The Dawn of a New Era: Targeting the "Undruggables" with Antibody-Based Therapeutics.

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more "undruggable" targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

Investigating molecular interactions between human transferrin and resveratrol through a unified experimental and computational approach: Role of natural compounds in Alzheimer's disease therapeutics.

Disruptions to iron metabolism and iron homeostasis have emerged as significant contributors to the development and progression of Alzheimer's disease (AD). Human transferrin plays a key part in maintaining iron equilibrium throughout the body, highlighting its importance in AD. Many plant-derived compounds and dietary constituents show promise for preventing AD. Polyphenols that are abundant in fruits, vegetables, teas, coffee, and herbs possess neuroprotective attributes. Resveratrol is a natural polyphenol present in various plant sources like grapes, berries, peanuts, and red wine that has garnered research interest due to its wide range of biological activities. Notably, resveratrol exhibits neuroprotective effects that may help prevent or treat AD through multiple mechanisms. In the present study, we employed a combination of molecular docking and all-atom molecular dynamic simulations (MD) along with experimental approaches to unravel the intricate interactions between transferrin and resveratrol deciphering the binding mechanism. Through molecular docking analysis, it was determined that resveratrol occupies the iron binding pocket of transferrin. Furthermore, MD simulations provided a more profound insight into the stability and conformational dynamics of the complex suggesting that the binding of resveratrol introduced localized flexibility, while maintaining overall stability. The spectroscopic observations yielded clear evidence of substantial binding between resveratrol and transferrin, confirming the computational findings. The identified binding mechanism and conformational stability hold potential for advancing the development of innovative therapeutic approaches targeting AD through resveratrol, particularly concerning iron homeostasis. These insights serve as a platform for considering the natural compounds in the realm of AD therapeutics.

A goal-oriented hemodynamic approach to acute myocardial infarction complicated by cardiogenic shock-A single center experience.

BACKGROUND: Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is the most common cause of mortality following AMI, and treatment algorithms vary widely. We report the results of an analysis using time-sensitive, hemodynamic goals in the treatment of AMI-CS in a single center study. METHODS: Consecutive patients with AMI-CS from November 2016 through December 2021 were included in our retrospective analysis. Clinical characteristics and outcomes were analyzed using the electronic medical records. We identified 63 total patients who were admitted to our center with AMI-CS, and we excluded patients who did not have clear timing of AMI onset or CS onset. We evaluated the rate of survival to hospital discharge based on the quantity of certain time-sensitive hemodynamic goals were met. RESULTS: We identified 63 patients who met criteria for AMI-CS, 39 (62%) of whom survived to hospital discharge. Odds of survival were closely related to the achievement of four time-dependent goals: cardiac power output (CPO) >0.6 Watts (W), pulmonary artery pulsatility index (PAPi) >1, lactate <4 mmol/L, and <2 vasopressors required. Of the 63 total patients, 36 (57%) received intra-aortic balloon pump (IABP) and 18 (29%) received an Impella CP (Abiomed) as an initial mechanical circulatory support strategy. Six patients were escalated from IABP to Impella CP for additional hemodynamic support. Nine patients were treated with vasopressors/inotropes alone. Regarding the 39 patients who survived to hospital discharge, 75% of patients met 3 or 4 goals at 24 h, whereas only 16% of deceased patients met 3 or 4 goals at 24 h. Of the 24 patients who did not survive to hospital discharge, 18 (75%) met either 0-1 goal at 24 h. There was no effect of the initial treatment strategy on achieving 3-4 goals at 24 h. CONCLUSION: Our study evaluated the association of meeting 4 time-sensitive goals (CPO >0.6 W, PAPi >1, <2 vasopressors, and lactate <4 mmol/L) at 24 h after treatment for AMI-CS with in-hospital mortality. Our data show, in line with previous data, that the higher number of goals met at 24 h was associated with improved in-hospital mortality regardless of treatment strategy.

Therapeutic anti-amyloid ß antibodies cause neuronal disturbances.

INTRODUCTION: Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and edema in the brain, following administration of Biogen's Aduhelm/aducanumab (amino acids 3-7 of the Aß peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aß peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aß peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic edema, respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aß antibodies remain largely unknown, however, recent reports demonstrated that therapeutic anti-prion antibodies activate neuronal allergenic proteomes following cross-linking cellular prion protein. METHODS: Here, we report that treatment of human induced pluripotent stem cells- derived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aß1-6, or anti-Aß17-23 antibodies activate a significant number of allergenic-related proteins as assessed by mass spectrometry. RESULTS: Interestingly, a large proportion of the identified proteins included cytokines such as interleukin (IL)-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aß1-6, or anti-Aß17-23 antibody treatment. DISCUSSION: These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD. HIGHLIGHTS: Allergenic-related proteins are often linked with Alzheimer's disease (AD). We investigated the effects of amyloid beta (Aß) immunotherapy on stem cell derived neurons and primary neuronal cells co-cultured with microglia. Anti-Aß antibody treatment of neurons or neurons co-cultured with microglia led to activation of a substantial number of allergenic-related genes. These allergenic-related genes are associated with endothelial dysfunction possibly responsible for ARIA.

Bacillus amyloliquefaciens AK-12 Helps Rapeseed Establish a Protection against Brevicoryne brassicae.

Aphids are a serious threat to rapeseed (Brassica napus L.) production, and cause unmanageable loss. Therefore, effective prevention and management strategies are urgently required to avoid losses. Bacillus amyloliquefaciens AK-12 isolated from a dead aphid with aphicidal activity was tagged with a green fluorescent protein through a natural transformation. The transformed strains were checked for stability and growth, and the best-performing strain was tested for its colonization inside and outside the rapeseed plant. The stability of AK-12-GFP reached more than 95%, and the growth curve was consistent with that of AK-12. After 30 days of treatment, the colonization of 1 × 106 CFU/g was recorded in rapeseed leaves. Interestingly, AK-12 reduced the aphid transmission rate compared with the control and improved the growth of the rapeseed seedlings. Meanwhile, the AK-12 strain also exhibited phosphorus, potassium-solubilizing, and nitrogen-fixing activity, and produced 2.61 µg/mL of IAA at 24 h. Regulation in the activity of four enzymes was detected after the AK-12 treatment. Phenylalanine ammonia lyase (PAL) was recorded at a maximum of 86.84 U/g after 36 h, and catalase (CAT) decreased after 48 h; however, peroxidase (POD) and polyphenol oxidase (PPO) reached the maximum within 12 h of AK-12 application. Additionally, important resistance genes related to these enzymes were upregulated, indicating the activation of a defense response in the rapeseed against aphids. In conclusion, defense enzymes and defense-related gene activation could improve the pest resistance in rapeseed, which has good application prospects for the future to be developed into biopesticide.

Rapid Detection of Cd2+ Ions in the Aqueous Medium Using a Highly Sensitive and Selective Turn-On Fluorescent Chemosensor.

Herein, a novel optical chemosensor, (CM1 = 2, 6-di((E)-benzylidene)-4-methylcyclohexan-1-one), was designed/synthesized and characterized by 1H-NMR and FT-IR spectroscopy. The experimental observations indicated that CM1 is an efficient and selective chemosensor towards Cd2+, even in the presence of other metal ions, such as Mn2+, Cu2+, Co2+, Ce3+, K+, Hg2+,, and Zn2+ in the aqueous medium. The newly synthesized chemosensor, CM1, showed a significant change in the fluorescence emission spectrum upon coordination with Cd2+. The formation of the Cd2+ complex with CM1 was confirmed from the fluorometric response. The 1:2 combination of Cd2+ with CM1 was found optimum for the desired optical properties, which was confirmed through fluorescent titration, Job's plot, and DFT calculation. Moreover, CM1 showed high sensitivity towards Cd2+ with a very low detection limit (19.25 nM). Additionally, the CM1 was recovered and recycled by the addition of EDTA solution that combines with Cd2+ ion and, hence, frees up the chemosensor.

Randomized Trial of Platelet-Transfusion Thresholds in Neonates.

BACKGROUND: Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia. METHODS: In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization. RESULTS: A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67). CONCLUSIONS: Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).

Robust contrast enhancement method using a retinex model with adaptive brightness for detection applications.

Low light image enhancement with adaptive brightness, color and contrast preservation in degraded visual conditions (e.g., extreme dark background, lowlight, back-light, mist. etc.) is becoming more challenging for machine cognition applications than anticipated. A realistic image enhancement framework should preserve brightness and contrast in robust scenarios. The extant direct enhancement methods amplify objectionable structure and texture artifacts, whereas network-based enhancement approaches are based on paired or large-scale training datasets, raising fundamental concerns about their real-world applicability. This paper presents a new framework to get deep into darkness in degraded visual conditions following the fundamental of retinex-based image decomposition. We separate the reflection and illumination components to perform independent weighted enhancement operations on each component to preserve the visual details with a balance of brightness and contrast. A comprehensive weighting strategy is proposed to constrain image decomposition while disrupting the irregularities of high frequency reflection and illumination to improve the contrast. At the same time, we propose to guide the illumination component with a high-frequency component for structure and texture preservation in degraded visual conditions. Unlike existing approaches, the proposed method works regardless of the training data type (i.e., low light, normal light, or normal and low light pairs). A deep into darkness network (D2D-Net) is proposed to maintain the visual balance of smoothness without compromising the image quality. We conduct extensive experiments to demonstrate the superiority of the proposed enhancement. We test the performance of our method for object detection tasks in extremely dark scenarios. Experimental results demonstrate that our method maintains the balance of visual smoothness, making it more viable for future interactive visual applications.

A study on the uptake of methylene blue by biodegradable and eco-friendly carboxylated starch grafted polyvinyl pyrrolidone.

This study is based on the removal of methylene blue (MB) from aqueous solution by cost effective and biodegradable adsorbent carboxymethyl starch grafted polyvinyl pyrolidone (Car-St-g-PVP). The Car-St-g-PVP was synthesized by grafting vinyl pyrolidone onto carboxymethyl starch by free radical polymerization reaction. The structure and different properties of Car-St-g-PVP were determined by 1H NMR, FT-IR, XRD, TGA and SEM. A series of batch experiments were conducted for the removal of MB, The adsorption affecting factors such as temperature, contact time, initial concentration of MB dye, dose of Car-St-g-PVP and pH were studied in detail. The other parameters like the thermodynamic study, kinetics and isothermal models were fitted to the experimental data. The results showed that pseudo 2nd order kinetics and Langmuir's adsorption isotherms were best fitted to experimental data with regression coefficient R2 viz. 0.99 and 0.97. The kinetic study showed that the adsorption mechanism favored chemisorption. The Gibbs free energy (ΔG°) for the adsorption process was found to be -7.31 kJ/mol, -8.23 kJ/mol, -9.00 kJ/mol and -10.10 kJ/mol at 25 °C, 35 °C, 45 °C and 55 °C respectively. The negative values of ΔG° suggested the spontaneous nature of the adsorption process. Similarly, the positive values of entropy (ΔS°) and enthalpy (ΔH°) 91.27 J/k.mol and 19.90 kJ/mol showed the increasing randomness and endothermic nature of the adsorption process. The value of separation factor (RL) was found to be less than one (RL < 1), which supported the feasibility of the adsorption process. The maximum MB removal percentage (% R) was found to be 98.6%. So, these findings show that Car-St-g-PVP can be meritoriously used for the treatment of MB from wastewater.

Use of ballasted flocculation (BF) sludge for the manufacturing of lightweight aggregates.

Ballasted flocculation (BF) is an efficient way to remove the turbidity from surface water. The objective of the present study is to optimize the ballast (magnetite), coagulant (poly aluminum chloride) concentration and pH for efficient turbidity removal from surface water. To do this, the sludge produced from an optimized dose of a BF treatment was utilized for the production of lightweight (LW) aggregates by combining it with hard clay and sewage sludge. The LW aggregates were formed by means of rapid sintering in the temperature range of 1000-1200 °C with an exposure time of 10 min. The physical properties of the LW aggregates, in this case the leaching of heavy metals, the bulk density and the microstructure, were investigated. The results indicated that corresponding ballast and coagulant concentrations of 0.75 g/L and 30 mg/L (poly aluminum chloride (PAC)) resulted in the maximum removal efficiency of ≈95%. Using a mixture of BF sludge (30 wt%), dry sewage sludge (20 wt%), and hard clay (50 wt%), aggregates with a density of around 1.0 g/cm3 could be produced. In addition, it was confirmed that the manufactured aggregate was environmentally stable as the elution of heavy metals was suppressed.

Coagulation Behavior of Antimony Oxyanions in Water: Influence of pH, Inorganic and Organic Matter on the Physicochemical Characteristics of Iron Precipitates.

The presence of inorganic and organic substances may alter the physicochemical properties of iron (Fe) salt precipitates, thereby stabilizing the antimony (Sb) oxyanions in potable water during the chemical treatment process. Therefore, the present study aimed to examine the surface characteristics, size of Fe flocs and coagulation performance of Sb oxyanions under different aqueous matrices. The results showed that surface properties of Fe flocs significantly varies with pH in both Sb(III, V) suspensions, thereby increasing the mobility of Sb(V) ions in alkaline conditions. The negligible change in surface characteristics of Fe flocs was observed in pure water and Sb(III, V) suspension at pH 7. The key role of Van der Waals forces of attraction as well as hydration force in the aggregation of early formed flocs were found, with greater agglomeration capability at higher more ferric chloride dosage. The higher Sb(V) loading decreased the size of Fe flocs and reversed the surface charge of precipitates, resulting in a significant reduction in Sb(V) removal efficiency. The competitive inhibition effect on Sb(III, V) removal was noticed in the presence of phosphate anions, owing to lowering of ζ-potential values towards more negative trajectory. The presence of hydrophobic organic matter (humic acid) significantly altered the surface characteristics of Fe flocs, thereby affecting the coagulation behavior of Sb in water as compared to the hydrophilic (salicylic acid). Overall, the findings of this research may provide a new insight into the variation in physicochemical characteristics of Fe flocs and Sb removal behavior in the presence of inorganic and organic compounds during the drinking water treatment process.

Multifunctionality and intrinsic disorder of royal jelly proteome.

Royal Jelly (RJ) is a gelatinous white-yellowish fluid, possessing a sour taste and a slight phenolic smell that is secreted by the hypopharyngeal and mandibular salivary glands of the nurse honeybees, and is used in nutrition of larvae and adult queens. Similar to other substances associated with the activities of honeybees, RJ not only contains nutritive components, such as carbohydrates, proteins, peptides, lipids, vitamins, and mineral salts, but also represents a natural ingredient with cosmetic and health-promoting properties. RJ is characterized by remarkable multifunctionality, possessing numerous biological activities. Although this multifunctionality of RJ can be considered as a consequence of its complex nature, many proteins and peptides in RJ are polyfunctional entities themselves. In this article, we show that RJ proteins contain different levels of intrinsic disorder, have sites of post-translational modifications, can be found in multiple isoforms, and many of them possess disorder-based binding sites, suggesting that the conformational ensembles of the RJ proteins might undergo change as a result of their interaction with specific binding partners. All these observations suggest that the multifunctionality of proteins and peptides from RJ is determined by their structural heterogeneity and polymorphism, and serve as an illustration of the protein structure-function continuum concept.

Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy.

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.

Severe acute respiratory syndrome coronavirus 2 infection reaches the human nervous system: How?

Without protective and/or therapeutic agents the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection known as coronavirus disease 2019 is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body cross talk between organs. The majority of SARS-CoV-2-infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.

Evaluation of ThT augmentation and RLS inner filter effect caused by highly fluorescent coumarin derivative and establishing it as true inhibitor of amyloid fibrillation.

Screening of inhibitors that slow down or suppress amyloid fibrils formation relies on some simple but sensitive spectroscopy techniques. Thioflavin T (ThT) fluorescence assay is one of the most common, amyloid specific and sensitive method. However, if an inhibitor is itself fluorescent in the ThT fluorescence range, its screening becomes complicated and require complementary assays. One of such molecules, 6, 7-dihydroxycoumarin (6, 7-DHC, also known as aesculetin, esculetin, and cichorigenin) is fluorescent in the ThT emission range and absorbs in the ThT excitation range. Therefore, it can produce a subtractive effect attributed to primary inner filter effect and/or additive effect due to its self-fluorescence in ThT assay. Our study shows that 6, 7-DHC produces an additive effect in ThT fluorescence, which is minimized at high concentration of ThT and decrease in ThT fluorescence is solely due to its inhibitory effect against HSA fibrillation. These ThT fluorescence-based results are verified through other complementary assays, such as Rayleigh and dynamic light scattering and amyloid-specific Congo red binding assay. Furthermore, hydrophobicity reduction is studied through Nile red (NR) and kinetics through far-UV circular dichroism (far-UV CD) in place of the most commonly employed ThT assay owing to extremely high fluorescence of 6, 7-DHC during initial incubation period.

Inhibition and disruption of amyloid formation by the antibiotic levofloxacin: A new direction for antibiotics in an era of multi-drug resistance.

Neurodegenerative diseases are a group of debilitating maladies involving protein aggregation. To this day, all advances in neurodegenerative disease therapeutics have helped symptomatically but have not prevented the root cause of the disease, i.e., the aggregation of involved proteins. Antibiotics are becoming increasingly obsolete due to the rising multidrug resistance strains of bacteria. Thus, antibiotics, if put to different use as therapeutics against other diseases, could pave a new direction to the world of antibiotics. Hence, we studied the antibiotic levofloxacin for its potential anti-amyloidogenic behavior using human lysozyme, a protein involved in non-systemic amyloidosis, as a model system. At the sub-stoichiometric level, levofloxacin was able to inhibit amyloid formation in human lysozyme as observed by various spectroscopic and microscopic methods, with IC50 values as low as 8.8 ± 0.1 µM. Levofloxacin also displayed a retarding effect on seeding phenomena by elongating the lag-phase (from 0 to 88 h) at lower concentration, and arresting lysozyme fibrillation at the lag stage in sub-stoichiometric concentrations. Structural and computational analyses provided mechanistic insight showing that levofloxacin stabilizes the lysozyme in the native state by binding to the aggregation-prone residues, and thereby inhibiting amyloid fibrillation. Levofloxacin also showed the property of disrupting amyloid fibrils into a smaller polymeric form of proteins which were less cytotoxic as confirmed by hemolytic assay. Therefore, we throw new light on levofloxacin as an amyloid inhibitor and disruptor which could pave way to utilization of levofloxacin as a potential therapeutic against non-systemic amyloidosis and neurodegenerative diseases.

Self-Formation of Superhydrophobic Surfaces through Interfacial Energy Engineering between Liquids and Particles.

The superhydrophobic surface has been used in ultradry surface applications, such as the maritime industry, windshields, non-sticky surfaces, anti-icing surfaces, self-cleaning surfaces, and so forth. However, one of the main hurdles for the production of superhydrophobic surfaces is high-cost fabrication methods. Here, we report a handy process of self-synthesis fabrication of superhydrophobic surfaces with daily supplies. Driven by the physics of biscuit dunking, we introduce a method to self-synthesize superhydrophobic surfaces from daily supplies by coating a substrate with a liquid (liquids of paraffin from candles or polydimethylsiloxane) and subsequently sprinkling powders (food-desiccant silica, alumina, sugar, salt, or flour). A mechanistic study revealed that the capillary force, governed by surface energy difference, liquid viscosity, and powder pore size, draws the liquid solution into the porous channels within the powders. The entire surface of powders, in turn, is covered with the low-surface-energy liquid to maintain the porosity, creating a 3D porous nanostructure, resulting in a water contact angle over 160°. This work provides a scientific understanding that technological developments are closely related to the science that can be seen in our daily lives. Also, we believe that further intensive studies extended from this work could enable to home-fabricate a superhydrophobic surface, such as a bathtub and sink in bathrooms and a cooking area and sink in kitchens.

Deep image enhancement for ill light imaging.

Imaging in the natural scene under ill lighting conditions (e.g., low light, back-lit, over-exposed front-lit, and any combinations of them) suffers from both over- and under-exposure at the same time, whereas processing of such images often results in over- and under-enhancement. A single small image sensor can hardly provide satisfactory quality for ill lighting conditions with ordinary optical lenses in capturing devices. Challenges arise in the maintenance of a visual smoothness between those regions, while color and contrast should be well preserved. The problem has been approached by various methods, including multiple sensors and handcrafted parameters, but extant model capacity is limited to only some specific scenes (i.e., lighting conditions). Motivated by these challenges, in this paper, we propose a deep image enhancement method for color images captured under ill lighting conditions. In this method, input images are first decomposed into reflection and illumination maps with the proposed layer distribution loss net, where the illumination blindness and structure degradation problem can be subsequently solved via these two components, respectively. The hidden degradation in reflection and illumination is tuned with a knowledge-based adaptive enhancement constraint designed for ill illuminated images. The model can maintain a balance of smoothness and contribute to solving the problem of noise besides over- and under-enhancement. The local consistency in illumination is achieved via a repairing operation performed in the proposed Repair-Net. The total variation operator is optimized to acquire local consistency, and the image gradient is guided with the proposed enhancement constraint. Finally, a product of updated reflection and illumination maps reconstructs an enhanced image. Experiments are organized under both very low exposure and ill illumination conditions, where a new dataset is also proposed. Results on both experiments show that our method has superior performance in preserving structural and textural details compared to other states of the art, which suggests that our method is more practical in future visual applications.

Population pharmacokinetics of meropenem among post-operative patients in Pakistan.

BACKGROUND: Meropenem, a potent carbapenem is considered the first choice for the empirical treatment of severe infections. Being a hydrophilic drug, more than 83% of the administered dose is eliminated through the renal route, and therefore, the kidney status of the patient may have a significant effect on meropenem clearance (CL). MATERIALS AND METHODS: The data of 205 samples obtained from 59 patients treated with meropenem at the General Hospital Lahore, Pakistan, was used for the development of a population pharmacokinetic (-popPK) model by using nonlinear mixed-effects modeling software. The effect of age, body weight, creatinine clearance (CRCL), and gender was observed on meropenem CL through a stepwise covariate modeling approach. Simulations of 1,000 mg q8h and 1,500 mg q12h over 3-hour infusion were performed based on the renal status of the patients. RESULTS: A two-compartment model was used for popPK analysis, and the values of the pharmacokinetic parameters for CL, V1, V2, and Q were 12.2 L/h, 21.7 L, 7.74 L, and 3.28 L/h, respectively. Meropenem CL was significantly influenced by CRCL, while no significant effect of body weight, age, and sex was observed. Both simulated dosage regimens were equally effective if CRCL of the patient was ≤ 100 mL/min, while 1,000 mg q8h produced better results if CRCL was > 100 mL/min. CONCLUSION: The CL of meropenem depends on the renal status of the patients. The model can be used for dosing simulations based on the CRCL of the patients in order to tailor the dose of meropenem in Pakistani patients.