De novo identification of mammalian ciliary motility proteins using cryo-EM.

Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.

RTCpredictor: identification of read-through chimeric RNAs from RNA sequencing data.

Read-through chimeric RNAs are being recognized as a means to expand the functional transcriptome and contribute to cancer tumorigenesis when mis-regulated. However, current software tools often fail to predict them. We have developed RTCpredictor, utilizing a fast ripgrep tool to search for all possible exon-exon combinations of parental gene pairs. We also added exonic variants allowing searches containing common SNPs. To our knowledge, it is the first read-through chimeric RNA specific prediction method that also provides breakpoint coordinates. Compared with 10 other popular tools, RTCpredictor achieved high sensitivity on a simulated and three real datasets. In addition, RTCpredictor has less memory requirements and faster execution time, making it ideal for applying on large datasets.

Discovery of a polymorphic gene fusion via bottom-up chimeric RNA prediction.

Gene fusions and their chimeric products are commonly linked with cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. Large-scale efforts to annotate structural variations have identified gene fusions capable of generating chimeric transcripts even in normal tissues. In this study, we present a bottom-up approach targeting population-specific chimeric RNAs, identifying 58 such instances in the GTEx cohort, including notable cases such as SUZ12P1-CRLF3, TFG-ADGRG7 and TRPM4-PPFIA3, which possess distinct patterns across different ancestry groups. We provide direct evidence for an additional 29 polymorphic chimeric RNAs with associated structural variants, revealing 13 novel rare structural variants. Additionally, we utilize the All of Us dataset and a large cohort of clinical samples to characterize the association of the SUZ12P1-CRLF3-causing variant with patient phenotypes. Our study showcases SUZ12P1-CRLF3 as a representative example, illustrating the identification of elusive structural variants by focusing on those producing population-specific fusion transcripts.

Rhabdomyosarcomas are oncogene addicted to the activation of AVIL.

Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, MARS-AVIL formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, MARS, the AVIL locus is often amplified, and its RNA and protein expression are overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: Silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. AVIL is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.

Sphingosine kinases regulate ER contacts with late endocytic organelles and cholesterol trafficking.

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

TransCatheter aortic valve implantation and fractional flow reserve-guided percutaneous coronary intervention versus conventional surgical aortic valve replacement and coronary bypass grafting for treatment of patients with aortic valve stenosis and multivessel or advanced coronary disease: The transcatheter valve and vessels trial (TCW trial): Design and rationale.

BACKGROUND: Patients with severe aortic stenosis (AS) frequently present with concomitant obstructive coronary artery disease (CAD). In those, current guidelines recommend combined coronary artery bypass grafting (CABG) and surgical aortic valve replacement (SAVR) as the preferred treatment option, although this surgical approach is associated with a high rate of clinical events. Combined transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) with or without FFR have evolved as a valid alternative for cardiac surgery in patients with AS and multivessel or advanced CAD. To date, no dedicated trial has prospectively evaluated the outcomes of a percutaneous versus surgical treatment for patients with both severe AS and CAD. AIMS: To investigate whether fractional-flow reserve (FFR)-guided PCI and TAVI is noninferior to combined CABG and SAVR for the treatment of severe AS and multivessel or advanced CAD. METHODS: The Transcatheter Valve and Vessels (TCW) trial (clinicaltrial.gov: NCT03424941) is a prospective, randomized, controlled, open label, international trial. Patients ≥ 70 years with severe AS and multivessel (≥ 2 vessels) or advanced CAD, deemed feasible by the heart team for both; a full percutaneous or surgical treatment, will be randomised in a 1:1 fashion to either FFR-guided PCI followed by TAVI (intervention arm) vs. CABG and SAVR (control arm). The primary endpoint is a patient-oriented composite of all-cause mortality, myocardial infarction, disabling stroke, unscheduled clinically-driven target vessel revascularization, valve reintervention, and life threatening or disabling bleeding at 1 year. The TCW trial is powered for noninferiority, and if met, superiority will be tested. Assuming a primary endpoint rate of 30% in the CABG-SAVR arm, with a significance level α of 5%, a noninferiority limit delta of 15% and a loss to follow-up of 2%, a total of 328 patients are needed to obtain a power of 90%. The primary endpoint analysis is performed on an intention-to-treat basis. SUMMARY: The TCW Trial is the first prospective randomized trial that will study if a less invasive percutaneous treatment for severe AS and concomitant advanced CAD (i.e., FFR-guided PCI-TAVI) is noninferior to the guidelines recommended approach (CABG-SAVR).

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation.

Schizophrenia is a widespread psychiatric disorder that affects 0.5-1.0% of the world's population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.

Endothelial Senescence: From Macro- to Micro-Vasculature and Its Implications on Cardiovascular Health.

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases. Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific target(s) for therapeutic development of senolytic drugs.

Yin Yang 1 controls cerebellar astrocyte maturation.

Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.

Rezum water vapor therapy for patients with mild, moderate, or severe lower urinary tract symptoms: A retrospective study in a multiethnic population.

BACKGROUND: The Rezum System (Rezum) represents a novel, minimally invasive surgical therapy used to treat lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). We evaluated the safety and efficacy of Rezum in patients with mild, moderate, or severe LUTS. METHODS: A single office, retrospective study was conducted on patients from a multiethnic population treated with Rezum between 2017 and 2019. Patients were categorized into three cohorts based on baseline International Prostate Symptom Score (IPSS) LUTS severity: mild LUTS (IPSS ≤ 7), moderate LUTS (IPSS 8-19), or severe LUTS (IPSS ≥ 20) cohorts. Outcome measures, including IPSS, quality of life (QoL), maximum urinary flow rate (Qmax), postvoid residual (PVR), BPH medication usage, and adverse events (AEs) were collected and analyzed at baseline, 1-, 3-, 6-, and/or 12-months postoperatively. RESULTS: A total of 238 patients were included: 33 with mild LUTS, 109 with moderate LUTS, and 96 with severe LUTS. At 1-month follow-up, the moderate and severe LUTS cohorts saw significant improvements in IPSS (moderate LUTS: -3.0 [-6.0, 1.5], p < 0.001; severe LUTS: -10.0 [-16.0, -5.0], p < 0.001) and QoL (moderate LUTS: -1.0 [-3.0, 0.0], p < 0.001; severe LUTS: -1.0 [-3.0, 0.0], p < 0.001) and improvements remained durable up to 12-months (p < 0.001). The mild LUTS cohort saw significant worsening in IPSS by 2.0 (0.0, 12.0) at 1-month (p = 0.002) but returned to baseline at 3-months (p = 0.114). However, the mild LUTS cohort experienced significant improvements in QoL by -0.5 (-3.0, 0.0) at 3-months (p = 0.035) and nocturia by 0.0 (-1.0, 0.0) at 6-months (p = 0.002), both of which remained durable to 12-months (p < 0.05). Most AEs were transient and nonserious, with gross hematuria (66.5%) being most common. There were no significant differences in QoL point reduction, Qmax improvement, PVR reduction, and AE occurrence between the cohorts at 12-months (p > 0.05). At 12-months, 80.0%, 87.5%, and 66.0% of the patients in the mild, moderate, and severe LUTS cohorts discontinued their BPH medications, respectively. CONCLUSIONS: Rezum provides rapid and durable relief in LUTS in patients with moderate or severe LUTS and can be offered to patients with mild LUTS who have bothersome nocturia and wish to discontinue their BPH medications.

Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products.

Breast cancer is the prominent cause of cancer-related death in women globally in terms of incidence and mortality. Despite, recent advances in the management of breast cancer, there are still a lot of cases of resistance to medicines, which is currently one of the biggest problems faced by researchers across the globe. Out of several mechanisms, breast cancer resistance protein (BCRP) arbitrated drug resistance is a major concern. Hormonal, cytotoxic and immunotherapeutic drugs are used in the systemic therapy of breast cancer. It is vital to choose drugs based on the clinical and molecular attributes of the tumor to provide better treatment with greater efficacy and minimal harm. Given the aforementioned necessity, the use of marine flora in treating breast cancer cannot be neglected. The scientists also stressed the value of marine-derived goods in avoiding breast cancer resistance. Future research into the identification of anticancer drugs will heavily draw upon the marine environment's ample supply of marine-derived natural products (MNPs), which have a wide range of biological functions. Cell cycle arrest, induction of apoptosis and anti-angiogenic, anti-proliferative and anti-metastasis actions are all part of their processes. The overview of breast cancer, the mechanisms underlying its resistance, recent clinical trials based on marine-derived products in breast cancer and the use of marine products in the treatment of breast cancer are highlighted in this paper. Moreover, the authors also emphasised the importance of marine-derived products in preventing breast cancer resistance.

Therapeutic potential of melatonin and its derivatives in aging and neurodegenerative diseases.

Aging is associated with increasing impairments in brain homeostasis and represents the main risk factor across most neurodegenerative disorders. Melatonin, a neuroendocrine hormone that regulates mammalian chronobiology and endocrine functions is well known for its antioxidant potential, exhibiting both cytoprotective and chronobiotic abilities. Age-related decline of melatonin disrupting mitochondrial homeostasis and cytosolic DNA-mediated inflammatory reactions in neurons is a major contributory factor in the emergence of neurological abnormalities. There is scattered literature on the possible use of melatonin against neurodegenerative mechanisms in the aging process and its associated diseases. We have searched PUBMED with many combinations of key words for available literature spanning two decades. Based on the vast number of experimental papers, we hereby review recent advancements concerning the potential impact of melatonin on cellular redox balance and mitochondrial dynamics in the context of neurodegeneration. Next, we discuss a broader explanation of the involvement of disrupted redox homeostasis in the pathophysiology of age-related diseases and its connection to circadian mechanisms. Our effort may result in the discovery of novel therapeutic approaches. Finally, we summarize the current knowledge on molecular and circadian regulatory mechanisms of melatonin to overcome neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, however, these findings need to be confirmed by larger, well-designed clinical trials. This review is also expected to uncover the associated molecular alterations in the aging brain and explain how melatonin-mediated circadian restoration of neuronal homeodynamics may increase healthy lifespan in age-related NDDs.

Pelvic pain is a common prolapse symptom and improvement after ventral mesh rectopexy is more frequent than deterioration or de novo pain.

AIM: The aim of this work was to assess the relationship between pelvic pain and rectal prolapse both before prolapse surgery and in the long term after ventral mesh rectopexy (VMR). METHOD: Patients undergoing VMR between 2004 and 2017 were contacted. Outcomes including the severity of pelvic pain were recorded using a numeric rating scale. RESULTS: Four hundred and seventy eight of the 749 patients (64%) were successfully contacted. Of these, 39% reported pre-existing pelvic pain prior to VMR (group A) and 61% were pain free (group B). The median follow-up time was 8.0 years (interquartile range 5.0-10.0 years). Symptoms of obstructed defaecation were significantly more common (p = 0.002) in group A (91/187, 49%) than in group B (101/291, 35%). In contrast, faecal incontinence was more common (p = 0.007) in group B (75/291, 26%) than in group A (29/187, 15%). In group A, 76% showed improvement in pelvic pain after VMR: 61% were pain free and 39% had partial improvement in their pre-existing pelvic pain. Patients with persistent pelvic pain were younger (p = 0.01) and more likely to have revisional surgery after VMR (p = 0.0003), but there was no relation to the indication for surgery (p = 0.59). In group B, 15% reported de novo pelvic pain after VMR, and this was more common in women under 50 years old (p = 0.001), when obstructed defaecation was the indication (p = 0.03), in mesh erosion (p = <0.05) and when associated with revisional surgery (p = 0.005). CONCLUSION: Pelvic pain is common (39%) in patients undergoing prolapse surgery, and VMR improves this pain in most patients (76%). However, a significant number of patients fail to improve (12%), experience worsening of pain (12%) or develop de novo pelvic pain (15%).

Global distribution of pesticides in freshwater resources and their remediation approaches.

The role of pesticides in enhancing global agricultural production is magnificent. However, their unmanaged use threatens water resources and individual health. A significant pesticide concentration leaches to groundwater or reaches surface waters through runoff. Water contaminated with pesticides may cause acute or chronic toxicity to impacted populations and exert adverse environmental effects. It necessitates the monitoring and removing pesticides from water resources as prime global concerns. This work reviewed the global occurrences of pesticides in potable water and discussed the conventional and advanced technologies for the removal of pesticides. The concentration of pesticides highly varies in freshwater resources across the globe. The highest concentration of α-HCH (6.538 µg/L, at Yucatan, Mexico), lindane (6.08 µg/L at Chilka lake, Odisha, India), 2,4, DDT (0.90 µg/L, at Akkar, Lebanon), chlorpyrifos (9.1 µg/L, at Kota, Rajasthan, India), malathion (5.3 µg/L, at Kota, Rajasthan, India), atrazine (28.0 µg/L, at Venado Tuerto City, Argentina), endosulfan (0.78 µg/L, at Yavtmal, Maharashtra, India), parathion (4.17 µg/L, at Akkar, Lebanon), endrin (3.48 µg/L, at KwaZuln-Natl Province, South Africa) and imidacloprid (1.53 µg/L, at Son-La province, Vietnam) are reported. Pesticides can be significantly removed through physical, chemical, and biological treatment. Mycoremediation technology has the potential for up to 90% pesticide removal from water resources. Complete removal of the pesticides through a single biological treatment approach such as mycoremediation, phytoremediation, bioremediation, and microbial fuel cells is still a challenging task, however, the integration of two or more biological treatment approaches can attain complete removal of pesticides from water resources. Physical methods along with oxidation methods can be employed for complete removal of pesticides from drinking water.

Outcomes of rectal prolapse surgery in patients with benign joint hypermobility syndrome.

BACKGROUND: Rectal prolapse is a debilitating disorder of the pelvic floor, and treatment outcomes are variable. Previous studies have identified underlying benign joint hypermobility syndrome (BJHS) in some patients. We sought to determine the outcomes of these patients after undergoing ventral rectopexy surgery (VMR). METHODS: All consecutive patients who were referred to the pelvic floor unit at our institution between February 2010 and December 2011 were considered for recruitment into the study. Following recruitment, they were assessed using the Beighton criteria to determine the presence or absence of benign joint hypermobility syndrome. Both groups underwent similar surgical interventions and were then followed up. The need for revisional surgery was recorded in both groups. RESULTS: Fifty-two patients [34 normal; M:F, 1:6; median age 61 (range 22-84) years; 18 BJHS; M:F, 0:1; median age 52 (range 25-79) years] were recruited. A total of 42 patients completed the full 1-year follow-up (26 normal, 16 benign joint hypermobility syndrome). Patients with benign joint hypermobility syndrome were significantly younger (median age 52 versus 61 years, p < 0.001) with male to female ratio of 0:1 versus 1:6, respectively. In addition, they were significantly more likely to require revisional surgery than those without the condition (31% versus 8% p < 0.001). In most cases, this was in the form of a posterior stapled transanal resection of the rectum procedure. CONCLUSIONS: Patients with BJHS presenting for rectal prolapse surgery were younger and are more likely to require further surgery for rectal prolapse recurrence than those without the condition.

Comparison of "ligamentization" process between preserved insertion hamstring tendon autograft and bone-patellar tendon-bone autograft.

BACKGROUND: Ligamentization is a complex process and effect of preservation of hamstring tendon graft insertion on this process is not well studied. Present study was conducted to analyze and compare the ligamentization of semitendinosus gracilis graft with preserved tibial insertion (STGPI) and bone-patellar tendon-bone (BPTB) autografts. METHODS: A total of 50 sportspeople who underwent ACL reconstruction using either BPTB (group A; n = 25) or STGPI (group B; n = 25) autografts were included in the study. Contrast enhanced MRI was done at 8 months and 14 months post-ACL reconstruction to evaluate the ligamentization using Signal noise quotient (SNQ), graft intensity and enhancement index. Clinical outcomes (Lysholm score) and knee laxity were also assessed at 8 months and 14 months. RESULTS: 18/23 (78%) patients in group A and 14/23 (61%) patients in group B had hyperintense graft signal at 8 months (n.s.) and at 14 months, 1/23 patients in group A and none of the patients in group B had hyperintense graft. SNQ at 8 months was 3.6 ± 2 and 3.7 ± 2 in group A and B respectively (n.s.) and at 14 months, SNQ was 2.5 ± 1.5 in group A and 2.4 ± 1.3 in group B (n.s.). Enhancement index at 8 months was 1.5 ± 0.3 and 1.2 ± 0.3 in group A and B respectively (p = 0.0001). Enhancement index at 14 months was 1.21 ± 0.2 in group A and 1.07 ± 0.2 in group B (p = 0.003). Functional outcomes and knee laxity were comparable in both the groups at 8 and 14 months (n.s.). CONCLUSION: Both the grafts i.e. BPTB and STGPI are similar in terms of rate and extent of ligamentization. Clinical outcomes and knee laxity are also comparable between two grafts.

Nitric Oxide as a Determinant of Human Longevity and Health Span.

The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage-L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

Tryptophan in Nutrition and Health 2.0.

This editorial summarizes the eight articles that have been collected for the Special Issue entitled "Tryptophan in Nutrition and Health 2 [...].

Functions of Astrocytes under Normal Conditions and after a Brain Disease.

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS.