Structural basis of RNA conformational switching in the transcriptional regulator 7SK RNP.

7SK non-coding RNA (7SK) negatively regulates RNA polymerase II (RNA Pol II) elongation by inhibiting positive transcription elongation factor b (P-TEFb), and its ribonucleoprotein complex (RNP) is hijacked by HIV-1 for viral transcription and replication. Methylphosphate capping enzyme (MePCE) and La-related protein 7 (Larp7) constitutively associate with 7SK to form a core RNP, while P-TEFb and other proteins dynamically assemble to form different complexes. Here, we present the cryo-EM structures of 7SK core RNP formed with two 7SK conformations, circular and linear, and uncover a common RNA-dependent MePCE-Larp7 complex. Together with NMR, biochemical, and cellular data, these structures reveal the mechanism of MePCE catalytic inactivation in the core RNP, unexpected interactions between Larp7 and RNA that facilitate a role as an RNP chaperone, and that MePCE-7SK-Larp7 core RNP serves as a scaffold for switching between different 7SK conformations essential for RNP assembly and regulation of P-TEFb sequestration and release.

Guide RNA acrobatics: positioning consecutive uridines for pseudouridylation by H/ACA pseudouridylation loops with dual guide capacity.

Site-specific pseudouridylation of human ribosomal and spliceosomal RNAs is directed by H/ACA guide RNAs composed of two hairpins carrying internal pseudouridylation guide loops. The distal "antisense" sequences of the pseudouridylation loop base-pair with the target RNA to position two unpaired target nucleotides 5'-UN-3', including the 5' substrate U, under the base of the distal stem topping the guide loop. Therefore, each pseudouridylation loop is expected to direct synthesis of a single pseudouridine (Ψ) in the target sequence. However, in this study, genetic depletion and restoration and RNA mutational analyses demonstrate that at least four human H/ACA RNAs (SNORA53, SNORA57, SCARNA8, and SCARNA1) carry pseudouridylation loops supporting efficient and specific synthesis of two consecutive pseudouridines (ΨΨ or ΨNΨ) in the 28S (Ψ3747/Ψ3749), 18S (Ψ1045/Ψ1046), and U2 (Ψ43/Ψ44 and Ψ89/Ψ91) RNAs, respectively. In order to position two substrate Us for pseudouridylation, the dual guide loops form alternative base-pairing interactions with their target RNAs. This remarkable structural flexibility of dual pseudouridylation loops provides an unexpected versatility for RNA-directed pseudouridylation without compromising its efficiency and accuracy. Besides supporting synthesis of at least 6% of human ribosomal and spliceosomal Ψs, evidence indicates that dual pseudouridylation loops also participate in pseudouridylation of yeast and archaeal rRNAs.

Cooperative 2'-O-methylation of the wobble cytidine of human elongator tRNAMet(CAT) by a nucleolar and a Cajal body-specific box C/D RNP.

Site-specific 2'-O-ribose methylation of mammalian rRNAs and RNA polymerase II-synthesized spliceosomal small nuclear RNAs (snRNAs) is mediated by small nucleolar and small Cajal body (CB)-specific box C/D ribonucleoprotein particles (RNPs) in the nucleolus and the nucleoplasmic CBs, respectively. Here, we demonstrate that 2'-O-methylation of the C34 wobble cytidine of human elongator tRNAMet(CAT) is achieved by collaboration of a nucleolar and a CB-specific box C/D RNP carrying the SNORD97 and SCARNA97 box C/D 2'-O-methylation guide RNAs. Methylation of C34 prevents site-specific cleavage of tRNAMet(CAT) by the stress-induced endoribonuclease angiogenin, implicating box C/D guide RNPs in controlling stress-responsive production of putative regulatory tRNA fragments.

Splenectomy at early stage of autoimmune arthritis delayed inflammatory response and reduced joint deterioration in mice.

The spleen plays a role in innate and adaptive immunity, and autoimmune diseases like rheumatoid arthritis (RA). We investigated the effect of splenectomy in early and moderate stages of autoimmune arthritis in a mouse model. To induce recombinant human G1-induced arthritis (GIA), BALB/c mice were immunized intraperitoneally three times in 4-week intervals with the rhG1 antigen. Mice were splenectomized on day 7 (SPE1) or day 35 (SPE2) after the initiation of immunization; tested for clinical severity, joint radiological and histological changes, serum levels of inflammatory cytokines and autoantibodies, and rhG1-specific immune responses; and compared to those in control mice with spleen left intact. Circulating Tregs and T-helper subset ratios in the spleen and inguinal lymph nodes (LNs) were also examined using flow cytometry. The onset of severe inflammatory response was significantly delayed in SPE1 and SPE2 groups compared to control mice at early stages of GIA, which was associated with increased circulating Tregs. After the third immunization, as disease progressed, the severity scores were robustly increased in all mice. Nevertheless, in splenectomized mice, we observed reduced joint deterioration and cartilage damage, more Th2 cells in LNs, and reduced levels of pro-inflammatory cytokines and autoantibodies in their sera. Mesenteric LN cells of splenectomized mice exhibited weaker response in vitro against the rhG1 antigen compared to control mice spleen. In conclusion, splenectomy in the early stages of GIA delayed the inflammatory response, suggesting a protective effect against the development and progression of severe destructive arthritis.

Is the collateral circulation pattern in the hard palate affected by cleft deformity?

OBJECTIVES: To evaluate the influence of collateral vascularization on surgical cleft palate closure and deformities. MATERIALS AND METHODS: Corrosion casting was performed using red-colored acrylic resin in twelve fresh adult cadavers with a normal hard palate. Additionally, white-colored barium sulfate was injected into a fetus with a unilateral complete cleft palate, and layer-by-layer tissue dissection was performed. Both substances were injected into the external carotid arteries. Corrosion casting involved dissolving the soft and hard tissues of the orofacial area utilizing an enzymatic solution. RESULTS: In normal palates, bilateral intraosseous infraorbital arteries formed a network in the premaxilla with the intraosseous nasopalatine- and greater palatine arteries (GPAs). The perforating GPAs anastomosed with the sphenopalatine artery sub-branches. Bilateral extraosseous GPA anastomoses penetrated the median palatine suture. Complex vascularization in the retrotuberal area was detected. In the cleft zone, anastomoses were omitted, whereas in the non-cleft zone, enlarged GPAs were distributed along the cleft edges and followed the anatomical course anteriorly to initiate the network with facial artery sub-branches. CONCLUSIONS: The anatomical subunits of the palate exhibited distinct anastomosis patterns. Despite omitted anastomoses with collateral circulation in the cleft zone, arteries maintained their anatomical pattern as seen in the normal specimen in the non-cleft zone. CLINICAL RELEVANCE: Based on the findings in normal- and cleft palates, surgeons may expect developed anastomosis patterns in the non-cleft zone. Due to the lack of microcirculation in the cleft zone, the existent anastomoses should be maintained as much as possible by the surgical technique. This applies anteriorly in the incisive canal territory, alveolar ridges, and posteriorly in the retrotuberal area.

Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms.

Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin-muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1αß knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of an IL-1ß floxed(fl/fl) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1ß, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

Effect of Pre-Heating on the Monomer Elution and Porosity of Conventional and Bulk-Fill Resin-Based Dental Composites.

The pre-heating of dental resin-based composites (RBCs) improves adaptability to cavity walls, reducing microleakages. However, the rapid cooling of the pre-heated RBC may change the polymerization kinetics, and thus the final network configuration of the RBC. It is well known that unreacted monomers remaining in the set RBC can leach into the oral cavity. However, it is still not clear how the pre-heating and cooling of RBCs alter monomer elution (ME). Thus, the purpose was to determine the ME from room-temperature and pre-heated RBCs, in addition to determining the closed porosity (CP) volume. Bulk-filled RBCs and layered conventional RBC samples were prepared. The pre-polymerization temperature was set at 24 °C and 55/65 °C. The ME from RBC samples was assessed with high-performance liquid chromatography using standard monomers. CP was measured with micro-computed tomography. ME decreased significantly from bulk fills and increased from layered samples as a result of pre-heating. Pre-heating was unfavorable in terms of CP in most RBCs. Based on the effect size analysis, ME and CP were greatly influenced by both material composition, pre-polymerization temperature, and their interaction. While the pre-heating of high-viscosity bulk-fill RBCs is advantageous from a clinical aspect regarding biocompatibility, it increases CP, which is undesirable from a mechanical point of view.

The 7SK snRNP associates with the little elongation complex to promote snRNA gene expression.

The 7SK small nuclear RNP (snRNP), composed of the 7SK small nuclear RNA (snRNA), MePCE, and Larp7, regulates the mRNA elongation capacity of RNA polymerase II (RNAPII) through controlling the nuclear activity of positive transcription elongation factor b (P-TEFb). Here, we demonstrate that the human 7SK snRNP also functions as a canonical transcription factor that, in collaboration with the little elongation complex (LEC) comprising ELL, Ice1, Ice2, and ZC3H8, promotes transcription of RNAPII-specific spliceosomal snRNA and small nucleolar RNA (snoRNA) genes. The 7SK snRNA specifically associates with a fraction of RNAPII hyperphosphorylated at Ser5 and Ser7, which is a hallmark of RNAPII engaged in snRNA synthesis. Chromatin immunoprecipitation (ChIP) and chromatin isolation by RNA purification (ChIRP) experiments revealed enrichments for all components of the 7SK snRNP on RNAPII-specific sn/snoRNA genes. Depletion of 7SK snRNA or Larp7 disrupts LEC integrity, inhibits RNAPII recruitment to RNAPII-specific sn/snoRNA genes, and reduces nascent snRNA and snoRNA synthesis. Thus, through controlling both mRNA elongation and sn/snoRNA synthesis, the 7SK snRNP is a key regulator of nuclear RNA production by RNAPII.

Obesity-induced cognitive impairment in older adults: a microvascular perspective.

Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

Demonstration of age-related blood-brain barrier disruption and cerebromicrovascular rarefaction in mice by longitudinal intravital two-photon microscopy and optical coherence tomography.

Age-related blood-brain barrier (BBB) disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research, there is an urgent need for sensitive and easy-to-adapt imaging methods that enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice and that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that, in 24-mo-old C57BL/6J mice, cumulative permeability of the microvessels to fluorescent tracers of different molecular masses (0.3 to 40 kDa) is significantly increased compared with that of 5-mo-old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 wk) in vivo assessment of cerebromicrovascular health in preclinical geroscience research.NEW & NOTEWORTHY Methods are presented for longitudinal detection of age-related increase in blood-brain barrier permeability and microvascular rarefaction in the mouse cerebral cortex by intravital two-photon microscopy and optical coherence tomography.

Acute blockade of NR2C/D subunit-containing N-methyl-D-aspartate receptors modifies sleep and neural oscillations in mice.

N-methyl-d-aspartate receptors (NMDARs) play an important role in excitatory neurotransmission and have been associated with psychiatric conditions including schizophrenia and major depressive disorder. NMDARs are composed of two NR1 and two NR2 subunits. The type of NR2 subunit determines electrophysiological and pharmacological properties of the receptor. As the precise role of NR2C/D subunit-containing NMDARs is poorly understood in vivo, we have performed behavioural, quantitative electroencephalographic (qEEG) and polysomnographic analysis following acute pharmacological blockade of these receptor subtypes in adult male CD1 mice. We found that NR2C/D blockade impaired motor coordination and decreased the amount of gross movement. Moreover, EEG power in multiple frequency bands including theta and sigma were found to decrease significantly together with a decrease of theta oscillation frequency. Changes of these qEEG measures were accompanied by a decrease in time spent in slow-wave and rapid eye movement sleep, but an increase of time spent in quiet wakefulness. Furthermore, there was a significant decrease of sleep spindle oscillation density. These findings highlight the importance of NR2C/D-containing NMDARs and take a step towards establishing a link between electrophysiological correlates of psychiatric disorders and underlying synaptic dysfunctions.

Dynamic association of human mRNP proteins with mitochondrial tRNAs in the cytosol.

Cytoplasmic localization, stability, and translation of mRNAs are controlled by their dynamic association of numerous mRNA-binding (mRNP) proteins, including cold shock domain (CSD)-containing proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), and serine/arginine-rich (SR) proteins. Here, we demonstrate that the most abundant human mRNP protein, the CSD-containing Y-box-binding protein 1 (YBX1), the closely related YBX3 protein, and other mRNP proteins, such as SRSF1, SRSF2, SRSF3, hnRNP A1, and H, specifically and efficiently interact with overlapping sets of mitochondrial tRNAs (mt tRNAs). In vitro reconstitution and in vivo binding experiments show that YBX1 recognizes the D- and/or T-stem-loop regions of mt tRNAs through relying on the RNA-binding capacity of its CSD. Cell fractionation and in vivo RNA-protein cross-linking experiments demonstrate that YBX1 and YBX3 interact with mt tRNAs in the cytosol outside of mitochondria. Cell fractionation and fluorescence in situ hybridization experiments provide evidence that mitochondrial autophagy promotes the release of mt tRNAs from the mitochondria into the cytoplasm. Association of mRNP proteins with mt tRNAs is highly dynamic; it is rapidly increased upon transcription inhibition and decreased during apoptosis. Although the cytoplasmic function of mt tRNAs remains elusive, their dynamic interactions with key mRNA-binding proteins may influence cytoplasmic mRNA stability and/or translation.

Ser7 phosphorylation of the CTD recruits the RPAP2 Ser5 phosphatase to snRNA genes.

The carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (Pol II) comprises multiple heptapeptide repeats of the consensus Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Reversible phosphorylation of Ser2, Ser5, and Ser7 during the transcription cycle mediates the sequential recruitment of transcription/RNA processing factors. Phosphorylation of Ser7 is required for recruitment of the gene type-specific Integrator complex to the Pol II-transcribed small nuclear (sn)RNA genes. Here, we show that RNA Pol II-associated protein 2 (RPAP2) specifically recognizes the phospho-Ser7 mark on the Pol II CTD and also interacts with Integrator subunits. siRNA-mediated knockdown of RPAP2 and mutation of Ser7 to alanine cause similar defects in snRNA gene expression. In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.

Human intron-encoded Alu RNAs are processed and packaged into Wdr79-associated nucleoplasmic box H/ACA RNPs.

Alu repetitive sequences are the most abundant short interspersed DNA elements in the human genome. Full-length Alu elements are composed of two tandem sequence monomers, the left and right Alu arms, both derived from the 7SL signal recognition particle RNA. Since Alu elements are common in protein-coding genes, they are frequently transcribed into pre-mRNAs. Here, we demonstrate that the right arms of nascent Alu transcripts synthesized within pre-mRNA introns are processed into metabolically stable small RNAs. The intron-encoded Alu RNAs, termed AluACA RNAs, are structurally highly reminiscent of box H/ACA small Cajal body (CB) RNAs (scaRNAs). They are composed of two hairpin units followed by the essential H (AnAnnA) and ACA box motifs. The mature AluACA RNAs associate with the four H/ACA core proteins: dyskerin, Nop10, Nhp2, and Gar1. Moreover, the 3' hairpin of AluACA RNAs carries two closely spaced CB localization motifs, CAB boxes (UGAG), which bind Wdr79 in a cumulative fashion. In contrast to canonical H/ACA scaRNPs, which concentrate in CBs, the AluACA RNPs accumulate in the nucleoplasm. Identification of 348 human AluACA RNAs demonstrates that intron-encoded AluACA RNAs represent a novel, large subgroup of H/ACA RNAs, which are apparently confined to human or primate cells.

Ameliorated Autoimmune Arthritis and Impaired B Cell Receptor-Mediated Ca2+ Influx in Nkx2-3 Knock-out Mice.

B cells play a crucial role in the pathogenesis of rheumatoid arthritis. In Nkx2-3-deficient mice (Nkx2-3-/-) the spleen's histological structure is fundamentally changed; therefore, B cell homeostasis is seriously disturbed. Based on this, we were curious, whether autoimmune arthritis could be induced in Nkx2-3-/- mice and how B cell activation and function were affected. We induced arthritis with immunization of recombinant human proteoglycan aggrecan G1 domain in Nkx2-3-/- and control BALB/c mice. We followed the clinical picture, characterized the radiological changes, the immune response, and intracellular Ca2+ signaling of B cells. Incidence of the autoimmune arthritis was lower, and the disease severity was milder in Nkx2-3-/- mice than in control BALB/c mice. The radiological changes were in line with the clinical picture. In Nkx2-3-/- mice, we measured decreased antigen-induced proliferation and cytokine production in spleen cell cultures; in the sera, we found less anti-CCP-IgG2a, IL-17 and IFNγ, but more IL-1ß, IL-4 and IL-6. B cells isolated from the lymph nodes of Nkx2-3-/- mice showed decreased intracellular Ca2+ signaling compared to those isolated from BALB/c mice. Our findings show that the transcription factor Nkx2-3 might regulate the development of autoimmune arthritis most likely through modifying B cell activation.

Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models.

The Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel expressed on capsaicin-sensitive afferents, immune and endothelial cells is activated by inflammatory mediators and exogenous irritants, e.g., endotoxins, nicotine, crotonaldehyde and acrolein. We investigated its involvement in acute and chronic pulmonary inflammation using Trpa1 gene-deleted (Trpa1-/-) mice. Acute pneumonitis was evoked by intranasal Escherichia coli endotoxin (lipopolysaccharide: LPS) administration, chronic bronchitis by daily cigarette smoke exposure (CSE) for 4 months. Frequency, peak inspiratory/expiratory flows, minute ventilation determined by unrestrained whole-body plethysmography were significantly greater, while tidal volume, inspiratory/expiratory/relaxation times were smaller in Trpa1-/- mice. LPS-induced bronchial hyperreactivity, myeloperoxidase activity, frequency-decrease were significantly greater in Trpa1-/- mice. CSE significantly decreased tidal volume, minute ventilation, peak inspiratory/expiratory flows in wildtypes, but not in Trpa1-/- mice. CSE remarkably increased the mean linear intercept (histopathology), as an emphysema indicator after 2 months in wildtypes, but only after 4 months in Trpa1-/- mice. Semiquantitative histopathological scores were not different between strains in either models. TRPA1 has a complex role in basal airway function regulation and inflammatory mechanisms. It protects against LPS-induced acute pneumonitis and hyperresponsiveness, but is required for CSE-evoked emphysema and respiratory deterioration. Further research is needed to determine TRPA1 as a potential pharmacological target in the lung.

Marginal and internal fit of full ceramic crowns milled using CADCAM systems on cadaver full arch scans.

BACKGROUND: Chairside systems are becoming more popular for fabricating full-ceramic single restorations, but there is very little knowledge about the effect of the entire workflow process on restoration fit. Therefore, this study aimed to compare the absolute marginal discrepancy (AMD) and the full internal fit (FULL) of all-ceramic crowns made by two chairside systems, Planmeca FIT and CEREC, with detailed and standard mill settings. METHODS: One upper molar was prepared for an all-ceramic crown in human cadaver maxilla. Full-arch scans were made by Emerald or Omnicam four times each. Twenty-four e.max crowns were designed and milled by the Planmill 30s or 40s or CEREC MCXL mills with either detailed or standard settings. The cadaver tooth was extracted, and each crown was fixed on it and scanned by a high-resolution microCT scanner. The AMD and FULL were measured digitally in mesio-distal and bucco-lingual 2D slices. The actual and predicted times of the milling were also registered. RESULTS: No differences were observed between detailed or standard settings in either system. The AMD was significantly higher with CEREC (132 ± 12 µm) than with either Planmill 30s (71 ± 6.9 µm) or 40s (78 ± 7.7 µm). In standard mode, the FULL was significantly higher with CEREC (224 ± 9.6 µm) than with either Planmill 30s (169 ± 8.1 µm) or 40s (178 ± 8.5 µm). There was no difference between actual and predicted time with the two Planmeca models, but with CEREC, the actual time was significantly higher than the predicted time. The 30s had significantly higher actual and predicted times compared to all other models. Across all models, the average milling time was 7.2 min less in standard mode than in detailed mode. CONCLUSIONS: All fit parameters were in an acceptable range. No differences in fit between Planmeca models suggest no effect of spindle number on accuracy. The detailed setting has no improvement in the marginal or internal fit of the restoration, yet it increases milling time.

Role of endothelial NAD+ deficiency in age-related vascular dysfunction.

Age-related alterations in endothelium and the resulting vascular dysfunction critically contribute to a range of pathological conditions associated with old age. To develop therapies rationally that improve vascular health and thereby increase health span and life span in older adults, it will be essential to understand the cellular and molecular mechanisms contributing to vascular aging. Preclinical studies in model organisms demonstrate that NAD+ availability decreases with age in multiple tissues and that supplemental NAD+ precursors can ameliorate many age-related cellular impairments. Here, we provide a comprehensive overview of NAD+-dependent pathways [including the NAD+-using silent information regulator-2-like enzymes and poly(ADP-ribose) polymerase enzymes] and the potential consequences of endothelial NAD+ deficiency in vascular aging. The multifaceted vasoprotective effects of treatments that reverse the age-related decline in cellular NAD+ levels, as well as their potential limitations, are discussed. The preventive and therapeutic potential of NAD+ intermediates as effective, clinically relevant interventions in older adults at risk for ischemic heart disease, vascular cognitive impairment, and other common geriatric conditions and diseases that involve vascular pathologies (e.g., sarcopenia, frailty) are critically discussed. We propose that NAD+ precursors [e.g., nicotinamide (Nam) riboside, Nam mononucleotide, niacin] should be considered as critical components of combination therapies to slow the vascular aging process and increase cardiovascular health span.

Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment.

There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.

Phase transition in iterated quantum protocols for noisy inputs.

Quantum information processing exploits all the features quantum mechanics offers. Among them there is the possibility to induce nonlinear maps on a quantum system by involving two or more identical copies of the given system in the same state. Such maps play a central role in distillation protocols used for quantum key distribution. We determine that such protocols may exhibit sensitive, quasi-chaotic evolution not only for pure initial states but also for mixed states, i.e., the complex dynamical behavior is not destroyed by small initial uncertainty. We show that the appearance of sensitive, complex dynamics associated with a fractal structure in the parameter space of the system has the character of a phase transition. The purity of the initial state plays the role of the control parameter, and the dimension of the fractal structure is independent of the purity value after passing the phase transition point. The critical purity coincides with the purity of a repelling fixed point of the dynamics, and we show that all the pre-images of states from the close neighborhood of pure chaotic initial states have purity larger than this. Initial states from this set can be considered as quasi-chaotic.