Bioaccumulation of therapeutic drugs by human gut bacteria.

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

ELM-the Eukaryotic Linear Motif resource-2024 update.

Short Linear Motifs (SLiMs) are the smallest structural and functional components of modular eukaryotic proteins. They are also the most abundant, especially when considering post-translational modifications. As well as being found throughout the cell as part of regulatory processes, SLiMs are extensively mimicked by intracellular pathogens. At the heart of the Eukaryotic Linear Motif (ELM) Resource is a representative (not comprehensive) database. The ELM entries are created by a growing community of skilled annotators and provide an introduction to linear motif functionality for biomedical researchers. The 2024 ELM update includes 346 novel motif instances in areas ranging from innate immunity to both protein and RNA degradation systems. In total, 39 classes of newly annotated motifs have been added, and another 17 existing entries have been updated in the database. The 2024 ELM release now includes 356 motif classes incorporating 4283 individual motif instances manually curated from 4274 scientific publications and including >700 links to experimentally determined 3D structures. In a recent development, the InterPro protein module resource now also includes ELM data. ELM is available at: http://elm.eu.org.

Fast and scalable querying of eukaryotic linear motifs with gget elm.

MOTIVATION: Eukaryotic linear motifs (ELMs), or Short Linear Motifs, are protein interaction modules that play an essential role in cellular processes and signaling networks and are often involved in diseases like cancer. The ELM database is a collection of manually curated motif knowledge from scientific papers. It has become a crucial resource for investigating motif biology and recognizing candidate ELMs in novel amino acid sequences. Users can search amino acid sequences or UniProt Accessions on the ELM resource web interface. However, as with many web services, there are limitations in the swift processing of large-scale queries through the ELM web interface or API calls, and, therefore, integration into protein function analysis pipelines is limited. RESULTS: To allow swift, large-scale motif analyses on protein sequences using ELMs curated in the ELM database, we have extended the gget suite of Python and command line tools with a new module, gget elm, which does not rely on the ELM server for efficiently finding candidate ELMs in user-submitted amino acid sequences and UniProt Accessions. gget elm increases accessibility to the information stored in the ELM database and allows scalable searches for motif-mediated interaction sites in the amino acid sequences. AVAILABILITY AND IMPLEMENTATION: The manual and source code are available at https://github.com/pachterlab/gget.

Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.

Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

Fabrication of Unique Mixed-Valent CoICoII and CuICuII Metal-Organic Frameworks (MOFs) for Desulfurization of Fuels: A Combined Experimental and Theoretical Approach toward Green Fuel.

Herein, metal-organic framework (MOF)-based adsorbents are designed with distinct hard and soft metal building units, namely, [Co2ICoII(PD)2(BP)] (Co_PD-BP) and [Cu2ICuII(PD)2(BP)] (Cu_PD-BP), where H2PD = pyrazine-1,4-diide-2,3-dicarboxylic acid and BP = 4,4'-bipyridine. The designed MOFs were characterized via spectral and SCXRD techniques, which confirm the mixed-valent states (+1 and +2) of the metal ions. Topological analysis revealed the rare ths and gwg topologies for Co MOF, while Cu-MOF exhibits a unique 8T21 topology in the 8-c net (point symbol for net: {424·64}). Moreover, severe environmental issues can be resolved by effectively removing heterocyclic organosulfur compounds from fuels via adsorptive desulfurization. Further, the developed MOFs were investigated for sulfur removal via adsorptive desulfurization from a model fuel consisting of dibenzothiophene (DBT), benzothiophene (BT), and thiophene (T) in the liquid phase using n-octane as a solvent. The findings revealed that Cu_PD-BP effectively removes the DBT with a removal efficiency of 86% at 300 ppm and an operating temperature of 25 °C, with a recyclability of up to four cycles. The adsorption kinetic analysis showed that the pseudo-first-order model could fit better with the experimental data indicating the physisorption process. Further, the studies revealed that adsorption capacity increased with the increasing initial DBT concentration with a remarkable capacity of 70.5 mg/g, and the adsorption process was well described by the Langmuir isotherm. The plausible reason behind the enhanced removal efficiency shown by Cu_PD-BP as compared to Co_PD-BP could be the soft-soft interactions between soft sulfur and soft Cu metal centers. Interestingly, density functional theory (DFT) studies were done in order to predict the mechanism of binding of thiophenic compounds with Cu_PD-BP, which further ascertained that along with other interactions, the S···π and S···Cu interactions predominate, resulting in a high uptake of DBT as compared to others. In essence, Cu_PD-BP turns out to be a promising adsorbent in the field of fuel desulfurization for the benefit of mankind.

C-H bond activation by high-valent iron/cobalt-oxo complexes: a quantum chemical modeling approach.

High-valent metal-oxo species serve as key intermediates in the activation of inert C-H bonds. Here, we present a comprehensive DFT analysis of the parameters that have been proposed as influencing factors in modeled high-valent metal-oxo mediated C-H activation reactions. Our approach involves utilizing DFT calculations to explore the electronic structures of modeled FeIVO (species 1) and CoIVO ↔ CoIII-O˙ (species 2), scrutinizing their capacity to predict improved catalytic activity. DFT and DLPNO-CCSD(T) calculations predict that the iron-oxo species possesses a triplet as the ground state, while the cobalt-oxo has a doublet as the ground state. Furthermore, we have investigated the mechanistic pathways for the first C-H bond activation, as well as the desaturation of the alkanes. The mechanism was determined to be a two-step process, wherein the first hydrogen atom abstraction (HAA) represents the rate-limiting step, involving the proton-coupled electron transfer (PCET) process. However, we found that the second HAA step is highly exothermic for both species. Our calculations suggest that the iron-oxo species (Fe-O = 1.672 Å) exhibit relatively sluggish behavior compared to the cobalt-oxo species (Co-O = 1.854 Å) in C-H bond activation, attributed to a weak metal-oxygen bond. MO, NBO, and deformation energy analysis reveal the importance of weakening the M-O bond in the cobalt species, thereby reducing the overall barrier to the reaction. This catalyst was found to have a C-H activation barrier relatively smaller than that previously reported in the literature.

The Eukaryotic Linear Motif resource: 2022 release.

Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge. In the current update, 30 novel motif classes have been added and five existing classes have undergone major revisions. The update includes 411 new motif instances mostly focused on cell-cycle regulation, control of the actin cytoskeleton, membrane remodelling and vesicle trafficking pathways, liquid-liquid phase separation and integrin signalling. Many of the newly annotated motif-mediated interactions are targets of pathogenic motif mimicry by viral, bacterial or eukaryotic pathogens, providing invaluable insights into the molecular mechanisms underlying infectious diseases. The current ELM release includes 317 motif classes incorporating 3934 individual motif instances manually curated from 3867 scientific publications. ELM is available at: http://elm.eu.org.

Investigation of efficient photoconduction and enhanced luminescence characteristics of Ce-doped ZnO nanophosphors for UV sensors.

This study involves the single-step, mass-scale productive synthesis, photoconduction, and luminescence characteristics of pure and cerium rare-earth-ion-doped ZnO (CZO) nanophosphors with different Ce concentrations (Ce: 0, 2, 4, 6, and 8 wt.%) synthesized using the solid-state reaction method. The synthesized nanophosphors were characterized for their structural, morphological, optical, and photoconductivity (PC) properties using X-ray diffraction (XRD), field-effect scanning electron microscopy (FE-SEM), energy dispersive spectroscopy, Fourier-transform infrared (FT-IR), photoluminescence (PL), and PC measurements. The sharp diffraction peaks of XRD results exhibit the formation of crystalline hexagonal wurtzite ZnO nanostructures. The decrease in diffraction peak intensities of CZO with an increase in Ce concentrations signifies the deterioration of the ZnO crystal. FE-SEM images exhibit the good crystalline quality of nanophosphors composed of spherical- and elongated-shaped nanoparticles that are distributed consistently on the surface. The energy dispersive X-ray pattern of the 4 wt.% Ce-doped ZnO (CZO4 ) sample confirms the doping of Ce in ZnO. The presence of chemical bonds and functional groups corresponds to transmittance peaks established using FT-IR spectroscopy. Deconvoluted PL spectra show two major emission peaks, one in the UV region, which is near-band-edge, and the other in the visible region ranging from ~456 to 561 nm. In PC studies, current-voltage (I-V) and current-time (I-T) characteristics, that is, rise/decayin current under dark as well as UV light conditions, are also investigated. Efficient photoconduction is observed in CZO samples. The obtained results indicate the suitability to luminescent and photosensor applications.

Improving Zinc and Iron Biofortification in Wheat through Genomics Approaches.

Globally, about 20% of calories (energy) come from wheat. In some countries, it is more than 70%. More than 2 billion people are at risk for zinc deficiency and even more, people are at risk of iron deficiency, nearly a quarter of all children underage group of 5 are physically and cognitively stunted, and lack of dietary zinc is a major contributing factor. Biofortified wheat with elevated levels of zinc and iron has several potential advantages as a delivery vehicle for micronutrients in the diets of resource-poor consumers who depend on cereal-based diets. The conventional breeding strategies have been successful in the introduction of novel alleles for grain Zn and Fe that led to the release of competitive Zn enriched wheat varieties in South Asia. The major challenge over the next few decades will be to maintain the rates of genetic gains for grain yield along with increased grain Zn/Fe concentration to meet the food and nutritional security challenges. Therefore, to remain competitive, the performance of Zn-enhanced lines/varieties must be equal or superior to that of current non-biofortified elite lines/varieties. Since both yield and Zn content are invisible and quantitatively inherited traits except few intermediate effect QTL regions identified for grain Zn, increased breeding efforts and new approaches are required to combine them at high frequency, ensuring that Zn levels are steadily increased to the required levels across the breeding pipelines. The current review article provides a comprehensive list of genomic regions for enhancing grain Zn and Fe concentrations in wheat including key candidate gene families such NAS, ZIP, VLT, ZIFL, and YSL. Implementing forward breeding by taking advantage of the rapid cycling trait pipeline approaches would simultaneously introgress high Zn and Fe QTL into the high Zn and normal elite lines, further increasing Zn and Fe concentrations.

ELM-the eukaryotic linear motif resource in 2020.

The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology community for investigating functional regions in many proteins. In this update, we have added 21 novel motif classes, made major revisions to 12 motif classes and added >400 new instances mostly focused on DNA damage, the cytoskeleton, SH2-binding phosphotyrosine motifs and motif mimicry by pathogenic bacterial effector proteins. The current release of the ELM database contains 289 motif classes and 3523 individual protein motif instances manually curated from 3467 scientific publications. ELM is available at: http://elm.eu.org.

Male Genital Injuries in Infants Caused by the Bite of Pet Pups: Case Series and Literature Review.

Injuries to male genitalia of infants due to bite of a pet pup are a rare occurrence. Few dog bite injuries to the genitalia of male infants have been reported, however, similar injuries have not been reported by the bite of pet puppies. Male genital injury in three male infants aged 8, 10, and 11 months, by the bite of pet puppies aged 1-2 months, ranged from avulsion of penile and part of scrotal skin with loss of both testes in case 1, a near circumferential laceration of penile skin at the base of penis with scrotal laceration in case 2, and laceration in mid penile shaft resulting in degloving and complete transaction of distal penile urethra with scrotal laceration in case 3. All these infants were appropriately managed surgically (case 1 and 3) and conservatively (case 2) and were given thorough toileting of wound, antibiotics, prophylaxis for tetanus and rabies. Some of these injuries may require complex surgical procedures to reconstruct the male genitalia. Timely management with aggressive intent and conserving the local tissue is the key to success. We describe a case series of injury to the external genitalia of three male infants by the bite of pet puppies, their possible predisposing factors, treatment, and follow-up. A case report and series like this have not been reported in literature so far to the best of our knowledge.

Anticancer properties, apoptosis and catecholase mimic activities of dinuclear cobalt(II) and copper(II) Schiff base complexes.

The present work describes coordination chemistry and biological evaluation of two novel dinuclear complexes [Co2(HL1)2(H2O)2]·8H2O (1) and [Cu2(L2)2] (2) obtained from the Schiff base ligands, H3L1 and H2L2 (formed in situ). The two complexes are characterized by single crystal X-ray, spectral and variable temperature magnetic and theoretical (DFT/TDDFT) analysis. X-ray analysis confirms both the complexes to be dinuclear with distorted octahedral and square pyramidal geometry around Co(II) and Cu(II) ions, respectively. Magnetic studies reveal presence of moderate ferromagnetic interactions in both the complexes with J = 98 (1) and 32 (2) cm-1. The magnetic interactions are further corroborated by DFT studies. Co(II) complex (1) exhibited enhanced catecholase activity with Kcat = 213.48 h-1, which is attributed to the greater extent of charge contribution on Co2+ as compared to Cu2+ as determined by DFT calculations. Furthermore, both the complexes show potent anticancer activity toward HeLa (cervical) and A549 (lung) cancer cell lines with IC50 = 6-7 µM at 48 h, which ascertains both the complexes as better anticancer drugs than cisplatin. Furthermore, 1 and 2 exhibit apoptosis of HeLa cells by demonstrating nuclear blebbings with shrinking morphology. Hence, the present complexes could be employed as a model for metalloenzymes as well as potential anticancer substituents of cisplatin in future course.

The eukaryotic linear motif resource - 2018 update.

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome.

Early Excision and Grafting in Burns: An Experience in a Tertiary Care Industrial Hospital of Eastern India.

Introduction To compare the burn patients undergoing early excision and grafting (within 7 days of burn injury) with the patients undergoing late surgeries (more than 7 days after burn injury) to see if there was any difference in surgical and outcome parameters including length of stay, expenditure, and overall outcome of the patients. Material and Methods A retrospective analysis of the data collected from the burn care unit records over a period of one year was done. Fifty-eight patients who matched with our inclusion criteria were divided into two groups. An early excision group who underwent surgery within 7 days of sustaining burn injury ( n = 24) and a late excision group who underwent excision and grafting/debridement after 7 days of sustaining burn ( n = 34). Data recorded included demographic variables like age, sex, percentage total body surface area (TBSA) burn; nature of burn; date of sustaining burn; date of admission to the burn care unit; and treatment and outcome parameters like date of surgery, days from burn injury to first surgery, number of surgeries, type of surgery, percentage of TBSA resurfaced with skin graft, blood products used, length of stay, outcome, and total expenditure incurred by patients. Results There was no statistically significant difference in the number of surgeries done, the units of packed cell used, and the number of fresh frozen plasma (FFP) used between the early excision group and the late excision group. The length of stay was significantly low in the early excision group as compared with the late excision group. The expenditure incurred in the treatment of the early excision group was significantly lower than the cost of treatment of the late excision group. Conclusion Early excision and grafting in burn cases reduces the length of the stay of burn patients and, in turn, reduces the cost of treatment. However, having a dedicated burn care unit is important for the hospitals and both public and private hospitals should make a move in that direction.

Short, Tin-Free Synthesis of All Three Inthomycins.

The inthomycins are a family of structurally and biologically rich natural products isolated from Streptomyces species. Herein the implementation of a modular synthetic route is reported that has enabled the enantioselective synthesis of all three inthomycins. Key steps include Suzuki and Sonogashira cross-couplings and an enantioselective Kiyooka aldol reaction.

ELM 2016--data update and new functionality of the eukaryotic linear motif resource.

The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats.

From Pacemaker to Wearable: Techniques for ECG Detection Systems.

With the alarming rise in the deaths due to cardiovascular diseases (CVD), present medical research scenario places notable importance on techniques and methods to detect CVDs. As adduced by world health organization, technological proceeds in the field of cardiac function assessment have become the nucleus and heart of all leading research studies in CVDs in which electrocardiogram (ECG) analysis is the most functional and convenient tool used to test the range of heart-related irregularities. Most of the approaches present in the literature of ECG signal analysis consider noise removal, rhythm-based analysis, and heartbeat detection to improve the performance of a cardiac pacemaker. Advancements achieved in the field of ECG segments detection and beat classification have a limited evaluation and still require clinical approvals. In this paper, approaches on techniques to implement on-chip ECG detector for a cardiac pacemaker system are discussed. Moreover, different challenges regarding the ECG signal morphology analysis deriving from medical literature is extensively reviewed. It is found that robustness to noise, wavelet parameter choice, numerical efficiency, and detection performance are essential performance indicators required by a state-of-the-art ECG detector. Furthermore, many algorithms described in the existing literature are not verified using ECG data from the standard databases. Some ECG detection algorithms show very high detection performance with the total number of detected QRS complexes. However, the high detection performance of the algorithm is verified using only a few datasets. Finally, gaps in current advancements and testing are identified, and the primary challenge remains to be implementing bullseye test for morphology analysis evaluation.

Design of a Biorthogonal Wavelet Transform Based R-Peak Detection and Data Compression Scheme for Implantable Cardiac Pacemaker Systems.

Bradycardia can be modulated using the cardiac pacemaker, an implantable medical device which sets and balances the patient's cardiac health. The device has been widely used to detect and monitor the patient's heart rate. The data collected hence has the highest authenticity assurance and is convenient for further electric stimulation. In the pacemaker, ECG detector is one of the most important element. The device is available in its new digital form, which is more efficient and accurate in performance with the added advantage of economical power consumption platform. In this work, a joint algorithm based on biorthogonal wavelet transform and run-length encoding (RLE) is proposed for QRS complex detection of the ECG signal and compressing the detected ECG data. Biorthogonal wavelet transform of the input ECG signal is first calculated using a modified demand based filter bank architecture which consists of a series combination of three lowpass filters with a highpass filter. Lowpass and highpass filters are realized using a linear phase structure which reduces the hardware cost of the proposed design approximately by 50%. Then, the location of the R-peak is found by comparing the denoised ECG signal with the threshold value. The proposed R-peak detector achieves the highest sensitivity and positive predictivity of 99.75 and 99.98 respectively with the MIT-BIH arrhythmia database. Also, the proposed R-peak detector achieves a comparatively low data error rate (DER) of 0.002. The use of RLE for the compression of detected ECG data achieves a higher compression ratio (CR) of 17.1. To justify the effectiveness of the proposed algorithm, the results have been compared with the existing methods, like Huffman coding/simple predictor, Huffman coding/adaptive, and slope predictor/fixed length packaging.

Monitoring Early-Stage Protein Aggregation by an Aggregation-Induced Emission Fluorogen.

Highly ordered protein aggregates, termed amyloid fibrils, are associated with a broad range of diseases, many of which are neurodegenerative, for example, Alzheimer's and Parkinson's. The transition from soluble, functional protein into insoluble amyloid fibril occurs via a complex process involving the initial generation of highly dynamic early stage aggregates or prefibrillar species. Amyloid probes, for example, thioflavin T and Congo red, have been used for decades as the gold standard for detecting amyloid fibrils in solution and tissue sections. However, these well-established dyes do not detect the presence of prefibrillar species formed during the early stages of protein aggregation. Prefibillar species have been proposed to play a key role in the cytotoxicity of amyloid fibrils and the pathogenesis of neurodegenerative diseases. Herein, we report a novel fluorescent dye (bis(triphenylphosphonium) tetraphenylethene (TPE-TPP)) with aggregation-induced emission characteristics for monitoring the aggregation process of amyloid fibrils. An increase in TPE-TPP fluorescence intensity is observed only with ordered protein aggregation, such as amyloid fibril formation, and not with stable molten globules states or amorphously aggregating species. Importantly, TPE-TPP can detect the presence of prefibrillar species formed early during fibril formation. TPE-TPP exhibits a distinctive spectral shift in the presence of prefibrillar species, indicating a unique structural feature of these intermediates. Using fluorescence polarization, which reflects the mobility of the emitting entity, the specific oligomeric pathways undertaken by various proteins during fibrillation could be discerned. Furthermore, we demonstrate the broad applicability of TPE-TPP to monitor amyloid fibril aggregation, including under diverse conditions such as at acidic pH and elevated temperature, or in the presence of amyloid inhibitors.