An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents.

Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program-apnea, vocal fold adduction, swallowing, and expiratory reflexes. Ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous laryngeal terminal types, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.

Sensory Neurons that Detect Stretch and Nutrients in the Digestive System.

Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.

Vagal Sensory Neuron Subtypes that Differentially Control Breathing.

Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping revealed that these neurons densely innervate the lung and send long-range projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers, while P2ry1 neurons are largely fast-conducting A fibers that contact pulmonary endocrine cells (neuroepithelial bodies). Optogenetic stimulation of P2ry1 neurons acutely silences respiration, trapping animals in exhalation, while stimulating Npy2r neurons causes rapid, shallow breathing. Activating P2ry1 neurons did not impact heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.

Neurological manifestations of polyarteritis nodosa: a tour of the neuroaxis by case series.

BACKGROUND: Heterogenous central nervous system (CNS) neurologic manifestations of polyarteritis nodosa (PAN) are underrecognized. We review three cases of patients with PAN that illustrate a range of nervous system pathology, including the classical mononeuritis multiplex as well as uncommon brain and spinal cord vascular manifestations. CASE PRESENTATION: Case 1 presented with mononeuritis multiplex and characteristic skin findings. Case 2 presented with thunderclap headache and myelopathy due to spinal artery aneurysm rupture. Both patients experienced disease remission upon treatment. Case 3 presented with headache and bulbar symptoms due to partially thrombosed intracranial aneurysms, followed by systemic manifestations related to visceral aneurysms. She demonstrated clinical improvement with treatment, was lost to follow-up, then clinically deteriorated and entered hospice care. CONCLUSIONS: Although the peripheral manifestations of PAN are well-known, PAN association with CNS neurovascular disease is relatively underappreciated. Clinician awareness of the spectrum of neurologic disease is required to reduce diagnostic delay and promote prompt diagnosis and treatment with immunosuppressants.

Molecular targeting of renal inflammation using drug delivery technology to inhibit NF-κB improves renal recovery in chronic kidney disease.

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.

Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease.

BACKGROUND: Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. METHODS: Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). RESULTS: Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. CONCLUSIONS: Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

Genetically Targeted All-Optical Electrophysiology with a Transgenic Cre-Dependent Optopatch Mouse.

Recent advances in optogenetics have enabled simultaneous optical perturbation and optical readout of membrane potential in diverse cell types. Here, we develop and characterize a Cre-dependent transgenic Optopatch2 mouse line that we call Floxopatch. The animals expressed a blue-shifted channelrhodopsin, CheRiff, and a near infrared Archaerhodopsin-derived voltage indicator, QuasAr2, via targeted knock-in at the rosa26 locus. In Optopatch-expressing animals, we tested for overall health, genetically targeted expression, and function of the optogenetic components. In offspring of Floxopatch mice crossed with a variety of Cre driver lines, we observed spontaneous and optically evoked activity in vitro in acute brain slices and in vivo in somatosensory ganglia. Cell-type-specific expression allowed classification and characterization of neuronal subtypes based on their firing patterns. The Floxopatch mouse line is a useful tool for fast and sensitive characterization of neural activity in genetically specified cell types in intact tissue. SIGNIFICANCE STATEMENT: Optical recordings of neural activity offer the promise of rapid and spatially resolved mapping of neural function. Calcium imaging has been widely applied in this mode, but is insensitive to the details of action potential waveforms and subthreshold events. Simultaneous optical perturbation and optical readout of single-cell electrical activity ("Optopatch") has been demonstrated in cultured neurons and in organotypic brain slices, but not in acute brain slices or in vivo Here, we describe a transgenic mouse in which expression of Optopatch constructs is controlled by the Cre-recombinase enzyme. This animal enables fast and robust optical measurements of single-cell electrical excitability in acute brain slices and in somatosensory ganglia in vivo, opening the door to rapid optical mapping of neuronal excitability.

Interdisciplinary collaborative eye examinations to protect preterm infant neurodevelopment: a quality improvement project.

Introduction: Infants born <31 weeks gestational age with birth weight ≤ 1,500 grams receive routine eye examinations to screen for Retinopathy of Prematurity (ROP) while in the Neonatal Intensive Care Unit (NICU) to help prevent vision threatening complications; however, preterm infants' sensory systems are underdeveloped, and repeated exposure to painful stimuli is associated with worse developmental outcomes. Methods: An interdisciplinary NICU team designed a collaborative eye exam model (CEEM) incorporating best practice recommendations for infant pain control during exams. Pain scores and vital signs were recorded before, during, and after exams. Two sets of mixed-effects regression models with a random intercept on infants were established to investigate relationships between the intervention, birth gestational age (BGA), postmenstrual age (PMA), and outcomes associated with painful stimuli. Survey feedback was elicited from NICU stakeholders about the CEEM. Results: Thirty standard of care (SC) and 35 CEEM exams of 37 infants were included in final analysis. In infants of the same BGA, the number of desaturation events was significantly reduced in the CEEM group (p = 0.003) and became 1.53 times smaller with each additional week of BGA (p = 0.009). Probability of heart rate recovery within 15 min lowered significantly in the CEEM group (p = 0.04). In SC or CEEM or between infants of the same PMA, no differences were observed for bradycardia, heart rate range, chance of heart rate recovery, or pain scores. Increases in tachycardia (p < 0.001) events and desaturations p = 0.006 were discovered in the CEEM group. When considering interaction effects, the CEEM appeared to reduce the number of desaturations to a greater degree for infants at earliest BGAs with attenuation of this effect with greater BGA. Regarding PMA, bradycardia and tachycardia events were reduced for infants across PMAs in the CEEM, but the effect for tachycardia improves with age, while the effect for bradycardia diminishes with age. Stakeholders agreed that the infant's eye exam experience and the staff experience was "very much" improved by the CEEM. Discussion: Despite variable findings in selected outcome measures, the CEEM was positively viewed by staff. Infants may benefit from the CEEM differently based on BGA and PMA.

Agenesis of Pectoralis Major Muscle in Late-Onset GFPT1-Related Congenital Myasthenic Syndrome: A Case Report.

Objectives: The objective of this study was to expand the phenotypic spectrum of glutamine-fructose-6-phosphate transaminase 1 (GFPT1)-related congenital myasthenia syndrome (CMS). Methods: A 61-year-old man with agenesis of the left pectoralis major muscle presented with progressive muscle weakness for a decade that transiently improved after exertion. Results: His examination revealed proximal and distal muscle weakness in upper extremities and proximal muscle weakness in lower extremities. Muscle enzymes were elevated. An electromyogram revealed a myopathic pattern; however, a muscle biopsy of deltoid muscle and genetic testing for limb-girdle muscular dystrophies were nondiagnostic. A 3-Hz repetitive nerve stimulation of the spinal accessory nerve recording from trapezius muscle demonstrated a >20% drop in amplitude of the 5th compound motor action potential relative to 1st at both baseline and after 45-second exercise. Acetylcholine receptor binding, lipoprotein-related protein 4, muscle-specific kinase, and voltage-gated calcium channel P/Q antibodies were negative. Genetic testing targeting CMS revealed 2 likely pathogenic variants within GFPT1: novel c.7+2T>G (intron 1) that was predicted to result in a null allele and known c*22 C>A (exon 19) associated with reduced GFPT1 expression. His muscle strength dramatically improved after pyridostigmine initiation. Discussion: In addition to other reported neurodevelopmental abnormalities, pectoralis major muscle agenesis (or Poland syndrome) may be a clinical manifestation of GFPT1-related CMS.

Neurologic Manifestations of the World Health Organization's List of Pandemic and Epidemic Diseases.

The World Health Organization (WHO) monitors the spread of diseases globally and maintains a list of diseases with epidemic or pandemic potential. Currently listed diseases include Chikungunya, cholera, Crimean-Congo hemorrhagic fever, Ebola virus disease, Hendra virus infection, influenza, Lassa fever, Marburg virus disease, Neisseria meningitis, MERS-CoV, monkeypox, Nipah virus infection, novel coronavirus (COVID-19), plague, Rift Valley fever, SARS, smallpox, tularemia, yellow fever, and Zika virus disease. The associated pathogens are increasingly important on the global stage. The majority of these diseases have neurological manifestations. Those with less frequent neurological manifestations may also have important consequences. This is highlighted now in particular through the ongoing COVID-19 pandemic and reinforces that pathogens with the potential to spread rapidly and widely, in spite of concerted global efforts, may affect the nervous system. We searched the scientific literature, dating from 1934 to August 2020, to compile data on the cause, epidemiology, clinical presentation, neuroimaging features, and treatment of each of the diseases of epidemic or pandemic potential as viewed through a neurologist's lens. We included articles with an abstract or full text in English in this topical and scoping review. Diseases with epidemic and pandemic potential can be spread directly from human to human, animal to human, via mosquitoes or other insects, or via environmental contamination. Manifestations include central neurologic conditions (meningitis, encephalitis, intraparenchymal hemorrhage, seizures), peripheral and cranial nerve syndromes (sensory neuropathy, sensorineural hearing loss, ophthalmoplegia), post-infectious syndromes (acute inflammatory polyneuropathy), and congenital syndromes (fetal microcephaly), among others. Some diseases have not been well-characterized from a neurological standpoint, but all have at least scattered case reports of neurological features. Some of the diseases have curative treatments available while in other cases, supportive care remains the only management option. Regardless of the pathogen, prompt, and aggressive measures to control the spread of these agents are the most important factors in lowering the overall morbidity and mortality they can cause.

OROS methylphenidate in the treatment of adults with ADHD: a 6-month, open-label, follow-up study.

BACKGROUND: This open-label trial followed a previously reported randomized, placebo-controlled trial of osmotic release oral system (OROS) methylphenidate (MPH) for the treatment of personality disorder (PD). Important findings from the double-blind phase are reexamined for long-term significance. METHODS: Of 41 patients who completed the double-blind, placebo-controlled trial, 34 continued into this open-label phase. The Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) measured outcome. Patients were categorized using previously defined attention-deficit/hyperactivity disorder (ADHD) groups: ADHD alone, ADHD with emotional dysregulation (ADHD + ED), and ADHD plus emotional dysregulation plus oppositional symptoms (ADHD + ED + ODD); and 3 post hoc personality categories: patients with no PD (PD-negative), patients with 1 PD (PD-positive), and patients meeting criteria for 2 or more PDs (PD-plus). RESULTS: Three WRAADDS-defined ADHD dimensions improved at similar levels (attention + disorganization, 61%; hyperactivity + impulsivity, 60%; and emotional dysregulation, 66%). All ADHD subgroups (ADHD alone, ADHD + ED, and ADHD + ED + ODD) improved. ADHD + ED + ODD patients had the highest level of social maladjustment at baseline and showed the most long-term improvement in this area. PD-plus patients were less likely to complete the study or show improvement. Sixty-five percent of treatment responders were on moderate doses (< or =54 mg/d) of OROS MPH. Vital signs and ECGs did not differ from baseline. CONCLUSIONS: Eighteen (44%) patients completed the trial. All 3 ADHD dimensions showed similar, well-maintained improvement. Patients with several PDs responded poorly to treatment in this small trial.

Personality disorders in ADHD Part 3: Personality disorder, social adjustment, and their relation to dimensions of adult ADHD.

BACKGROUND: This study explored the relationship between the dimensions of adult attention-deficit/hyperactivity disorder (ADHD), personality disorder (PD), and adverse social adjustment. METHODS: In a controlled trial of osmotic release oral system methylphenidate, PD was assessed using the Wisconsin Personality Disorders Inventory IV (WISPI-IV), the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II), and a final consensus diagnosis. Participants were categorized 2 ways: (1) ADHD alone, ADHD with emotional dysregulation (ADHD + ED), and ADHD plus emotional dysregulation plus oppositional symptoms (ADHD + ED + ODD); and (2) those with no PD (PD-negative), 1 (PD-positive), and 2 or more (PD-plus) PDs. RESULTS: None of the ADHD-alone patients had a PD compared with 33% of ADHD + ED patients and 68% of ADHD + ED + ODD patients. The level of ADHD-related emotional and oppositional symptoms correlated significantly with the severity of PD dimensions as assessed by WISPI-IV z scores and the number of items endorsed on the SCID-II screening questionnaire. Complex presentations (define by both ADHD and personality categories) were associated with high childhood ADHD ratings and problems in work, extended family, and economic functioning. CONCLUSION: The ADHD symptoms of emotional dysregulation and oppositional symptoms were associated with increased Axis II disorders. Adverse outcomes were concentrated in patients with ADHD combined with emotional and oppositional symptoms, and in those with comorbid PDs.

Personality disorder in ADHD Part 1: Assessment of personality disorder in adult ADHD using data from a clinical trial of OROS methylphenidate.

BACKGROUND: Comorbidity of personality disorder (PD) and attention-deficit/hyperactivity disorder (ADHD) has been suggested in several reports. However, assessment of PD is problematic, and studies have over-relied on baseline evaluations. METHODS: Forty-seven patients entered a double-blind trial of osmotic release oral system (OROS) methylphenidate (MPH). Patients were assessed at baseline with the Wisconsin Personality Inventory IV (WISPI-IV) and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Following the study, all information-including tests, family reports, and extended clinical observations-produced a final PD diagnosis. Three post hoc categories were created: PD-negative (no PD), PD-positive (1 PD), and PD-plus (2 or more PDs). RESULTS: Twenty-one (45%) patients had a PD on the final assessment vs 62% using SCID-II and 33% using WISPI-IV; final PD diagnosis revealed 9% cluster A, 17% cluster B, and 28% cluster C. Twenty-one percent of patients experienced multiple disorders. Using a weighted kappa, the number of PDs on the final assessment correlated with the WISPI-IV (kappa=.53; P > .001) and the SCID-II (kappa =.70; P < .001). However the SCID-II overidentified and the WISPI-IV underidentified PD. CONCLUSION: Almost all PDs were represented in this sample, and past emphasis on cluster B appears unwarranted. Although the SCID-II and WISPI-IV had limited success in identifying specific PDs, they were more successful in identifying the number of PDs present in each patient. The small sample makes these findings preliminary.

Personality disorders in ADHD Part 2: The effect of symptoms of personality disorder on response to treatment with OROS methylphenidate in adults with ADHD.

BACKGROUND: This study explored the relationship between personality disorder (PD) and treatment response in a randomized, double-blind, clinical trial of osmotic release oral system (OROS) methylphenidate (MPH). METHODS: Forty-seven patients entered a crossover trial using the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) to assess outcome. A final personality diagnosis was made using staff consensus and information from the Wisconsin Personality Inventory IV (WISPI-IV) and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Three post hoc categories were created: PD-negative (no PD; n = 26), PD-positive (patients with 1 PD; n = 11), and PD-plus (patients with 2 or more PDs; n = 10). Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms was assessed using a mixed-model analysis with treatment and personality categories as fixed variables. Average z scores on the WISPI-IV and items endorsed on SCID-II provided dimensional measures of PD severity. RESULTS: Different treatment effects were observed for the PD subgroups (P < .001). PD-negative patients improved 40% on OROS MPH vs 7% on placebo, and PD-positive patients improved 66% on OROS MPH vs 9% on placebo. In contrast, PD-plus patients improved 26% on OROS MPH vs 23% on placebo. CONCLUSION: Most patients experienced significantly reduced ADHD symptoms on OROS MPH; however, patients with 2 or more PDs did not. The 2 alternate measures of PD supported this observation in this small exploratory study.

A Boolean Model of Microvascular Rarefaction to Predict Treatment Outcomes in Renal Disease.

Despite advances in renovascular disease (RVD) research, gaps remain between experimental and clinical outcomes, translation of results, and the understanding of pathophysiological mechanisms. A predictive tool to indicate support (or lack of) for biological findings may aid clinical translation of therapies. We created a Boolean model of RVD and hypothesized that it would predict outcomes observed in our previous studies using a translational swine model of RVD. Our studies have focused on developing treatments to halt renal microvascular (MV) rarefaction in RVD, a major feature of renal injury. A network topology of 20 factors involved in renal MV rarefaction that allowed simulation of 5 previously tested treatments was created. Each factor was assigned a function based upon its interactions with other variables and assumed to be "on" or "off". Simulations of interventions were performed until outcomes reached a steady state and analyzed to determine pathological processes that were activated, inactivated, or unchanged vs. RVD with no intervention. Boolean simulations mimicked the results of our previous studies, confirming the importance of MV integrity on treatment outcomes in RVD. Furthermore, our study supports the potential application of a mathematical tool to predict therapeutic feasibility, which may guide the design of future studies for RVD.

Greatwall kinase: a nuclear protein required for proper chromosome condensation and mitotic progression in Drosophila.

Mutations in the Drosophila gene greatwall cause improper chromosome condensation and delay cell cycle progression in larval neuroblasts. Chromosomes are highly undercondensed, particularly in the euchromatin, but nevertheless contain phosphorylated histone H3, condensin, and topoisomerase II. Cells take much longer to transit the period of chromosome condensation from late G2 through nuclear envelope breakdown. Mutant cells are also subsequently delayed at metaphase, due to spindle checkpoint activity. These mutant phenotypes are not caused by spindle aberrations, by global defects in chromosome replication, or by activation of a caffeine-sensitive checkpoint. The Greatwall proteins in insects and vertebrates are located in the nucleus and belong to the AGC family of serine/threonine protein kinases; the kinase domain of Greatwall is interrupted by a long stretch of unrelated amino acids.

Narrow-band blue-light treatment of seasonal affective disorder in adults and the influence of additional nonseasonal symptoms.

BACKGROUND: Bright visible-spectrum light therapy has proven effective in the treatment of seasonal affective disorder (SAD) and recent basic research suggests that blue wavelengths approximately 470 nm account for that effectiveness. To more stringently test the importance of these wavelengths, bright red-light was used for the placebo (control) condition. METHODS: Thirty subjects meeting DSM-IV criteria for SAD were randomized to narrow-band light-emitting diode panels emitting blue- or red-light in this 3-week, parallel, double-blind trial. Twenty-five subjects participated in an open-label blue-light follow-up. Subjects were divided in a blinded, post hoc manner into two groups: SAD only and those experiencing depression with seasonal intensification. The outcome was assessed using Hamilton Depression Rating Scale-17 item version (HAMD-17) and the Structured Interview Guide for the Hamilton Depression Rating Scale-SAD version. Responders were defined by Clinical Global Impression-Improvement scale. RESULTS: HAMD-17 scores improved more under the blue-light condition (51%) than under the red-light condition (32%) (P=.05). Further, in the blue arm 60% of subjects responded compared with 13% in the red arm (P=.01). During the open-label phase, subjects from both double-blind arms improved over baseline. SAD alone patients responded numerically better to treatment than those experiencing depression with seasonal intensification during both treatment periods. CONCLUSIONS: Narrow bandwidth blue-light therapy proved superior to red-light therapy. Blue-light therapy produced results similar to both previous 10,000 lux visible-spectrum light studies and many medication studies. The use of bright red panels supported claims that wavelengths of approximately 470 nm account for the documented effectiveness of light therapy.

Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization.

Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

Two putative acetyltransferases, san and deco, are required for establishing sister chromatid cohesion in Drosophila.

BACKGROUND: Sister chromatid cohesion is needed for proper alignment and segregation of chromosomes during cell division. Chromatids are linked by the multiprotein cohesin complex, which binds to DNA during G(1) and then establishes cohesion during S phase DNA replication. However, many aspects of the mechanisms that establish and maintain cohesion during mitosis remain unclear. RESULTS: We found that mutations in two evolutionarily conserved Drosophila genes, san (separation anxiety) and deco (Drosophila eco1), disrupt centromeric sister chromatid cohesion very early in division. This failure of sister chromatid cohesion does not require separase and is correlated with a failure of the cohesin component Scc1 to accumulate in centromeric regions. It thus appears that these mutations interfere with the establishment of centromeric sister chromatid cohesion. Secondary consequences of these mutations include activation of the spindle checkpoint, causing metaphase delay or arrest. Some cells eventually escape the block but incur many errors in anaphase chromosome segregation. Both san and deco are predicted to encode acetyltransferases, which transfer acetyl groups either to internal lysine residues or to the N terminus of other proteins. The San protein is itself acetylated, and it associates with the Nat1 and Ard1 subunits of the NatA acetyltransferase. CONCLUSIONS: At least two diverse acetyltransferases play vital roles in regulating sister chromatid cohesion during Drosophila mitosis.

Zwilch, a new component of the ZW10/ROD complex required for kinetochore functions.

The Zeste-White 10 (ZW10) and Rough Deal (ROD) proteins are part of a complex necessary for accurate chromosome segregation. This complex recruits cytoplasmic dynein to the kinetochore and participates in the spindle checkpoint. We used immunoaffinity chromatography and mass spectroscopy to identify the Drosophila proteins in this complex. We found that the complex contains an additional protein we name Zwilch. Zwilch localizes to kinetochores and kinetochore microtubules in a manner identical to ZW10 and ROD. We have also isolated a zwilch mutant, which exhibits the same mitotic phenotypes associated with zw10 and rod mutations: lagging chromosomes at anaphase and precocious sister chromatid separation upon activation of the spindle checkpoint. Zwilch's role within the context of this complex is evolutionarily conserved. The human Zwilch protein (hZwilch) coimmunoprecipitates with hZW10 and hROD from HeLa cell extracts and localizes to the kinetochores at prometaphase. Finally, we discuss immunoaffinity chromatography results that suggest the existence of a weak interaction between the ZW10/ROD/Zwilch complex and the kinesin-like kinetochore component CENP-meta.