GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-ß-Induced Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-ß-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-ß. NFPS pretreatment prevented amyloid-ß-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-ß injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-ß-induced hippocampal damage.

Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia.

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as L-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model.

Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Elimination of rNMPs from mitochondrial DNA has no effect on its stability.

Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent in SAMHD1-/- mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.

Performance Analysis of Relative GPS Positioning for Low-Cost Receiver-Equipped Agricultural Rovers.

Global navigation satellite systems (GNSSs) became an integral part of all aspects of our lives, whether for positioning, navigation, or timing services. These systems are central to a range of applications including road, aviation, maritime, and location-based services, agriculture, and surveying. The Global Positioning System (GPS) Standard Position Service (SPS) provides position accuracy up to 10 m. However, some modern-day applications, such as precision agriculture (PA), smart farms, and Agriculture 4.0, have demanded navigation technologies able to provide more accurate positioning at a low cost, especially for vehicle guidance and variable rate technology purposes. The Society of Automotive Engineers (SAE), for instance, through its standard J2945 defines a maximum of 1.5 m of horizontal positioning error at 68% probability (1σ), aiming at terrestrial vehicle-to-vehicle (V2V) applications. GPS position accuracy may be improved by addressing the common-mode errors contained in its observables, and relative GNSS (RGNSS) is a well-known technique for overcoming this issue. This paper builds upon previous research conducted by the authors and investigates the sensitivity of the position estimation accuracy of low-cost receiver-equipped agricultural rovers as a function of two degradation factors that RGNSS is susceptible to: communication failures and baseline distances between GPS receivers. The extended Kalman filter (EKF) approach is used for position estimation, based on which we show that it is possible to achieve 1.5 m horizontal accuracy at 68% probability (1σ) for communication failures up to 3000 s and baseline separation of around 1500 km. Experimental data from the Brazilian Network for Continuous Monitoring of GNSS (RBMC) and a moving agricultural rover equipped with a low-cost GPS receiver are used to validate the analysis.

Cell adhesion proteins in the cerebrospinal fluid of neonates prenatally exposed to Zika virus: A case-control study.

To compare cell adhesion molecules levels in cerebrospinal fluid (CSF) between Zika virus (ZIKV)-exposed neonates with/without microcephaly (cases) and controls, 16 neonates (cases), 8 (50%) with and 8 (50%) without microcephaly, who underwent lumbar puncture (LP) during the ZIKV epidemic (2015-2016) were included. All mothers reported ZIKV clinical symptoms during gestation, all neonates presented with congenital infection findings, and other congenital infections were ruled out. Fourteen control neonates underwent LP in the same laboratory (2017-2018). Five cell adhesion proteins were measured in the CSF using mass spectrometry. Neurexin-1 (3.50 [2.00-4.00] vs. 7.5 [5.00-10.25], P = 0.001), neurexin-3 (0.00 [0.00-0.00] vs. 3.00 [1.50-4.00], P = 0.001) and neural cell adhesion molecule 2 (NCAM2) (0.00 [0.00-0.75] vs. 1.00 [1.00-2.00], P = 0.001) were significantly lower in microcephalic and non-microcephalic cases than in controls. When these two sub-groups of prenatally ZIKA-exposed children were compared to controls separately, the same results were found. When cases with and without microcephaly were compared, no difference was found. Neurexin-3 (18.8% vs. 78.6%, P = 0.001) and NCAM2 (25.0% vs. 85.7%, P = 0.001) were less frequently found among the cases. A positive correlation was found between cephalic perimeter and levels of these two proteins. Neurexin-2 and neurexin-2b presented no significant differences. Levels of three cell adhesion proteins were significantly lower in CSF of neonates exposed to ZIKV before birth than in controls, irrespective of presence of congenital microcephaly. Moreover, the smaller the cephalic perimeter, the lower CSF cell adhesion protein levels. These findings suggest that low CSF levels of neurexin-1, neurexin-3 and NCAM2 may reflect the effects of ZIKV on foetal brain development.

Revisiting the cave-dwelling sand flies (Diptera, Psychodidae, Phlebotominae) from Brazil: Diversity and potential role in the transmission of Leishmania Ross, 1903 (Kinetoplastida: Trypanosomatidae).

Brazilian caves, one of the many tourist attractions of the country, may act as a shelter for insects, such as sand flies (Diptera: Psychodidae), natural hosts of various microorganisms including parasites of the genus Leishmania Ross, 1903. In the last decades, with the increasing global need for sustainable development, ecotourism has emerged as one of the major activities in Brazil. However, the constant monitoring in environmentally protected areas is not often carried out, endangering visitors and professionals, especially due to the occurrence of zoonoses. Several sand fly species have already been recorded in Brazilian caves, drawing attention to the possibility of Leishmania transmission at this ecotope. Indeed, this current systematic review summarizes the fauna of cave-dwelling sand flies in Brazil, focusing on their biological behaviour and the occurrence of potential vectors of Leishmania parasites.

Minilaparoscopic CLIPLESS Cholecystectomy: Tips, Tricks and Advanced Maneuvers.

As the world sought the 'Holy Grail' of scarless surgery, minimizing access seemed to be the natural path to follow, and minilaparoscopy (MINI) was considered to be a natural advancement of standard laparoscopy. It aims at minimizing surgical trauma by further reducing the diameter of standard instruments, without compromising range of motion, triangulation or safety. Several different terms have been coined to address this sophisticated reduced-port technique, which is characterized by the use of instruments 3 mm or less in diameter: acuscopic surgery, minilaparoscopy, needlescopic surgery and microlaparoscopy. The early adoption of MINI was mostly inhibited by the limitations of first-generation instruments, especially with respect to functionality, cost and durability. Furthermore, mini cholecystectomy demanded the use of mini optics, which suffered from poor imaging quality and a short lifetime of the scopes. Newer-generation mini instruments have mitigated these issues through the use of improved effector tips, better insulation, strength and durability, and superior optics. During the early MINI years, surgeons clipped most structures, but sturdy mini clip appliers were either unavailable or did not hold the requisite-size clips. Clipping with MINI required the use of a standard clip applier and the scope had to be changed several times during a procedure, making MINI not only more complicated but also boring and time-consuming. The development and popularization of the clipless technique allowed the surgeon to get free from the expensive and cumbersome minilaparoscopic clip appliers, and replace clips with knots. The marked improvements in instrumentation and the development of the clipless technique have occurred simultaneously with the development of NOTES, LESS and Robotic surgery, which may have contributed to a greater push towards MINI. MINI has been proven to offer more than just better cosmesis. Other advantages include better visualization of the surgical field and, with the development of precisely engineered low-friction trocars, which enhance surgical precision during dynamic and delicate tasks (knotting and suturing small structures), less stress and higher efficiency, which makes the procedure easier to perform. Furthermore, transmission of electro cautery through mini instruments has led to less lateral spread of electric current and subsequent less tissue trauma. For more than 20 years, our team has successfully used minilaparoscopy. Even with the rising popularity of robotic surgery, which still uses 8 mm instruments, minilaparoscopy remains an attractive option that is far from becoming obsolete.

The role of neurogenesis in neurorepair after ischemic stroke.

Stroke consists of an abrupt reduction of cerebral blood flow resulting in hypoxia that triggers an excitotoxicity, oxidative stress, and neuroinflammation. After the ischemic process, neural precursor cells present in the subventricular zone of the lateral ventricle and subgranular zone of the dentate gyrus proliferate and migrate towards the lesion, contributing to the brain repair. The neurogenesis is induced by signal transduction pathways, growth factors, attractive factors for neuroblasts, transcription factors, pro and anti-inflammatory mediators and specific neurotransmissions. However, this endogenous neurogenesis occurs slowly and does not allow a complete restoration of brain function. Despite that, understanding the mechanisms of neurogenesis could improve the therapeutic strategies for brain repair. This review presents the current knowledge about brain repair process after stroke and the perspectives regarding the development of promising therapies that aim to improve neurogenesis and its potential to form new neural networks.

Error Analysis of Accelerometer- and Magnetometer-Based Stationary Alignment.

This paper revisits the stationary attitude initialization problem, i.e., the stationary alignment, of Attitude and Heading Reference Systems (AHRSs). A detailed and comprehensive error analysis is proposed for four of the most representative accelerometer- and magnetometer-based stationary attitude determination methods, namely, the Three-Axis Attitude Determination (TRIAD), the QUaternion ESTimator (QUEST), the Factored Quaternion Algorithm (FQA), and the Arc-TANgent (ATAN). For the purpose of the error analysis, constant biases in the accelerometer and magnetometer measurements are considered (encompassing, hence, the effect of hard-iron magnetism), in addition to systematic errors in the local gravity and Earth magnetic field models (flux density magnitude, declination angle, and inclination angle). The contributions of this paper are novel closed-form formulae for the residual errors (normality, orthogonality, and alignment errors) developed in the computed Direction Cosine Matrices (DCM). As a consequence, analytical insight is provided into the problem, allowing us to properly compare the performance of the investigated alignment formulations (in terms of ultimate accuracy), as well as to remove some misleading conclusions reported in previous works. The adequacy of the proposed error analysis is validated through simulation and experimental results.

Twenty years of mini-laparoscopy in Brazil: What we have learned so far.

The mini-laparoscopic cholecystectomy (MLC) was first performed in 1996, as the logical advancement of the conventional laparoscopic cholecystectomy. In Brazil, mini-laparoscopy was first performed in 1998, by Professors Peter Goh and Go Wakabaiashi, who performed a cholecystectomy using 3-mm instruments. The first study, with a considerable number of patients, was performed in Recife by Dr. Carvalho, and he reported that 719 patients were submitted to a MLC with a small rate of conversion for conventional laparoscopy. We discuss the development of mini-laparoscopy in Brazil for the past 20 years.

PrimPol is required for replication reinitiation after mtDNA damage.

Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria. Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved. Here we demonstrate in vivo and in vitro that PrimPol can reinitiate stalled mtDNA replication and can prime mtDNA replication from nonconventional origins. Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication.

The influence of social media in minimally invasive surgery education: How surgeons exchange experience and knowledge in these platforms.

Engagement with social media is increasing within medical professionals. There are many different platforms, such as Facebook, Instagram, Whatsapp, Twitter, Telegram, and so on. Social media is a new and important tool for surgical education. More and more surgeons are joining restricted groups to discuss surgical techniques, manuscripts, etc in a daily basis. It is important that residents and surgeons have a very critical opinion about what they look online. Not everything is good or feasible.

Resection of a giant nonparasitic splenic cyst by minilaparoscopy.

A female patient, 20 years old, with a history of a progressive increase in abdominal volume on the left side, starting 3 years ago, with no associated symptoms and no history of trauma. Ultrasonography and a computed tomography scan of the abdomen were performed, which revealed a large splenomegaly, and a partial minilaparoscopic splenectomy was indicated. We opted for unroofing of the cyst, and the procedure was uneventful, with a total surgical time of 47 min. The patient progressed clinically well, without abdominal pain, being discharged on the 2nd post-operative day.

A new hybrid mini-laparoscopic technique for Spigelian hernia.

We describe the original technique used for the treatment of a patient who presented with pain and bulging in the abdomen, who was diagnosed with Spigelian hernia (SH) using ultrasound. In this case, the hernia occurred in the anterolateral abdominal wall with herniation of the distal ileum and mesentery, in addition to a large right inguinal hernia. A mini-laparoscopic approach was proposed; due to Child-A hepatic cirrhosis, it was done by a hybrid technique, using a harmonic scalpel. The primary closure of the hernia defects was performed, followed by the placement of a polypropylene mesh in the preperitoneal space. The mesh was fixed. In this case, the inguinal hernia was homolateral to the SH. Following the surgery, the patient had no further complications, being discharged the day after the procedure.

Resection of giant hepatic cyst by hybrid minilaparoscopy.

A female patient, 59-year-old, was complaining of abdominal pain in the right hypochondrium and mesogastrium for 6 months. Ultrasonography and abdominal computed tomography were performed, both confirming a large hepatic cyst (10.6 cm × 7.6 cm × 7.3 cm) on the left lobe. A hybrid minilaparoscopic resection was proposed. We opted for unroofing the cyst, and the procedure was uneventfully performed, with a total surgical time of 60 min. In the post-operative the patient did well, with minimal abdominal pain, being discharged on the 5th post-operative day, after drain removal due to the use of intravenous antibiotic therapy.

Striving to meet targets for ideal treatment of acute myocardial infarction in Brazil: Data from the Midwest region.

OBJECTIVES: To evaluate the systematic chain of care for patients with acute ST-elevation myocardial infarction (STEMI) referred for primary angioplasty in a capital city in Midwestern Brazil. BACKGROUND: Acute myocardial infarction is recognized as an important cause of morbidity and mortality and as a public health problem worldwide. Early specialized care is crucial for a good prognosis. METHODS: All STEMI patients receiving care through the public health system at two tertiary care centers from March 2012 to June 2014 were retrospectively analyzed. Symptom onset-to-balloon time and door-to-balloon time were analyzed and compared with current guideline recommendations. RESULTS: A total of 835 patients were included. Median symptom onset-to-balloon time was 32 h. A total of 783 (94%) patients had had symptoms for more than 12 h and 507 (61%) for more than 24 h. Only 51 (6%) patients arrived within 12 h of symptom onset and were treated with primary angioplasty. Among these patients, median door-to-balloon time was 37 min, in accordance with guideline recommendations. CONCLUSION: Treatment of STEMI through the public health system in a capital city in Midwestern Brazil falls short of the recommended guidelines due to failure in the initial links of the chain of care. This potentially reversible failure has an important impact on patient outcomes and on health care burden.

VOSalophen: a vanadium complex with a stilbene derivative-induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis.

In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes.

In Vitro Antifungal Activity of Hexahydropyrimidine Derivatives against the Causative Agents of Dermatomycosis.

Nitrogenated heterocyclic compounds are present in both natural and synthetic drugs, and hexahydropyrimidine derivatives may prove to be efficient in treating dermatomycosis causing fungi. This study evaluated the antifungal activity of four hexahydropyrimidine derivatives against the dermatomycosis causing fungi. These derivatives were synthesized, characterized, and assessed in terms of their activity against Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Trichophyton rubrum, Fusarium oxysporum, and Epidermophyton floccosum between concentrations 7.8 and 1,000 µg mL-1. Scanning electron micrographs were assessed for the active derivatives and reference drugs, and these micrographs revealed that new agents cause morphological changes in fungi. The derivatives HHP1, HHP3, and HHP4 revealed poor activity against the four fungal strains (MICs range 500-1000 µg mL-1). Compound HHP3 was found to be the best potential antifungal agent among those tested and was the most effective among all the active derivatives that caused morphological changes in the susceptible strains.