacterial biomass, followed by fixation with formate or glutaraldehyde. TEM-SAED analyses confirmed that the cell associated PdNPs were polycrystalline with a face-centered cubic structure. Chemically formed PdNPs possessed a higher Pd(0):Pd(II) ratio and produced structurally similar nanoparticles as the biotic systems. These PdNPs were employed to catalyze two, reductive chemical reactions, transforming 4-nitrophenol (4-NP) and hexavalent chromium [Cr(VI)], into 4-aminophenol and Cr(IV), respectively. In the reduction of 4-NP, the catalytic performance was directly proportional to PdNP surface area, i.e., the smallest PdNPs in formate-PdCH34 cells had the fastest rate of reaction. The mass of Pd(0) as PdNPs was the main contributor to Cr(VI) reduction;the chemically synthesized PdNPs showed the highest removal efficiency with 96% at 20 min. The use of glutaraldehyde enhanced the reduction of Pd(II) and promoted PdNPs formation, i.e., creating an artefact of fixation;however, this treatment also enhanced the catalytic performance of these PdNPs.

摘要： Tyrosine kinase inhibitors (TKIs) that inhibit the transphosphorylation activity of the BCR-ABL1 oncoprotein by binding the ATP-binding site of the catalytic domain of protein kinases are well established as being effective drugs for the treatments of chronic myeloid leukemia (CML). However, the off-target kinase activities of these non-specific TKIs are associated with adverse events that can limit their suitability for the treatment of patients and can negatively impact quality of life. Therefore, a new drug combining high efficacy with minimal side-effects could provide substantial therapeutic advantages. Asciminib is a new investigational agent that at concentrations <10 micromolar has very little effect (residual activities ≥66%) on the transphosphorylation activity of a large panel comprising of 335wild-type protein kinases (including ABL1 and ABL2). In this study (33 PanQinase® Activity Assay, ProQinase GmbH, Freiburg, Germany) the radiometric kinase assay employed recombinant kinase constructs of the catalytic domains including the ATP-binding site. However, in isothermal calorimetry studies asciminib showed strong binding affinity (KD 0.5 nM) to a much larger construct ofwild-type ABL1 that contains the catalytic, SH2 and SH3 domains (residues 46-534, ABL46-534 ), with thermodynamic parameters (ΔH = -72.8 kJ/mol, ΔS = -65.3 J/mol/K, resulting in ΔG = -53.2 kJ/mol) indicating strong enthalpy-driven, entropically unfavorable binding. This binding translates to inhibition of tyrosine phosphorylation catalysed by the ABL64-515 construct with a mean IC50 value of 2.6 ± 0.8 nM (radiometric filter binding assay) and 0.5 ± 0.1 nM (fluorescence resonance energy transfer assay). This data shows that asciminib inhibits the kinase activity of ABL1 by an allosteric mechanism which does not involve direct interaction with the ATP-binding pocket. X-ray crystallographic studies of a ternary complex between asciminib, nilotinib and the ABL146-534 protein possessing Thr315Il

摘要： Background: Pre-anemic iron deficiency (ID) and ID anemia in infancy is associated with long-term effects on brain development. Iron is an essential micronutrient needed for multiple neurodevelopmental processes, including energy production, myelination and neurotransmission. Serum and cerebrospinal fluid (CSF) metabolomic and proteomic analyses can potentially characterize the metabolic and protein signatures of aberrant iron-dependent brain development pathways. A better understanding of the timing and course of the biochemical signatures of ID-induced dysfunction in the heme and intrathecal compartments may help with early diagnosis and treatment of iron deficiency prior to onset of anemia. Objective: To determine proteomic and metabolomic signatures of ID-induced dysfunction in serum and CSF of infant monkeys prior to the onset of iron deficiency anemia (IDA). Methods: Hematological parameters were determined in rhesus monkey infants (Macaca mulatta ) at 4 and 6 months of age as they progressed from preanemic ID to IDA (ID group; n=6) or remained iron-sufficient(IS group; n=12). Blood and CSF were collected at 4 and 6 months and metabolically profiled using HPLC/MS with isobaric standards for identification and quantification. Proteomic quantification utilized a custom TMT-labeled workflow with an Orbitrap Fusion Tribrid mass spectrometer. Serum and CSF metabolomic and proteomic profiles of the ID and IS groups were compared, along with a a third group of infants that became IDA earlier at 4 months of age (IDA group; n=3). Results: Evidence of pre-anemic ID was apparent in some infant at 4 months of age with clinical IDA evident at 6 months A (Hgb <10 g/dL and MCV <60 fL). A total of 1,128 CSF proteins and 251 serum proteins were identified and quantified. Over 4,000 metabolite features were observed in serum and CSF across three modalities including reverse phase positive, reverse phase negative and HILIC mode. Pathway analyses provided evidence of increased in

摘要： Background: Pica is characterized as repeatedly eating or chewing of a non-nutritious substance including, but not limited to ice, clay and dirt, starch, raw pasta, chalk, coal, paint, or paper. Life-threatening conditions, such as gastrointestinal infections and lead poisoning, may occur depending on the substance consumed. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition defines pica as an eating disorder, but with its strong link to iron deficiency, pica is also characterized as a hematological condition. Blood donation is associated with substantial iron loss. Blood donors often become iron deficient and are susceptible to pica, as well as restless legs syndrome (RLS), an often concurrent condition characterized by an irresistible urge to move legs due to uncomfortable sensations such as tingling, crawling, burn, and pain. The National Heart, Lung, and Blood Institute sponsored REDS-III program prospectively enrolled 13,403 racially diverse blood donors in its RBC Omics study to investigate demographic, clinical, hematological, and biochemical factors associated with pica. Methods: Demographic data, survey questions of pica behaviors and RLS, complete blood count (CBC), and ferritin were collected and analyzed using univariable and multivariable logistic regression analysis. Exclusion criteria were ferritin >800 ng/mL, body mass index (BMI) <17.5, and those with 9 or more donations in the 2 years prior to enrollment who were purposely oversampled for in RBC Omics. Pica was rigorously defined by questionnaire responses: 1) “Yes” to eating ice and, 2) Consumes “8 oz - 24 oz” or “more than 24 oz” of ice and, 3) At frequency of “once a day” or “several times a day”. Alternatively, “yes” to eating non-ice substances regardless of amount and frequency was also characterized as pica. Results: The analysis included 11,418 donors with 7,141 Caucasians, 1,581 African Americans, 1,601 Asians, and 1,170 Hispanics. Pica was present in 1.4% (158 out of

关键词： Cholesterol   Anatomy   Serum   Fluoropolymers   Peptides and proteins  

摘要： Although perfluoroalkyl ether carboxylic (PFECAs) and sulfonic acids (PFESAs) have been widely detected in environmental matrices, their occurrence in humans and impact on human health remains insufficiently understood. Here, we report on 13 PFECAs and PFESAs in 977 sera samples collected from residents living near a fluorochemical plant in Shandong, China. The sum concentration of these emerging PFECAs accounted for 13% of the total PFASs in the serum of the participants, with the frequent detection of several PFECAs (>95%) (PFMOAA, PFO4DA, and PFO5DoDA at median concentrations of 12.91, 0.142, and 0.987 ng/mL, respectively) and PFESAs ( 98.7%) (Nafion byproduct 2 at a median concentration of 0.097 ng/mL). Serum PFMOAA, PFO5DoDA, and 6:2 Cl-PFESA levels were significantly higher in males than in females. Positive relationships were observed between age and PFMOAA, 6:2 Cl-PFESA, and H-PFMO2OSA levels, whereas HFPO-TA and PFO5DoDA serum concentrations in the 0-40-year age group were lower than that in the >40-year age group. Furthermore, multivariate linear regression models and sensitivity analyses showed positive associations among PFO5DoDA levels, elevated lipid parameters (cholesterol, low-density lipoprotein cholesterol, and triglycerides), liver function markers (albumin levels and alanine transaminase, aspartate aminotransferase, and glutamyl transpeptidase activities), and uric acid levels. Thus, our results suggest potential health risks from exposure to novel PFESAs and PFECAs (especially PFO5DoDA).

关键词： 同伴教学法   思维导图   生物化学  

摘要： 本研究将思维导图结合同伴教学法应用到生物化学课堂上,能够充分发挥两者的优势,一方面促进和引导学生在课堂教学中积极主动参与,提升学生学习兴趣;另一方面学生在建立了系统的知识框架前提下,对书中知识点各个击破。希望能有效地改变传统的接受性机械训练式的教学方法,实现从以教师为中心向以学生为中心的转变。