Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options.

Major Depressive Disorder (MDD) is one of the most disabling diseases in the world. MDD is traditionally diagnosed based on a patient's symptoms, which can lead to misdiagnosis. Although the pathogenic mechanisms of MDD are unknown, several studies have identified mitochondrial dysfunction as a central factor in the onset and progression of MDD. In the context of MDD, alterations in mitochondrial metabolism can lead to imbalances in energy production and oxidative stress, contributing to the disorder´s underlying pathophysiological mechanisms. Consequently, the identification of mitochondrial dysfunction as a key biomarker for early and accurate diagnosis of MDD represents a significant challenge. Faced with the limits of traditional treatments with antidepressants, new pharmacological therapeutic targets are being investigated such as ketamine/esketamine, psychedelics, or anti-inflammatories. All of these drugs show potential antidepressant effects due to their speed of action and ability to modulate neuroplasticity and/or motor processing. In parallel, non-pharmacological therapeutic targets are studied, like Transcranial Magnetic Stimulation (TMS) and Deep Brain Stimulation (DBS), recognized for their ability to modulate neuronal activity and offer treatment alternatives. As cellular activity is directly related to mitochondrial respiration, the aim of this review is examining the link between mitochondrial dysfunction and MDD, assessing how mitochondrial biomarkers could provide a more objective and precise diagnostic tool, and exploring other treatments in addition to traditional antidepressants, with a specific focus on emerging therapeutic targets. Finally, a detailed analysis of the strengths, weaknesses, opportunities, and threats of these approaches was carried out, highlighting the key challenges that must be addressed.

Salvage of Infected Alloplastic Ear Reconstructions via Negative Pressure Wound Therapy.

This is the first description of Negative Pressure Wound Therapy (NPWT) use in rescuing alloplastic ear reconstructions. Previously considered a sign of certain impending failure, severe infections with frank purulence can be salvaged. As a more recently developed technique, porous polyethylene (PPE) ear reconstruction provides benefits when compared to rib techniques. Increasing surgeon awareness of complication management may lead to further adoption of the technique and improve reconstructive results. Described herein are two cases of draining infections following PPE ear reconstruction that were salvaged with satisfactory results. Laryngoscope, 2024.

Fermentation of whey-derived matrices by Kluyveromyces marxianus: alcoholic beverage development from whey and fruit juice mixes.

This research paper addresses the hypotheses that Kluyveromyces marxianus can be cultured with good alcohol production on different whey-derived matrices, and that the fermented product can be used in order to develop alcoholic beverages with acceptable sensory characteristics by mixtures with yeast-fermented fruit-based matrices. Growth and fermentative characteristics of Kluyveromyces marxianus LFIQK1 in different whey-derived matrices were explored by culturing (24 h, 30°C) on reconstituted whey, demineralized whey, heat-treated whey and milk permeate media. High lactose consumption, ethanol production and yield were observed. Reconstituted whey matrix was selected for mixing with orange or strawberry juices fermented using Saccharomyces cerevisiae to obtain alcoholic beverages (W-OR and W-ST, respectively). Consumer evaluation of beverages was performed using acceptability and Check-All-That-Apply (CATA) questions. Good acceptance was observed, significantly higher for W-ST than for W-OR. CATA questions gave information about organoleptic characteristics of beverages. Penalty analysis showed W-R and W-ST were positively associated with smooth/refreshing and fruity/natural, respectively. Liking was represented, accordingly with penalty analysis, by natural/refreshing. A novel alternative for utilization of whey and whey-related matrices by alcoholic beverages production with natural ingredients is presented.

Brucella-driven host N-glycome remodeling controls infection.

Many powerful methods have been employed to elucidate the global transcriptomic, proteomic, or metabolic responses to pathogen-infected host cells. However, the host glycome responses to bacterial infection remain largely unexplored, and hence, our understanding of the molecular mechanisms by which bacterial pathogens manipulate the host glycome to favor infection remains incomplete. Here, we address this gap by performing a systematic analysis of the host glycome during infection by the bacterial pathogen Brucella spp. that cause brucellosis. We discover, surprisingly, that a Brucella effector protein (EP) Rhg1 induces global reprogramming of the host cell N-glycome by interacting with components of the oligosaccharide transferase complex that controls N-linked protein glycosylation, and Rhg1 regulates Brucella replication and tissue colonization in a mouse model of brucellosis, demonstrating that Brucella exploits the EP Rhg1 to reprogram the host N-glycome and promote bacterial intracellular parasitism, thereby providing a paradigm for bacterial control of host cell infection.

Serological Antibodies against Kidney, Liver, and Spleen Membrane Antigens as Potential Biomarkers in Patients with Immune Disorders.

Immune disorders arise from complex genetic and environmental factors, which lead to dysregulation at the cellular and inflammatory levels and cause tissue damage. Recent research highlights the crucial role of reactive antibodies in autoimmune diseases and graft rejection, but their complex determination poses challenges for clinical use. Therefore, our study aimed to ascertain whether the presence of reactive antibodies against membrane antigens in tissues from both animal models and humans could serve as biomarkers in patients with autoimmune disorders. To address this issue, we examined the binding profile of serological antibodies against a diverse panel of cell membranes from the spleen, liver, and kidney tissues of monkeys, rats, and humans. After developing the cell membrane microarrays, human sera were immunologically assayed. The study was first conducted on sera from two groups, healthy subjects and patients with inflammatory and autoimmune disorders, and then optimized for kidney transplant patient sera. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in patients' serum as potential biomarkers of immune disorders. However, it is important to note that these results need to be verified in further studies with a larger sample size to confirm their relevance.

Lipid fingerprint-based histology accurately classifies nevus, primary melanoma, and metastatic melanoma samples.

Probably, the most important factor for the survival of a melanoma patient is early detection and precise diagnosis. Although in most cases these tasks are readily carried out by pathologists and dermatologists, there are still difficult cases in which no consensus among experts is achieved. To deal with such cases, new methodologies are required. Following this motivation, we explore here the use of lipid imaging mass spectrometry as a complementary tool for the aid in the diagnosis. Thus, 53 samples (15 nevus, 24 primary melanomas, and 14 metastasis) were explored with the aid of a mass spectrometer, using negative polarity. The rich lipid fingerprint obtained from the samples allowed us to set up an artificial intelligence-based classification model that achieved 100% of specificity and precision both in training and validation data sets. A deeper analysis of the image data shows that the technique reports important information on the tumor microenvironment that may give invaluable insights in the prognosis of the lesion, with the correct interpretation.

Immunisation with Neospora caninum subunits rsNcSAG4 and rsNcGRA1 (NcSAG4 and NcGRA1 epitopes construct) in BALB/c mice: the profile of the immune response and controlling the vertical transmission.

Neospora caninum is an apicomplexan protozoan that causes neosporosis, which has a high economic impact on cattle herds with no available vaccine. During infection, the secretion of dense granules and the expression of surface antigens play an important role in hosting immunomodulation. However, some epitopes of those antigens are immunogenic, and using these fractions could improve the subunit antigens in vaccine design. This study evaluates the recombinant peptides rsNcGRA1 and rsNcSAG4 derived from NcGRA1 and NcSAG4 native antigens as vaccine candidates produced by a fermentative process in the yeast culture system of Komagataella phaffii strain Km71, confirmed by colony PCR, SDS-PAGE, and western blotting. The assay was conducted in BALB/c mice using the peptides at low (25 µg) and standard (50 µg) dosages in monovalent and combined administrations at three time points with saponin as an adjuvant assessing the immunogenicity by antibodies response and cytokine production. We challenge the females after pregnancy confirmation using 2 × 105 NC-1 tachyzoites previously propagated in Vero cells. We assessed the chronic infection in dams and vertical transmission in the offspring by PCR and histopathology. Mice, especially those immunised with combined peptides and monovalent rsNcGRA1 at a standard dose, controlling the chronic infection in dams with the absence of clinical manifestations, showed an immune response with induction of IgG1, a proper balance between Th1/Th2 cytokines and reduced vertical transmission in the pups. In contrast, dams inoculated with a placebo vaccine showed clinical signs, low-scored brain lesions, augmented chronic infection with 80% positivity, 31% mortality in pups, and 81% vertical transmission. These findings indicate that rsNcGRA1 peptides in monovalent and combined with rsNCSAG4 at standard dose are potential vaccine candidates and improve the protective immune response against neosporosis in mice.

Neuroinflammation in the Evolution of Motor Function in Stroke and Trauma Patients: Treatment and Potential Biomarkers.

Neuroinflammation has a significant impact on different pathologies, such as stroke or spinal cord injury, intervening in their pathophysiology: expansion, progression, and resolution. Neuroinflammation involves oxidative stress, damage, and cell death, playing an important role in neuroplasticity and motor dysfunction by affecting the neuronal connection responsible for motor control. The diagnosis of this pathology is performed using neuroimaging techniques and molecular diagnostics based on identifying and measuring signaling molecules or specific markers. In parallel, new therapeutic targets are being investigated via the use of bionanomaterials and electrostimulation to modulate the neuroinflammatory response. These novel diagnostic and therapeutic strategies have the potential to facilitate the development of anticipatory patterns and deliver the most beneficial treatment to improve patients' quality of life and directly impact their motor skills. However, important challenges remain to be solved. Hence, the goal of this study was to review the implication of neuroinflammation in the evolution of motor function in stroke and trauma patients, with a particular focus on novel methods and potential biomarkers to aid clinicians in diagnosis, treatment, and therapy. A specific analysis of the strengths, weaknesses, threats, and opportunities was conducted, highlighting the key challenges to be faced in the coming years.

Thermoplastic Starch Biocomposite Films Reinforced with Nanocellulose from Agave tequilana Weber var. Azul Bagasse.

In this work, cellulose nanocrystals (CNCs), bleached cellulose nanofibers (bCNFs), and unbleached cellulose nanofibers (ubCNFs) isolated by acid hydrolysis from Agave tequilana Weber var. Azul bagasse, an agro-waste from the tequila industry, were used as reinforcements in a thermoplastic starch matrix to obtain environmentally friendly materials that can substitute contaminant polymers. A robust characterization of starting materials and biocomposites was carried out. Biocomposite mechanical, thermal, and antibacterial properties were evaluated, as well as color, crystallinity, morphology, rugosity, lateral texture, electrical conductivity, chemical identity, solubility, and water vapor permeability. Pulp fibers and nanocelluloses were analyzed via SEM, TEM, and AFM. The water vapor permeability (WVP) decreased by up to 20.69% with the presence of CNCs. The solubility decreases with the presence of CNFs and CNCs. The addition of CNCs and CNFs increased the tensile strength and Young's modulus and decreased the elongation at break. Biocomposites prepared with ubCNF showed the best tensile mechanical properties due to a better adhesion with the matrix. Images of bCNF-based biocomposites demonstrated that bCNFs are good reinforcing agents as the fibers were dispersed within the starch film and embedded within the matrix. Roughness increased with CNF content and decreased with CNC content. Films with CNCs did not show bacterial growth for Staphylococcus aureus and Escherichia coli. This study offers a new theoretical basis since it demonstrates that different proportions of bleached or unbleached nanofibers and nanocrystals can improve the properties of starch films.

Acquired Immune Deficiency Syndrome correlation with SARS-CoV-2 N genotypes.

BACKGROUND: Epigenetics and clinical observations referring to Betacoronavirus lead to the conjecture that Sarvecovirus may have the ability to infect lymphocytes using a different way than the spike protein. In addition to inducing the death of lymphocytes, thus drastically reducing their population and causing a serious immune deficiency, allows it to remain hidden for long periods of latency using them as a viral reservoir in what is named Long-Covid Disease. Exploring possibilities, the hypothesis is focused on that N protein may be the key of infecting lymphocytes. Method The present article exhibits a computational assay for the latest complete sequences reported to GISAID, correlating N genotypes with an enhancement in the affinity of the complex that causes immune deficiency in order to determine a good docking with the N protein and some receptors in lymphocytes. Results A novel high-interaction coupling of N-RBD and CD147 is presented as the main way of infecting lymphocytes, allowing to define those genotypes involved in their affinity enhancement. Conclusion The hypothesis is consistent with the mutagenic deriving observed on the in-silico assay, which reveals that genotypes N/120 and N/152 are determinant to reduce the Immune Response of the host infecting lymphocytes, allowing the virus persists indefinitely and causing an Acquire Immune Deficiency Syndrome.

Pediatric Spontaneous Cerebrospinal Fluid Leak Repair: An Endoscopic Endonasal Approach.

Background: Spontaneous cerebrospinal fluid (CSF) rhinorrhea in the pediatric population is an exceedingly rare condition that occurs when the dura mater is breached, resulting in CSF drainage from the subarachnoid space into surrounding sinonasal tissue. Objective: This work delineates a step-by-step surgical approach to visually demonstrate the feasibility of an uninarial endoscopic endonasal approach for pediatric spontaneous CSF leak repair. Postoperative Outcome: A 2-year-old male with a 6-month history of clear rhinorrhea, intermittent headaches, and a previous episode of bacterial meningitis was evaluated as an inpatient consultation. Computed tomography cisternography revealed active CSF extravasation at the right sphenoid sinus roof. An endoscopic endonasal approach was performed including a complete sphenoethmoidectomy plus middle turbinectomy to provide access to the skull base defect. Once identified, a middle turbinate free mucosal graft was placed for cranial base reconstruction given the child's young agre. Sinonasal debridement 3 weeks following surgery under anesthesia revealed an intact viable graft with no evidence of CSF leak. There was no evidence of CSF leak recurrence or complications 1 year following surgery. Conclusion: The uninarial endoscopic endonasal approach is a safe and effective option for the surgical management of spontaneous CSF leak rhinorrhea in the pediatric population.

Combined Phacoemulsification and STREAMLINE Surgical System Canal of Schlemm Transluminal Dilation in Eyes of Hispanic Patients with Mild to Moderate Glaucoma.

Purpose: To characterize clinical outcomes of transluminal dilation of the canal of Schlemm using the STREAMLINE Surgical System combined with phacoemulsification in eyes of Hispanic patients diagnosed with mild to moderate primary open-angle glaucoma. Methods: This was a prospective analysis of all cases performed and followed up to 12 months. All eyes underwent medication washout preoperatively. Reduction in intraocular pressure (IOP) from unmedicated baseline, as well as medications from pre-washout baseline, were analyzed at postoperative Day 1, Week 1, and Months 1, 3, 6, 9, and 12. Results: All 37 patients were Hispanic, 83.8% were female, and mean (standard deviation) age was 66.0 (10.5) years. Mean medicated preoperative IOP was 16.9 (3.2) mmHg using a mean of 2.1 (0.9) medications, unmedicated baseline IOP (after washout) was 23.2 (2.3) mmHg, and mean IOP at every postoperative study visit was significantly lower (p<0.0002). Mean IOP from month 1 through the first postoperative year ranged from 14.7-16.2 mmHg, representing a reduction of 7.0-8.5 mmHg (30.7-36.5%). At month 12, 80% of all eyes (28/35) and 77.8% of medication-free eyes (14/18) had IOP reduction ≥20% from unmedicated baseline, and 51.4% of eyes (18/35) were medication-free. Mean medication use was significantly reduced (by 59.9-74.6%, p<0.0001) at every postoperative study visit. The only adverse event occurring in >1 eye was high IOP (n=4) which was responsive to topical medical therapy; no adverse events were attributed to the transluminal dilation procedure. Conclusion: Transluminal dilation of the canal of Schlemm using the STREAMLINE Surgical System combined with phacoemulsification safely and effectively reduced both IOP and dependence on IOP-lowering medications in a Hispanic population diagnosed with POAG and should be considered at the time of phacoemulsification in Hispanic patients who have a need for IOP reduction, medication reduction, or both.

Aripiprazole attenuates the medial prefrontal cortex morphological and biochemical alterations in rats with neonatal ventral hippocampus lesion.

Schizophrenia is a neurodevelopmental disorder characterized by a loss of dendritic spines in the medial prefrontal cortex (mPFC). Multiple subclinical and clinical studies have evidenced the ability of antipsychotics to improve neuroplasticity. In this study, it was evaluated the effect of the atypical antipsychotic aripiprazole (ARI) on the behavioral and mPFC neuronal disturbances of rats with neonatal ventral hippocampus lesion (nVHL), which is a heuristic developmental model relevant to the study of schizophrenia. ARI attenuated open field hyperlocomotion in the rats with nVHL. Also, ARI ameliorated structural neuroplasticity disturbances of the mPFC layer 3 pyramidal cells, but not in the layer 5 neurons. These effects can be associated with the ARI capability of increasing brain-derived neurotrophic factor (BDNF) levels. Moreover, in the animals with nVHL, ARI attenuated the immunoreactivity for some oxidative stress-related molecules such as the nitric oxide synthase 2 (NOS-2), 3-nitrotyrosine (3-NT), and cyclooxygenase 2 (COX-2), as well as the reactive astrogliosis in the mPFC. These results contribute to current knowledge about the neurotrophic, anti-inflammatory, and antioxidant properties of antipsychotics which may be contributing to their clinical effects and envision promising therapeutic targets for the treatment of schizophrenia.

Structural Behavior of Amphiphilic Triblock Copolymer P104/Water System.

A detailed study of the different structural transitions of the triblock copolymer PEO27-PPO61-PEO27 (P104) in water, in the dilute and semi-dilute regions, is addressed here as a function of temperature and P104 concentration (CP104) by mean of complimentary methods: viscosimetry, densimetry, dynamic light scattering, turbidimetry, polarized microscopy, and rheometry. The hydration profile was calculated through density and sound velocity measurements. It was possible to identify the regions where monomers exist, spherical micelle formation, elongated cylindrical micelles formation, clouding points, and liquid crystalline behavior. We report a partial phase diagram including information for P104 concentrations from 1 × 10-4 to 90 wt.% and temperatures from 20 to 75 °C that will be helpful for further interaction studies with hydrophobic molecules or active principles for drug delivery.

Deer mastadenovirus B pneumonia in a white-tailed deer fawn.

A 7-mo-old farmed white-tailed deer fawn (Odocoileus virginianus) died after several weeks of progressive deterioration associated with endoparasitism and respiratory signs. A field autopsy was performed, and lung tissue was submitted for histologic examination. The findings were consistent with necrosuppurative bronchointerstitial pneumonia with intranuclear viral inclusions. Immunofluorescence using fluorescently labeled polyclonal antibodies to bovine adenovirus 3 and 5 was positive. To rule out cross-reactivity with other adenoviruses, formalin-fixed, paraffin-embedded tissue sections were submitted for genome sequence analysis, which revealed a 99.6% match to Deer mastadenovirus B (formerly Odocoileus adenovirus 2, OdAdV2). To our knowledge, natural clinical disease associated with OdAdV2 has not been reported previously.

Endoscopic-Indocyanine Green Angiography Assisted Microtia Reconstruction.

Described herein is an innovative, minimally-invasive technique to harvest temporoparietal fascia flap used in implant-based ear reconstruction for children with microtia. This technique utilizes a never previously described application of intra-operative Indocyanine Green Angiography to optimize flap viability and minimizing the risk of facial nerve injury. Laryngoscope, 133:3615-3618, 2023.

Dual Option Microtia Clinic: A Comparison of Outcomes in Microtia Reconstruction Using Autologous Rib or Porous Polyethylene Implant.

Introduction: Auricular reconstruction techniques most frequently utilize either autologous costal cartilage or alloplastic porous polyethylene (PPE) implant. Objectives: To compare the aesthetic outcomes, number of surgeries, and complications in children who underwent microtia reconstruction with either rib or PPE implant by blinded photograph review. Methods: This retrospective cohort study included consecutive pediatric patients who underwent auricular reconstruction with either autologous cartilage or PPE between November 2017 and February 2022. Blinded observers rated each postoperative ear through a web-based survey. Data on patient characteristics, operative time, length of admission, and complications were collected, bivariate analyses were performed using chi-square or Fisher's exact tests for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: Forty-four ears were included, 28 of which (63.6%) were reconstructed with cartilage. Median patient age was 8 years (range 4-18 years) and 29 (65.9%) were male. The cartilage group had more surgeries (median 2.5 vs. 1.0, p < 0.001), and total operating time across all surgeries did not differ significantly. Conclusion: The two groups in our study had similar rates of complications and aesthetic scores, and aesthetic scores were worse for ears with wound complications requiring unplanned revisions.

Microarrays, Enzymatic Assays, and MALDI-MS for Determining Specific Alterations to Mitochondrial Electron Transport Chain Activity, ROS Formation, and Lipid Composition in a Monkey Model of Parkinson's Disease.

Multiple evidences suggest that mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease via the selective cell death of dopaminergic neurons, such as that which occurs after prolonged exposure to the mitochondrial electron transport chain (ETC) complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP). However, the effects of chronic MPTP on the ETC complexes and on enzymes of lipid metabolism have not yet been thoroughly determined. To face these questions, the enzymatic activities of ETC complexes and the lipidomic profile of MPTP-treated non-human primate samples were determined using cell membrane microarrays from different brain areas and tissues. MPTP treatment induced an increase in complex II activity in the olfactory bulb, putamen, caudate, and substantia nigra, where a decrease in complex IV activity was observed. The lipidomic profile was also altered in these areas, with a reduction in the phosphatidylserine (38:1) content being especially relevant. Thus, MPTP treatment not only modulates ETC enzymes, but also seems to alter other mitochondrial enzymes that regulate the lipid metabolism. Moreover, these results show that a combination of cell membrane microarrays, enzymatic assays, and MALDI-MS provides a powerful tool for identifying and validating new therapeutic targets that might accelerate the drug discovery process.

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program.

Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.