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Regulatory Toxicology and Pharmacology... Jun 2024Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable... (Review)
Review
Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable nonclinical efficacy tests. Two common tests used in nonclinical efficacy studies of antidepressants-the forced swim test (FST) and tail suspension test (TST)-have come under criticism in recent years for their inconsistency and lack of validity, yet they continue to be used in the pharmaceutical industry. In this review, we provide a rationale for why international pharmaceutical regulatory and guidance agencies should begin issuing direction on methods for non-clinical efficacy testing that traditionally use the FST and TST, particularly considering that some regulators, such as those in the U.S. and E.U., allow the authorization of clinical trials to proceed without requiring tests in animals. The area of antidepressant drug discovery represents an important opportunity for reducing the attrition of psychiatric drugs, harmonizing regulatory requirements, and reducing animal use. Specific recommendations for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have been provided.
PubMed: 38942190
DOI: 10.1016/j.yrtph.2024.105666 -
Behavioural Brain Research Jun 2024Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the...
Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals' depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS,which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving un-altered improvement in the FST and TST. Mechanically, we found thatISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicatingby decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. Thepresent findings further expand the potential role of ER stress in depression andprovide important details for a therapeutic path forward for PERK inhibitors in mood disorders.
PubMed: 38942086
DOI: 10.1016/j.bbr.2024.115122 -
European Journal of Dentistry Jun 2024This study aims to investigate DSM 17938's antibiofilm effects on and , common causes of alveolar osteitis. It seeks topical alternatives to prevent this condition...
OBJECTIVES
This study aims to investigate DSM 17938's antibiofilm effects on and , common causes of alveolar osteitis. It seeks topical alternatives to prevent this condition posttooth extraction. The secondary objective is to assess these effects under different pH conditions (pH 4.5 and pH 7), mimicking oral cavity saliva pH dynamics.
MATERIALS AND METHODS
Ethical approval was secured for the saliva collection process involving five healthy adult participants who had undergone wisdom tooth extraction. Saliva samples were diligently collected on the 7th day post-surgery. The unstimulated saliva underwent a series of treatments, including the addition of phenylmethylsulfonyl fluoride (PMSF), pH adjustments, centrifugation, and filtration. The pH levels were re-measured, and subsequent adjustments were made to achieve pH values of 4.5 or 7. DSM 17938, with a concentration of 1×10 colony-forming units (CFU) per 5 drops, was utilized in the study. Biofilm testing involved incubating saliva samples with varying pH (4.5 or 7) alongside bacterial suspensions (, or a mixed species). The Interlac suspension was introduced, and plates were anaerobically incubated for 24 hours. Biofilm results were obtained using a spectrometer. The test is conducted in triplicate.
STATISTICAL ANALYSIS
To scrutinize the impact of pH on biofilm development, the acquired data underwent a two-way ANOVA test in SPSS as part of the statistical analysis. A significance level of <0.05 was used to determine statistical significance.
RESULTS
DSM 17938 significantly reduced biofilm formation across bacterial strains ( = 0.000). Statistical analysis indicated a significant impact of pH on biofilm development ( = 0.000) compared to no saliva samples, with higher formation observed under acidic conditions (pH 4.5). However, the pH levels of 4.5 and 7 did not result in significantly different bacterial biofilm formation ( = 0.529).
CONCLUSION
This research highlights DSM 17938's potency in inhibiting biofilm formation of and . Salivary pH variations significantly influence biofilm development, emphasizing the need to consider pH when assessing probiotic effectiveness. Despite limitations in saliva sample sterilization, this study provides valuable insights into alternative approaches for preventing alveolar osteitis. Further research should explore clinical applications and refine sterilization methods for more accurate results.
PubMed: 38942052
DOI: 10.1055/s-0044-1786846 -
Medicine Jun 2024This study aimed to evaluate the clinical and radiological features of the patella fixation technique using Toggleloc suspension system in a single ellipsoidal blind...
BACKGROUND
This study aimed to evaluate the clinical and radiological features of the patella fixation technique using Toggleloc suspension system in a single ellipsoidal blind patellar tunnel during medial patellofemoral ligament (MPFL) reconstruction.
METHODS
This study included 52 patients (25 men, 27 women) who underwent MPFL reconstruction using a semitendinosus tendon graft. The graft was fixed to the ellipsoidal single blind tunnel opened on the medial side of the patella with an endobutton and was fixed to the femoral tunnel by using bioabsorbable screw. Clinical scores (Kujala score, Lysholm score, Tegner activity score and the visual analog scale [VAS] score) were evaluated preoperatively and at the end-follow up. Preoperative and postoperative radiological measurements (trochlea depth, sulcus angle, patellar height, patellar congruence angle, patellar tilt angle and lateral patellofemoral angle) were evaluated with X-ray (Merchant X-ray, anteroposterior and lateral radiography) and computed tomography (CT) of the knee.
RESULTS
Postoperative patellar redislocation or subluxation was not observed in any patient. Patellar congruence angle, patellar tilt angle and lateral patellofemoral angle mean values were found to return to normal values in the postoperative period and the results were statistically significant. Also statistically significant improvement in all clinical scores postoperatively. According to the Insall-Salvati index (ISI) and Caton-Deschamps index (CDI) on lateral radiography of the knee at 30° flexion, patellar height decreased in the postoperative period statistically significant. The CDI was above 1.3 in 17 (%32) of our patients. Thirteen of these values decreased to normal values. No radiological progression of patellofemoral osteoarthritis was observed in all patients at the final follow-up evaluation.
CONCLUSION
In cases of patellofemoral instability, fixation of the tendon graft in blind ellipsoid tunnel using the Toggleloc suspension system provides satisfactory patellar graft fixation strength, significant functional improvement and a low failure rate.
Topics: Humans; Female; Male; Adult; Patellofemoral Joint; Follow-Up Studies; Patella; Plastic Surgery Procedures; Young Adult; Ligaments, Articular; Treatment Outcome; Adolescent
PubMed: 38941440
DOI: 10.1097/MD.0000000000038379 -
Macromolecular Rapid Communications Jun 2024Creating bionic intelligent robotic systems that emulate human-like skin perception presents a considerable scientific challenge. This study introduces a multifunctional...
Creating bionic intelligent robotic systems that emulate human-like skin perception presents a considerable scientific challenge. This study introduces a multifunctional bionic electronic skin (e-skin) made from polyacrylic acid ionogel (PAIG), designed to detect human motion signals and transmit them to robotic systems for recognition and classification. The PAIG was synthesized using a suspension of liquid metal and graphene oxide nanosheets as initiators and cross-linkers. The resulting PAIGs demonstrate excellent mechanical properties, resistance to freezing and drying, and self-healing capabilities. Functionally, the PAIG effectively captures human motion signals through electromechanical sensing. Furthermore, we developed a bionic intelligent sorting robot system by integrating the PAIG-based e-skin with a robotic manipulator. This system leverages its ability to detect frictional electrical signals, enabling precise identification and sorting of materials. The innovations presented in this study hold significant potential for applications in artificial intelligence, rehabilitation training, and intelligent classification systems. This article is protected by copyright. All rights reserved.
PubMed: 38940242
DOI: 10.1002/marc.202400379 -
Frontiers in Bioscience (Elite Edition) May 2024Fall armyworm () is a highly destructive maize pest that significantly threatens agricultural productivity. Existing control methods, such as chemical insecticides and...
BACKGROUND
Fall armyworm () is a highly destructive maize pest that significantly threatens agricultural productivity. Existing control methods, such as chemical insecticides and entomopathogens, lack effectiveness, necessitating alternative approaches.
METHODS
Gut-associated bacteria were isolated from the gut samples of fall armyworm and screened based on their chitinase and protease-producing ability before characterization through 16S rRNA gene sequence analysis. The efficient chitinase-producing FGE4 and FGE18 were chosen to test the biocontrol efficacy. As their respective cell suspensions and extracted crude chitinase enzyme, these two isolates were applied topically on the larvae, supplemented with their feed, and analyzed for their quantitative food use efficiency and survivability.
RESULTS
Twenty-one high chitinase and protease-producing bacterial isolates were chosen. Five genera were identified by 16S rRNA gene sequencing: , , , , and . In the biocontrol efficacy test, the consumption index and relative growth rate were lowered in larvae treated with FGE18 by topical application and feed supplementation. Similarly, topical treatment of FGE4 to larvae decreased consumption index, relative growth rate, conversion efficiency of ingested food, and digested food values.
CONCLUSION
The presence of gut bacteria with high chitinase activity negatively affects insect health. Utilizing gut-derived bacterial isolates with specific insecticidal traits offers a promising avenue to control fall armyworms. This research suggests a potential strategy for future pest management.
Topics: Animals; Spodoptera; Chitinases; RNA, Ribosomal, 16S; Bacteria; Bacillus licheniformis; Enterobacter cloacae; Larva; Pest Control, Biological; Gastrointestinal Tract
PubMed: 38939914
DOI: 10.31083/j.fbe1602015 -
Pharmaceutical Development and... Jun 2024The suspension wet media milling manufacturing process is a complex multi-unit operation, resulting in drug substance comminution to a target particle size. As a result... (Review)
Review
The suspension wet media milling manufacturing process is a complex multi-unit operation, resulting in drug substance comminution to a target particle size. As a result of this complexity, microbial contamination is of paramount concern, particularly for suspensions dosed for parenteral use. This perspective sought to review the influence of (4) critical manufacturing unit operations using a quality risk management approach to better identify and articulate impact of each unit operation on bioburden viability. The manufacturing unit operations in scope included slurry compounding, deaeration, milling, and filling. Bow tie risk analysis was used as a visual gap analysis tool to evaluate if conventional controls were appropriate to detect and mitigate potential for microbial contamination. A deep dive into these unit operations clarified that mechanisms such as turbohypobiosis, cavitation during deaeration, high energy milling, and inert overlay may have an appreciable influence on bioburden viability and proliferation. The resultant analysis also explicated that endotoxin oversight must be closely monitored through barriers (input material controls, water quality controls) to minimize impact to the product and patient. The identified manufacturing unit operations were not appropriate as mitigating controls for endotoxin. The output of this article relates risk intersections for microbial contamination during wet media milling and offers insights in critical areas for intervention.
PubMed: 38938157
DOI: 10.1080/10837450.2024.2372576 -
Anatomical Record (Hoboken, N.J. : 2007) Jun 2024Humboldt's woolly monkey (Lagothrix lagortricha) is a ceboid primate that more frequently engages in plantigrade quadrupedalism (~89%) but is, like most other members of...
Humboldt's woolly monkey (Lagothrix lagortricha) is a ceboid primate that more frequently engages in plantigrade quadrupedalism (~89%) but is, like most other members of the subfamily Atelinae, capable of suspensory postures and "tail assisted" brachiation. That taxon's decreased reliance on suspension is reflected in the skeletal anatomy of the upper limb which is less derived relative to more frequently suspensory atelines (Ateles, Brachyteles) but is in many ways (i.e., phalangeal curvature, enlarged joint surfaces, elongated diaphyses) intermediate between highly suspensory and quadrupedal anthropoids. Although it has been suggested that muscle may have morphogenetic primacy with respect to bone this has not been explicitly tested. The present study employs analyses of Lagothrix upper limb muscle fiber length, relative physiological cross-sectional area and relative muscle mass to test whether muscular adaptations for suspensory postures and locomotion in Lagothrix precede adaptive refinements in the skeletal tissues or appear more gradually in conjunction with related skeletal adaptations. Results demonstrate that Lagothrix upper limb musculature is most like committed quadrupeds but that limited aspects of the relative distribution of segmental muscle mass may approach suspensory hylobatids consistent with only a limited adaptive response in musculature prior to bone. Results specific to the shoulder were inconclusive owing to under-representation of quadrupedal shoulder musculature and future work should be focused more specifically on the adaptive and functional morphology of the muscular anatomy and microstructure of the scapulothoracic joint complex.
PubMed: 38938152
DOI: 10.1002/ar.25514 -
Plant Disease Jun 2024Blackleg and soft rot diseases represent a major threat to the health of potato () and other vegetable, ornamental and fruit crops worldwide; their main causal agents...
Blackleg and soft rot diseases represent a major threat to the health of potato () and other vegetable, ornamental and fruit crops worldwide; their main causal agents are species of and . In May 2022, 60% of potato plants (cv. Spunta) in a production field in Córdoba, Argentina (31°32'36''S 64°09'46''W) showed soft rot, blackleg and wilt. To isolate the causal agent, decayed plant tissues were disinfected in 2% NaClO, macerated in sterile water and streaked on crystal violet pectate (CVP) medium. Plates were incubated at 28°C for 48 h. Colonies that produced a pit on CVP medium were purified on nutrient agar. Two of the isolates, called 1Aia and 1B, were characterized by tests commonly employed for the identification of pectinolytic bacteria (Schaad et al. 2001). Both produced Gram-negative rods that were facultatively anaerobic, oxidase negative, nonfluorescent on King´s B, resistant to erythromycin and caused soft rot of potato slices. In addition, these isolates did not produce the blue pigment indigoidine and grew on nutrient glucose agar containing 5% NaCl. Phenotypic characteristics of the isolates 1Aia and 1B were compatible with spp. Genomic DNA was extracted using the commercially available Wizard® Genomic DNA Purification Kit (Promega) according to the manufacturer's instructions for the purification of DNA from Gram-negative bacteria. The isolates were positive in a PCR assay for (Duarte et al. 2004). The purified DNA of isolate 1Aia was used to construct a pooled Illumina library, which was sequenced at the Genomics Unit from the National Institute of Agricultural Technology (INTA, Argentina), by using high-throughput Illumina sequencing technology. Average nucleotide identity (ANI) calculation performed by FastANI v0.1.3 (Jain et al. 2018) showed 96.11% identity between the genome of the type strain LMG 21371 of (Acc. no. JQOE00000000) and our strain 1Aia (Acc. no. JAYGXQ000000000). For pathogenicity test, 3-weeks-old potato plants (cv. Spunta) planted in pots were infiltrated with 10 µl of a bacterial suspension (1x107 CFU/ml) 5 cm above the base of the stem using a sterile syringe. Negative controls were infiltrated with sterile water. Plants were kept under greenhouse conditions and regularly watered. The experiment was performed twice with six plants per treatment. Two days after inoculation, plants treated with strain 1Aia or 1B showed necrotic lesions on the stems and tubers soft rot symptoms while control plants remained asymptomatic. To fulfill Koch´s postulates, bacteria were re-isolated from symptomatic plants. Re-isolated bacteria, called 1Aia d and 1B d, were confirmed as according to biochemical and PCR results, as outlined above. Also, the % ANI value between isolates 1Aia and 1Aia d was 99.99% (Acc. no. JAYGXR000000000). To our knowledge, this is the first report of the occurrence of in Argentina. This pathogen has been observed causing blackleg and tuber soft rot on potato in Brazil (Duarte et al. 2004), Netherlands (Nunes Leite et al. 2014), Switzerland (de Werra et al. 2015), Russia (Voronina et al. 2019), Serbia (Loc et al. 2022) and USA (Zhang et al. 2023), among other countries worldwide. Due to the important economic and nutritional value of the crop, the distribution of needs to be investigated and monitored in order to develop effective control strategies.
PubMed: 38937930
DOI: 10.1094/PDIS-03-24-0558-PDN -
Gene Jun 2024Periodontitis is associated with Fusobacterium nucleatum (F.n) infection. Although the colonization of renal tissue by F.n is well documented, its specific role in...
OBJECTIVES
Periodontitis is associated with Fusobacterium nucleatum (F.n) infection. Although the colonization of renal tissue by F.n is well documented, its specific role in kidney disease has yet to be determined. This study aimed to investigate the potential association between F.n-induced periodontitis and renal interstitial fibrosis.
METHODS
The rat gingival sulcus was injected with F.n suspension, while the control group (NC) was injected with PBS. The levels of total protein (TP), albumin (ALB), creatinine, and urea nitrogen (BUN) in rat serum and/or urine were quantified using the appropriate kits. Renal interstitial fibrosis and epithelial-mesenchymal transition (EMT) were evaluated in rats using Masson staining, Periodic Schiff-Methenamine (PASM) staining, and immunohistochemical staining. The levels of fibrosis- and EMT-related proteins and the TGF-β/SMAD2/3 and β-catenin signaling pathways were determined using Western blot analysis. F.n in the kidney tissues was quantitatively determined using bacterial 16S rRNA technology.
RESULTS
Serum levels of TP, ALB, creatinine, and BUN were not significantly decreased in F.n-infected rats with periodontitis. The levels of creatinine and ALB in the urine were not statistically different between two groups. Masson and PASM staining showed that F.n-induced periodontitis could promote renal interstitial fibrosis in rats. The levels of collagen I, fibronectin (FN), vimentin, and α-SMA were upregulated in the kidney tissues of rats with F.n-induced periodontitis and in F.n-treated HK-2 cells. However, E-cadherin levels were reduced. F.n promoted renal interstitial and HK-2 cell fibrosis in rats by modulating the TGF-β/SMAD2/3 and β-catenin signaling pathways. F.n colonization increased renal interstitial fibrosis in rats.
CONCLUSION
F.n-induced periodontitis promoted EMT by activating the TGF-β/SMAD2/3 and β-catenin signaling pathways, thus promoting renal interstitial fibrosis in rats.
PubMed: 38936784
DOI: 10.1016/j.gene.2024.148729