Hasil untuk "Biochemistry"

S. Rothman

Z. Cohn, B. Benson

Tengwei Song, Long Yin, Zhen Han et al.

Predicting enzyme-substrate interactions has long been a fundamental problem in biochemistry and metabolic engineering. While existing methods could leverage databases of expert-curated enzyme-substrate pairs for models to learn from known pair interactions, the databases are often sparse, i.e., there are only limited and incomplete examples of such pairs, and also labor-intensive to maintain. This lack of sufficient training data significantly hinders the ability of traditional enzyme prediction models to generalize to unseen interactions. In this work, we try to exploit chemical reaction equations from domain-specific databases, given their easier accessibility and denser, more abundant data. However, interactions of multiple compounds, e.g., educts and products, with the same enzymes create complex relational data patterns that traditional models cannot easily capture. To tackle that, we represent chemical reaction equations as triples of (educt, enzyme, product) within a knowledge graph, such that we can take advantage of knowledge graph embedding (KGE) to infer missing enzyme-substrate pairs for graph completion. Particularly, in order to capture intricate relationships among compounds, we propose our knowledge-enhanced hypergraph model for enzyme prediction, i.e., Hyper-Enz, which integrates a hypergraph transformer with a KGE model to learn representations of the hyper-edges that involve multiple educts and products. Also, a multi-expert paradigm is introduced to guide the learning of enzyme-substrate interactions with both the proposed model and chemical reaction equations. Experimental results show a significant improvement, with up to a 88% relative improvement in average enzyme retrieval accuracy and 30% improvement in pair-level prediction compared to traditional models, demonstrating the effectiveness of our approach.

Hao Li, He Cao, Shenyao Peng et al.

Language models are revolutionizing the biochemistry domain, assisting scientists in drug design and chemical synthesis with high efficiency. Yet current approaches struggle between small language models prone to hallucination and limited knowledge retention, and large cloud-based language models plagued by privacy risks and high inference costs. To bridge this gap, we introduce ChemCRAFT, a novel framework leveraging agentic reinforcement learning to decouple chemical reasoning from knowledge storage. Instead of forcing the model to memorize vast chemical data, our approach empowers the language model to interact with a sandbox for precise information retrieval. This externalization of knowledge allows a locally deployable small model to achieve superior performance with minimal inference costs. To enable small language models for agent-calling ability, we build an agentic trajectory construction pipeline and a comprehensive chemical-agent sandbox. Based on sandbox interactions, we constructed ChemToolDataset, the first large-scale chemical tool trajectory dataset. Simultaneously, we propose SMILES-GRPO to build a dense chemical reward function, promoting the model's ability to call chemical agents. Evaluations across diverse aspects of drug design show that ChemCRAFT outperforms current cloud-based LLMs in molecular structure analysis, molecular optimization, and synthesis pathway prediction, demonstrating that scientific reasoning is not solely an emergent ability of model scale, but a learnable policy of tool orchestration. This work establishes a cost-effective and privacy-preserving paradigm for AI-aided chemistry, opening new avenues for accelerating molecular discovery with locally deployable agents. Code available at https://github.com/HowardLi1984/ChemCraft.

Dipanjan Bhattacharyya, Mariana Oliveira de Paula, Simon Koscielniak et al.

E. Armstrong

Zhao Jinhua

Background and Aims: Pegylated interferon (PEG-IFN) combined with oral antiviral agents is currently the most widely used and highly effective treatment regimen for chronic hepatitis B virus (HBV) infection. While effectively suppressing HBV replication, its impact on liver histopathological fibrosis and inflammation remains a critical concern for clinicians and patients. Methods : A total of 625 patients who completed 48 weeks of PEG-IFN combined with oral antiviral therapy were enrolled in this real-world study. Based on their virological response at 48 weeks, patients were categorized into Clearance group and Non-clearance group. Changes in liver biochemistry, fibrosis, and renal function were compared between groups and before/after treatment. Results: No significant differences were observed in baseline blood tests, liver biochemical markers, or histopathological features between the Clearance group and Non-clearance group. Similarly, baseline renal function showed no significant variation. Further analysis revealed that the Clearance group exhibited significant aggravation of liver fibrosis after 48 weeks of treatment, which correlated strongly with alterations in liver enzyme levels. However, one patient who underwent paired liver biopsies before and after treatment demonstrated marked histopathological improvement in fibrosis. This finding underscores the irreplaceable role of liver histopathology in assessing fibrosis and inflammation. Conclusion: PEG-IFN combined with oral antiviral therapy exerts favorable effects on liver fibrosis and inflammation in chronic HBV patients. Non-invasive fibrosis assessment models can monitor fibrotic progression but are susceptible to confounding by hepatic inflammation.

Dunja Simicic, Katarzyna Pierzchala, Olivier Braissant et al.

Background & Aims: Patients with type C hepatic encephalopathy (HE) present diverse symptoms indicating that various brain regions are affected. Understanding the distinct metabolic and cellular changes across these regions could help explain the clinical variability of HE. We analyzed, for the first time, the longitudinal in-vivo neurometabolic and morphological changes in astrocytes, neurons and microglia in the hippocampus, striatum and cerebellum during the progression of CLD-induced type C HE in the bile duct ligated (BDL) rat model. Methods: Wistar rats underwent BDL and their brains were studied before BDL and at post-operative weeks-2, 4, 6 and 8 using in-vivo 1H-MRS (9.4T) of the hippocampus, striatum and cerebellum along with histological assessment (astrocytes, microglia, and neurons) and blood biochemistry. Results: Across all brain regions, glutamine (Gln) was the first metabolite to increase, followed by a decrease in osmolytes and neurotransmitters. The cerebellum was characterized by the highest Gln burden (+134%), elevated Lactate (+84%) and decreased GABA (-23%), suggesting its increased vulnerability. This coincided with pronounced alterations in astrocyte morphology, possibly related to the high Gln load. In contrast, the striatum displayed the lowest Gln increase (+48%) but the strongest osmolyte decrease, with milder astrocytic changes. We also showed mutual and distinct regional morphological changes in microglia (activation) and neurons (decreased dendritic spine density, soma size alterations). Conclusions: Our findings highlight both common and differential metabolic and cellular responses to CLD across the brain regions, with cerebellum and striatum showing differential responses. We also hypothesized that glutamine is one of the initial brain metabolic markers of type C HE, impacting astrocytes and inevitably neurons contributing to cognitive decline.

Qiushi Sun, Zhoumianze Liu, Chang Ma et al.

Large Language Models (LLMs) have extended their impact beyond Natural Language Processing, substantially fostering the development of interdisciplinary research. Recently, various LLM-based agents have been developed to assist scientific discovery progress across multiple aspects and domains. Among these, computer-using agents, capable of interacting with operating systems as humans do, are paving the way to automated scientific problem-solving and addressing routines in researchers' workflows. Recognizing the transformative potential of these agents, we introduce ScienceBoard, which encompasses two complementary contributions: (i) a realistic, multi-domain environment featuring dynamic and visually rich scientific workflows with integrated professional software, where agents can autonomously interact via different interfaces to accelerate complex research tasks and experiments; and (ii) a challenging benchmark of 169 high-quality, rigorously validated real-world tasks curated by humans, spanning scientific-discovery workflows in domains such as biochemistry, astronomy, and geoinformatics. Extensive evaluations of agents with state-of-the-art backbones (e.g., GPT-4o, Claude 3.7, UI-TARS) show that, despite some promising results, they still fall short of reliably assisting scientists in complex workflows, achieving only a 15% overall success rate. In-depth analysis further provides valuable insights for addressing current agent limitations and more effective design principles, paving the way to build more capable agents for scientific discovery. Our code, environment, and benchmark are at https://qiushisun.github.io/ScienceBoard-Home/.

Christopher J. Miller, Byunghoon Lee, Jacob A. Barrett et al.

Recent reports show [FeFe] hydrogenase mimics are active for the electrochemical reduction of CO2 to formate (HCOO−). Herein, the electrochemical reduction of CO2 with the [FeFe] hydrogenase mimic [Fe2(μ‐pdt)(CO)6, 1, where pdt = propane‐1,3‐dithiolate] in acetonitrile is reported. In the presence of the weak acid, methanol (MeOH), 1 reduces CO2 to both CO (Faradaic Efficiency maximum [FEmax] of 16 ± 6%) and HCOO− (FEmax = 20%) and produces H2 (FEmax = 56 ± 4%). Without added MeOH, 1 reacts with adventitious water to form H2 (FEmax = 85 ± 1%), HCOO− (FEmax = 7.8%), and CO (FEmax = 7 ± 3%) with CO32− being detected by infrared spectroscopy.  Product formation is potential dependent: more negative potentials increases selectivity for HCOO− over CO. The first reduction of 1 forms a pdt‐bridged dimer, 2. However, the reduction of 2 at the potentials required for electrochemical CO2 reduction leads to two new species. Using density functional theory, and infrared spectroelectrochemistry (IR‐SEC), these structures are identified to be [Fe(CO)4]2− (3) and a trinuclear Fe3 species (4). While these species can reduce CO2 to CO and HCOO−, the predominant formation of H2 reveals kinetic issues in  CO2 reduction. The work offers to consider alternate competing mechanistic pathways and explains the lack of product selectivity when using hydrogen evolution reaction catalyst for CO2 reduction to HCOO−.

Xiaoyue Shang, Nina Bartels, Johann Moritz Weck et al.

Abstract Background Cluster of differentiation 95 (CD95/Fas/Apo1) as part of the Tumor-necrosis factor (TNF) receptor family is a prototypic trigger of the ‘extrinsic’ apoptotic pathway and its activation by the trimeric ligand CD95L is of high interest. However, CD95L, when presented in solution, exhibits a low efficiency to induce apoptosis signaling in human cells. Results Here, we design a recombinant CD95L exhibiting an isoleucine zipper (IZ) motif at the N-terminus for stabilization of the trimerized CD95L and demonstrate its high apoptosis initiation efficiency. This efficiency is further enhanced by antibody-mediated crosslinking of IZ-CD95L.A cysteine amino acid fused behind the IZ is used as a versatile coupling site for bionanotechnological applications or for the development of biomedical assays. A fast, cheap, and efficient production of CD95L via the HEK293T secretory expression system is presented, along with CD95L affinity purification and functionalization. We verified the biological activity of the purified protein and identified a stabilized trimeric CD95L structure as the most potent inducer of apoptosis signaling. Conclusions The workflow and the findings reported here will streamline a wide array of future low- or high-throughput TNF-ligand screens, and their modification towards improving apoptosis induction efficiency and, potentially, anticancer therapy.

D. T.

H. Keberle

J. Needham

Ole Jakob Jørgensen, Johan Edvard Steineger, Andreas Hillarp et al.

Abstract Objectives The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemorrhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Methods Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital—Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical history with an emphasis on thromboembolic events. Measurements of blood constituents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. Results One hundred and thirty‐four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Conclusion Thromboembolic events are highly prevalent in the Norwegian HHT population and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measurements should be repeated in HHT patients to assess the risk of thromboembolic events. Level of Evidence 4.

Tatik Hernawati, Suherni Susilowati, Tri Wahyu Suprayogi et al.

One of the many efforts to increase the quality of livestock genetics is through artificial insemination (AI). Other than increasing it, AI can be conducted to preserve semen. A successful AI is determined by seminal quality, therefore, a method to preserve semen for a longer storage time is needed. The method used is adding an extender that fulfills prerequisites for a semen extender such as coconut water combined with egg yolk citrate extender. Coconut water is rich in carbohydrates, protein, vitamins, and antioxidants while egg yolk contains lecithin. This study aims to find out the Pote buck spermatozoa quality stored in coconut water and egg yolk extender. This study uses three groups of treatments (T0: 0.1 ml semen + 0.9 ml egg yolk citrate, T1: 0.1 ml semen + 0.9 ml coconut water, and T2: 0.1 ml semen + egg yolk citrate (20%) + coconut water). All three of these are stored at 5oC and evaluated every day until day 5 of their motility, viability, intact plasma membrane, abnormality, and MDA level. Data analysis used is ANOVA and a further test called BNT is conducted if a significant difference is determined. No significant difference was found between T0 and T1 (p>0.05). The highest progressive motility, viability, and intact plasma membrane (%) among the three groups of treatments happened to be from T2. Meanwhile, a low percentage of spermatozoa abnormality and MDA level were also found in T2 with its extender being coconut water combined with egg yolk citrate. To conclude, the best extender for storing Pote buck semen is stored at 5oC is coconut water combined with egg yolk citrate extender.

Alastair Claringbold, Paul Rimmer, Sarah Rugheimer et al.

The search for biosignatures on exoplanets connects the fields of biology and biochemistry to astronomical observation, with the hope that we might detect evidence of active biological processes on worlds outside the solar system. Here we focus on a complementary aspect of exoplanet characterisation connecting astronomy to prebiotic chemistry: the search for molecules associated with the origin of life, prebiosignatures. Prebiosignature surveys in planetary atmospheres offer the potential to both constrain the ubiquity of life in the galaxy and provide important tests of current prebiotic syntheses outside of the laboratory setting. Here, we quantify the minimum abundance of identified prebiosignature molecules that would be required for detection by transmission spectroscopy using JWST. We consider prebiosignatures on five classes of terrestrial planet: an ocean planet, a volcanic planet, a post-impact planet, a super-Earth, and an early Earth analogue. Using a novel modelling and detection test pipeline, with simulated JWST noise, we find the detection thresholds of hydrogen cyanide (HCN), hydrogen sulfide (H2S), cyanoacetylene (HC3N), ammonia (NH3), methane (CH4), acetylene (C2H2), sulfur dioxide (SO2), nitric oxide (NO), formaldehyde (CH2O), and carbon monoxide (CO) in a variety of low mean molecular weight (<5) atmospheres. We test the dependence of these detection thresholds on M dwarf target star and the number of observed transits, finding that a modest number of transits (1-10) are required to detect prebiosignatures in numerous candidate planets, including TRAPPIST-1e with a high mean molecular weight atmosphere. We find that the NIRSpec G395M/H instrument is best suited for detecting most prebiosignatures.

Karen Mudryk, Chin Lee, Lukáš Tomaník et al.

Site-specific information on how adenosine triphosphate in the aqueous phase (ATP$_{(aq)}$) interacts with magnesium (Mg$^{2+}_{(aq)}$) is a prerequisite to understanding its complex biochemistry. To gather such information, we apply liquid-jet photoelectron spectroscopy (LJ-PES) assisted by electronic-structure calculations to study ATP$_{(aq)}$ solutions with and without dissolved Mg$^{2+}$. Valence photoemission data reveal spectral changes in the phosphate and adenine features of ATP$_{(aq)}$ due to interactions with the divalent cation. Chemical shifts in Mg 2p, Mg 2s, P 2p, and P 2s core-level spectra as a function of the Mg$^{2+}$/ATP concentration ratio are correlated to the formation of [MgATP]$^{-2}_{(aq)}$ and Mg$_2$ATP$_{(aq)}$ complexes, demonstrating the element-sensitivity of the technique to Mg$^{2+}$-phosphate interactions. In addition, we report and compare P 2s data from ATP$_{(aq)}$ and adenosine mono- and di-phosphate (AMP$_{(aq)}$ and ADP$_{(aq)}$, respectively) solutions, probing the electronic structure of the phosphate chain and the local environment of individual phosphate units in ATP$_{(aq)}$. Finally, we have recorded intermolecular Coulombic decay (ICD) spectra initiated by ionization of Mg 1s electrons to probe ligand exchange in the Mg$^{2+}$-ATP$_{(aq)}$ coordination environment, demonstrating the unique capabilities of ICD for revealing structural information. Our results provide an overview of the electronic structure of ATP$_{(aq)}$ and Mg$^{2+}$-ATP$_{(aq)}$ moieties relevant to phosphorylation and dephosphorylation reactions that are central to bioenergetics in living organisms.

Sanghamitra Chakraborty, Phalguni Chakrabarti, Arpan Kumar Goswami et al.

Introduction: Absenteeism among medical undergraduate students during lecture classes is a worldwide problem in medical education. Their disengaged attitude towards attending lectures is associated with poor grades in examinations and contributes to poor professional socialisation. Aim: To identify the different factors responsible for absenteeism among medical undergraduate students during lecture classes and gather feedback that may help improve the content and delivery of these classes. Materials and Methods: This cross-sectional survey was conducted at the Department of Biochemistry, Bankura Sammilani Medical College, West Bengal, India. The study duration was six months, from October 2022 to March 2023. A total of 199 undergraduate medical students from phase-I voluntarily participated in the study out of a total of 200 students. A prevalidated questionnaire using the Likert scale was used as the study tool to determine the students’ perspectives on poor attendance. Additionally, a focused group discussion was held to obtain the students’ opinions on improving the presentation of lectures. The responses were recorded, and the Tastle and Wierman tests were conducted to derive a consensus opinion. Results: Among the participants, 169 (84.9%) strongly agreed and 125 (62.8%) agreed that access to multiple websites and a preference for self-study were factors leading to skipping lectures, respectively. There was a strong agreement, with a consensus score of 0.52, that factors such as the inability of the mental capacity to match the chosen course, poor content, and monotonous presentation were important contributors to absenteeism. A significant correlation was observed between internal assessment scores and lecture attendance (p-value <0.01, r-value=0.4). Approximately 44% of participants believed that a chalk and talk approach followed by small group discussions was the best teaching method. Conclusion: This cross-sectional survey identified multiple factors, such as access to various e-learning platforms, a preference for self/group study, and technical difficulties, as reasons for poor attendance in lecture classes. However, improvements in content, mode of presentation, and clinical relevance of topics may enhance students’ attitudes towards attending regular lectures and improve their performance.

Tomasz Stołtny, Michał Dobrakowski, Aleksander Augustyn et al.

Abstract Purpose Current epidemiological data forecast an almost 40% increase in the number of hip arthroplasty performed in the population of patients with osteoarthritis in 2060, compared to year 2018. On the basis of 10 years of observation, the failure rate after a metal-on-metal hip replacement is between 56.7 and 88.9%, depending on the used implant. Methods Seventy-six men operated using metaphyseal hip prostheses, with modular metal heads: the J&J DePuy ASR and Biomet Recap-Magnum systems, after a period of about 5–7 years after the procedure, were assessed twice (an interval of 6 months) in terms of the parameters of oxidative stress and the concentration of chromium, cobalt and ions nickel, as well as their impact on the current clinical status and quality of life. Results The mean values of the Co and Cr ion concentrations increased in a statistically significant manner at the individual stages of the study (13.20 Co and 18.16 Cr) for J&J DePuy ASR. Using the WOMAC-hip, HHS and SF-12 rating scales, the functional status of operated patients in both study groups did not change in a statistically significant manner during subsequent visits. There was a statistically significant increase in perceived pain in patients operated bilaterally with the J&J DePuy ASR system. The severity of pain could be related to the increase in the concentration of Co and Cr ions; however, it concerned a small group of bilaterally operated patients (n = 3 + n = 4). Conclusions Metal-on-metal configuration in hip arthroplasty significantly influences with the increase in the concentration of chromium and cobalt ions in a double assessment. A statistically significant increase in the concentration of the tested Co and Cr ions in the blood correlates with an increase in the intensity of pain, especially in patients undergoing bilateral surgery. The limitation of this study is the relatively small number of bilaterally operated patients. Elevated levels of Co and Cr ions in the blood of patients operated on with the J&J DePuy ASR system increased steadily during both follow-up visits.