Target-based discovery of a broad-spectrum flukicide.

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases-for example, the parasitic blood fluke infection schistosomiasis-are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPMPZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPMPZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad-spectrum flukicide.

Butein Increases Resistance to Oxidative Stress and Lifespan with Positive Effects on the Risk of Age-Related Diseases in Caenorhabditis elegans.

Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer's disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson's disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

Perioperative Low-Dose Aspirin Management for Planned Clipping Surgery: When, How Long, and With What Precautions?

BACKGROUND AND OBJECTIVE: Perioperative low-dose aspirin (ASA) management for open craniotomy surgery lacked information. We analyze to establish the perioperative ASA strategy to minimize both hemorrhagic and thromboembolic complications. METHODS: The investigators designed a multicenter retrospective study, which included patients scheduled to have clipping surgery for unruptured intracranial aneurysm. The incidence and risk factors were analyzed for postoperative hemorrhagic complications and major cardio- and cerebrovascular events (MACCEs) within 1 month postoperation. RESULTS: This study included 503 long-term ASA users of 3654 patients at three tertiary centers. The incidence of hemorrhagic complications and MACCEs was 7.4% (37/503) and 8.8% (44/503), respectively. Older age (>70 years, odds ratio [OR]: 2.928, 95% CI [1.337-6.416]), multiple aneurysms operation (OR: 2.201, 95% CI [1.017-4.765]), large aneurysm (>10 mm, OR: 4.483, 95% CI [1.485-13.533]), and ASA continuation (OR: 2.604, 95% CI [1.222-5.545]) were independent risk factors for postoperative hemorrhagic complications. Intracranial hemorrhage was the only type of hemorrhagic complication that increased in the ASA continuation group (10.6% vs 2.9%, P = .001). Between the ASA continuation and discontinuation groups, the overall incidence of MACCEs was not significantly different (log-rank P = .8). In the subgroup analysis, ASA discontinuation significantly increased the risk of MACCEs in the secondary prevention group (adjusted hazard ratio: 2.580, 95% CI [1.015-6.580]). CONCLUSION: ASA continuation increased the risk of postoperative intracranial hemorrhage. Simultaneously, ASA discontinuation was the major risk factor for postoperative MACCEs in the high-risk group. Without evidence of intracranial hemorrhage, early ASA resumption was indicated (a total cessation duration <7-10 days) in the secondary prevention group.

The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPMPZQ Orthologs.

The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPMPZQ, has recently been identified. Intriguingly, certain praziquantel derivatives show different activities against different parasites: for example, some praziquantel analogs are considerably more active against cestodes than against schistosomes. Here we interrogate whether the different activities of praziquantel analogs against different parasites are also reflected by unique structure-activity relationships at the TRPMPZQ channels found in these different organisms. To do this, several praziquantel analogs were synthesized and functionally profiled against schistosome and cestode TRPMPZQ channels. Data demonstrate that structure-activity relationships are closely mirrored between parasites and their TRPMPZQ orthologs, providing further support for TRPMPZQ as the therapeutically relevant target of praziquantel.

Target-based discovery of a broad spectrum flukicide.

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases - for example, the parasitic blood fluke infection, schistosomiasis - are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPMPZQ), in Fasciola species. Here we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPMPZQ dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad spectrum flukicide.

Coil embolization and recurrence of ruptured aneurysm originating from hyperplastic anterior choroidal artery.

Hyperplastic anterior choroidal artery (AchA) is an extremely rare congenital vascular variant that can be mistaken for other cerebral arteries. This case report presents a 38-year-old man who presented with a severe sudden-onset headache and was diagnosed with a ruptured aneurysm originating from a hyperplastic AchA. The aneurysm was successfully treated with coil embolization, but recurrence was detected after eight months, leading to additional surgical intervention. The discussion highlights the classification of hyperplastic AchA and emphasizes the importance of recognizing this anatomical variant to avoid complications during treatment. This case report underscores the need for awareness and understanding of hyperplastic AchA in the management of cerebral aneurysms.

Isolation of Latilactobacillus curvatus with Enhanced Nitric Oxide Synthesis from Korean Traditional Fermented Food and Investigation of Its Probiotic Properties.

Nitric oxide (NO) is a free radical associated with physiological functions such as blood pressure regulation, cardiovascular health, mitochondrial production, calcium transport, oxidative stress, and skeletal muscle repair. This study aimed to isolate Latilactobacillus curvatus strains with enhanced NO production from the traditional Korean fermented food, jangajji, and evaluate their probiotic properties for industrial purposes. When cells were co-cultured with various bacterial stimulants, NO production generally increased, and NO synthesis was observed in the range of 20-40 mg/mL. The selected strains of Lat. curvatus were resistant to acid and bile conditions and with variable effectiveness (1-14%) in adhering to Caco-2 cells. Most bacterial strains can inhibit the growth of various pathogens. In addition, they are capable of reducing cholesterol levels via assimilation of cholesterol at 10-50%. Among the selected NO synthases from Lat. curvatus strains, the strain JBCC38 showed the highest capacity to scavenge ABTS (30.1%) and DPPH radicals (39.4%). Moreover, these strains exhibited immunomodulatory properties. The production of TNF-α and IL-6 in the macrophages treated with various bacterial stimulants was induced in all the selected strains.

Probiotic Properties of Pediococcus pentosaceus JBCC 106 and Its Lactic Acid Fermentation on Broccoli Juice.

To understand the biological roles of Pediococcus pentosaceus strains as probiotics isolated from the traditional Korean fermented food, Jangajji, Pediococcus pentosaceus was selected based on its high cinnamoyl esterase (CE) and antioxidant activities. The acid and bile stability, intestinal adhesion, antagonistic activity against human pathogens, cholesterol-lowering effects, and immune system stimulation without inflammatory effects were evaluated. Nitric oxide (NO) levels were measured in co-culture with various bacterial stimulants. Fermentation ability was measured by using a broccoli matrix and the sulforaphane levels were measured. Resistance to acidic and bilious conditions and 8% adherence to Caco-2 cells were observed. Cholesterol levels were lowered by 51% by assimilation. Moreover, these strains exhibited immunomodulatory properties with induction of macrophage TNF-α and IL-6 and had microstatic effects on various pathogens. Co-culture with various bacterial stimulants resulted in increased NO production. Fermentation activity was increased with the strains, and higher sulforaphane levels were observed. Therefore, in the future, the applicability of the selected strain to broccoli matrix-based fermented functional foods should be confirmed.

Sniffer worm, C. elegans, as a toxicity evaluation model organism with sensing and locomotion abilities.

Additive manufacturing, or 3D printing, has revolutionized the way we create objects. However, its layer-by-layer process may lead to an increased incidence of local defects compared to traditional casting-based methods. Factors such as light intensity, depth of light penetration, component inhomogeneity, and fluctuations in nozzle temperature all contribute to defect formations. These defective regions can become sources of toxic component leakage, but pinpointing their locations in 3D printed materials remains a challenge. Traditional toxicological assessments rely on the extraction and subsequent exposure of living organisms to these harmful agents, thus only offering a passive detection approach. Therefore, the development of an active system to both identify and locate sources of toxicity is essential in the realm of 3D printing technologies. Herein, we introduce the use of the nematode model organism, Caenorhabditis elegans (C. elegans), for toxicity evaluation. C. elegans exhibits distinctive 'sensing' and 'locomotion' capabilities that enable it to actively navigate toward safe zones while steering clear of hazardous areas. This active behavior sets C. elegans apart from other aquatic and animal models, making it an exceptional choice for immediate and precise identification and localization of toxicity sources in 3D printed materials.

Metabolism of (R)-Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel.

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ , as well as serving as the primary site of oxidative metabolism which results in PZQ being a short-lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPMPZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

Two-dimensional material-based complementary ambipolar field-effect transistors with ohmic-like contacts.

Ambipolar field-effect transistors (FETs) possessing both electron and hole carriers enable implementation of novel reconfigurable transistors, artificial synaptic transistors, and output polarity controllable (OPC) amplifiers. Here, we fabricated a two-dimensional (2D) material-based complementary ambipolar FET and investigated its electrical characteristics. Properties of ohmic-like contacts at source/drain sides were verified from output characteristics and temperature-dependent measurements. The symmetry of electron and hole currents can be easily achieved by optimization of the MoS2or WSe2channels, different from the conventional ambipolar FET with fundamental issues related to Schottky barriers. In addition, we demonstrated successful operation of a complementary inverter and OPC amplifier, using the fabricated complementary ambipolar FET based on 2D materials.

Response to chemotherapy in juvenile myelomonocytic leukemia and its clinical implications for survival: A retrospective registry-based study of the Korean Pediatric Hematology-Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes.

Subdural hygroma and hemorrhagic conversion after microsurgical clipping for unruptured intracranial aneurysm.

BACKGROUND: Chronic subdural hematoma (cSDH) is a unique hemorrhagic complication associated with microsurgical clipping. We aimed to investigate the risk factors of subdural hygroma (SDG) formation and its hemorrhagic conversion to cSDH. METHODS: We reviewed the medical records of 229 patients who underwent microsurgical clipping for unruptured intracranial aneurysms (UIA) from 2016 to 2019. Risk factors for SDG and cSDH formation were analyzed. RESULTS: Male sex, age ≥ 60 years, higher degree of arachnoid dissection, severe brain atrophy, and a large volume of subdural fluid collection (SFC) before discharge were independent risk factors for SDG formation. The risk factors for hemorrhagic conversion from SDG were continuous use or early resumption of antiplatelet drugs (odds ratio (OR): 15.367, 95% CI: 1.172-201.402) and a larger volume of SFC before discharge (OR: 0.932, 95% CI: 0.886-0.980). In the early resumption group, antiplatelet drug was resumed at a mean duration of 7.48 days postoperatively, and hemorrhagic conversion was detected earlier than that in the late resumption or no-use groups (4.09 vs. 7.18 weeks, P = 0.046). Following the receiver operating characteristic analysis, the SFC cutoff volume for hemorrhagic conversion was determined to be 23.55 mL. CONCLUSION: These findings can assist clinicians in identifying patients at a high risk of SDG and cSDH formation. Antiplatelet resumption and its timing should be determined with consideration of the risk of cSDH formation as well as individual medical conditions.

Unraveling two distinct polymorph transition mechanisms in one n-type single crystal for dynamic electronics.

Cooperativity is used by living systems to circumvent energetic and entropic barriers to yield highly efficient molecular processes. Cooperative structural transitions involve the concerted displacement of molecules in a crystalline material, as opposed to typical molecule-by-molecule nucleation and growth mechanisms which often break single crystallinity. Cooperative transitions have acquired much attention for low transition barriers, ultrafast kinetics, and structural reversibility. However, cooperative transitions are rare in molecular crystals and their origin is poorly understood. Crystals of 2-dimensional quinoidal terthiophene (2DQTT-o-B), a high-performance n-type organic semiconductor, demonstrate two distinct thermally activated phase transitions following these mechanisms. Here we show reorientation of the alkyl side chains triggers cooperative behavior, tilting the molecules like dominos. Whereas, nucleation and growth transition is coincident with increasing alkyl chain disorder and driven by forming a biradical state. We establish alkyl chain engineering as integral to rationally controlling these polymorphic behaviors for novel electronic applications.

Electrophysiological characterization of a schistosome transient receptor potential channel activated by praziquantel.

Ion channels have proved to be productive targets for anthelmintic chemotherapy. One example is the recent discovery of a parasitic flatworm ion channel targeted by praziquantel (PZQ), the main clinical therapy used for treatment of schistosomiasis. The ion channel activated by PZQ - a transient receptor potential ion channel of the melastatin subfamily, named TRPMPZQ - is a Ca2+-permeable ion channel expressed in all parasitic flatworms that are PZQ-sensitive. However, little is currently known about the electrophysiological properties of this target that mediates the deleterious action of PZQ on many trematodes and cestodes. Here, we provide a detailed biophysical characterization of the properties of Schistosoma mansoni TRPMPZQ channel (Sm.TRPMPZQ) in response to PZQ. Single channel electrophysiological analysis demonstrated that Sm.TRPMPZQ when activated by PZQ is a non-selective, large conductance, voltage-insensitive cation channel that displays distinct properties from human TRPM paralogs. Sm.TRPMPZQ is Ca2+-permeable but does not require Ca2+ for channel gating in response to PZQ. TRPMPZQ from Schistosoma japonicum (Sj.TRPMPZQ) and Schistosoma haematobium (Sh.TRPMPZQ) displayed similar characteristics. Profiling Sm.TRPMPZQ responsiveness to PZQ has established a biophysical signature for this channel that will aid future investigation of endogenous TRPMPZQ activity, as well as analyses of endogenous and exogenous regulators of this novel, druggable antiparasitic target.

Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity.

The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified- a transient receptor potential ion channel in the melastatin subfamily (TRPMPZQ)-however, little is known about the properties of TRPMPZQ in other parasitic flatworms. Here, TRPMPZQ orthologs were scrutinized from all currently available parasitic flatworm genomes. TRPMPZQ is present in all parasitic flatworms, and the consensus PZQ binding site was well conserved. Functional profiling of trematode, cestode, and a free-living flatworm TRPMPZQ ortholog revealed differing sensitives (~300-fold) of these TRPMPZQ channels toward PZQ, which matched the varied sensitivities of these different flatworms to PZQ. Three loci of variation were defined across the parasitic flatworm TRPMPZQ pocketome with the identity of an acidic residue in the TRP domain acting as a gatekeeper residue impacting PZQ residency within the TRPMPZQ ligand binding pocket. In trematodes and cyclophyllidean cestodes, which display high sensitivity to PZQ, this TRP domain residue is an aspartic acid which is permissive for potent activation by PZQ. However, the presence of a glutamic acid residue found in other parasitic and free-living flatworm TRPMPZQ was associated with lower sensitivity to PZQ. The definition of these different binding pocket architectures explains why PZQ shows high therapeutic effectiveness against specific fluke and tapeworm infections and will help the development of better tailored therapies toward other parasitic infections of humans, livestock, and fish.

Retreatment of a recurrent giant aneurysm of the internal carotid artery after treatment with a flow-diverting stent.

Flow-diverting stents (FDSs) have proven advantageous for the treatment of large, fusiform, and dissecting aneurysms that are otherwise difficult to treat. Retreatment strategies for recurrent large or giant aneurysms after FDSs are limited to overlapping implantation of an additional FDS or definitive occlusion of the parent vessel. We report a recurrent giant aneurysm that was initially treated with an FDS with coils and was successfully treated with an additional FDS. Visual symptoms due to the mass effect of the recurrent aneurysm were completely resolved, and follow-up digital subtraction angiography revealed complete obliteration of the aneurysm. Additional FDS implantation for the retreatment of incompletely occluded aneurysms after the initial FDS treatment may be feasible and safe. Further studies are required to validate these results.

Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data.

PURPOSE: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. MATERIALS AND METHODS: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. RESULTS: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). CONCLUSION: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.