Identifying low-dimensional features that describe large-scale neural recordings is a major challenge in neuroscience. Repeated temporal patterns (sequences) are thought to be a salient feature of ...neural dynamics, but are not succinctly captured by traditional dimensionality reduction techniques. Here, we describe a software toolbox-called seqNMF-with new methods for extracting informative, non-redundant, sequences from high-dimensional neural data, testing the significance of these extracted patterns, and assessing the prevalence of sequential structure in data. We test these methods on simulated data under multiple noise conditions, and on several real neural and behavioral datas. In hippocampal data, seqNMF identifies neural sequences that match those calculated manually by reference to behavioral events. In songbird data, seqNMF discovers neural sequences in untutored birds that lack stereotyped songs. Thus, by identifying temporal structure directly from neural data, seqNMF enables dissection of complex neural circuits without relying on temporal references from stimuli or behavioral outputs.
Modulation of the kallikrein-kinin system (KKS) has been shown to have beneficial effects on glucose homeostasis and several other physiological responses relevant to the progression of type 2 ...diabetes mellitus (T2D). The importance of bradykinin and its receptors in mediating these responses is well documented, but the role of tissue kallikrein-1, the protease that generates bradykinin in situ, is much less understood. We developed and tested DM199, recombinant human tissue kallikrein-1 protein (rhKLK-1), as a potential novel therapeutic for T2D. Hyperinsulinemic-euglycemic clamp studies suggest that DM199 increases whole body glucose disposal in non-diabetic rats. Single-dose administration of DM199 in obese db/db mice and ZDF rats, showed an acute, dose-dependent improvement in whole-body glucose utilization. Sub-acute dosing for a week in ZDF rats improved glucose utilization, with a concomitant rise in fasting insulin levels and HOMA1-%B scores. After cessation of sub-acute dosing, fasting blood glucose levels were significantly lower in ZDF rats during a drug wash-out period. Our studies show for the first time that DM199 administration results in acute anti-hyperglycemic effects in several preclinical models, and demonstrate the potential for further development of DM199 as a novel therapeutic for T2D.
Survival characteristics of patients who have recurrent nonsmall-cell lung cancer after surgical resection are not well understood. Little objective evidence exists to justify treatment for these ...patients.
We prospectively followed 1,361 consecutive patients with nonsmall-cell lung cancer who underwent complete surgical resection at our institution from January 1997 to December 2001. Only patients having recurrent cancer were included in the analysis. Multivariable Cox proportional hazards models were used to evaluate the effect of prognostic factors on postrecurrence survival.
Follow-up was achieved in 1,073 patients, and recurrent cancer developed in 445. Complete information was available on 390 patients for analysis. There were 262 men and 128 women. Median age at time of recurrence was 69 years. Median time from surgical resection to recurrence was 11.5 months, and median postrecurrence survival was 8.1 months. Recurrence was intrathoracic in 171 patients, extrathoracic in 172, and a combination of both in 47. Treatments after recurrence included surgery in 43 patients, chemotherapy in 59, radiation in 73, and a combination in 96. All patients who received treatment survived longer than those who received no treatment. Preoperative chemotherapy and postoperative radiotherapy for the primary lung cancer, poor Eastern Cooperative Oncology Group Performance Status, decreased disease-free interval from initial resection to recurrence, symptoms at recurrence, and certain location of recurrence significantly decreased postrecurrence survival.
In our experience, treatment for recurrent nonsmall-cell lung cancer significantly prolongs survival. Various treatment modalities including surgery should be considered in patients with postoperative recurrent nonsmall-cell lung cancer.
The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation ...of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.
ABSTRACT With a large, unique spectroscopic survey in the fields of 28 galaxy-scale strong gravitational lenses, we identify groups of galaxies in the 26 adequately sampled fields. Using a ...group-finding algorithm, we find 210 groups with at least 5 member galaxies; the median number of members is 8. Our sample spans redshifts of 0.04 ≤ zgrp ≤ 0.76 with a median of 0.31, including 174 groups with 0.1 < zgrp < 0.6. The groups have radial velocity dispersions of 60 ≤ grp ≤ 1200 km s−1 with a median of 350 km s−1. We also discover a supergroup in field B0712+472 at z = 0.29 that consists of three main groups. We recover groups similar to ∼85% of those previously reported in these fields within our redshift range of sensitivity and find 187 new groups with at least five members. The properties of our group catalog, specifically, (1) the distribution of grp, (2) the fraction of all sample galaxies that are group members, and (3) the fraction of groups with significant substructure, are consistent with those for other catalogs. The distribution of group virial masses agrees well with theoretical expectations. Of the lens galaxies, 12 of 26 (46%) (B1422+231, B1600+434, B2114+022, FBQS J0951+2635, HE0435-1223, HST J14113+5211, MG0751+2716, MGJ1654+1346, PG 1115+080, Q ER 0047-2808, RXJ1131-1231, and WFI J2033-4723) are members of groups with at least five galaxies, and one more (B0712+472) belongs to an additional, visually identified group candidate. There are groups not associated with the lens that still are likely to affect the lens model; in six of 25 (24%) fields (excluding the supergroup), there is at least one massive ( grp ≥ 500 km s−1) group or group candidate projected within 2′ of the lens.
Prevalence of chronic kidney disease (CKD) in people with diagnosed diabetes is known to be high, but little is known about the prevalence of CKD in those with undiagnosed diabetes or prediabetes. We ...aimed to estimate and compare the community prevalence of CKD among people with diagnosed diabetes, undiagnosed diabetes, prediabetes, or no diabetes.
The 1999 through 2006 National Health and Nutrition Examination Survey is a representative survey of the civilian, noninstitutionalized US population. Participants who were aged > or =20 years; responded to the diabetes questionnaire; and had fasting plasma glucose (FPG), serum creatinine, and urinary albumin-creatinine ratio measurements were included (N = 8188). Diabetes status was defined as follows: Diagnosed diabetes, self-reported provider diagnosis (n = 826); undiagnosed diabetes, FPG > or =126 mg/dl without self-reported diagnosis (n = 299); prediabetes, FPG > or =100 and <126 mg/dl (n = 2272); and no diabetes, FPG <100 mg/dl (n = 4791). Prevalence of CKD was defined by estimated GFR 15 to 59 ml/min per 1.73 m(2) or albumin-creatinine ratio > or =30 mg/g; adjustment was performed with multivariable logistic regression.
Fully 39.6% of people with diagnosed and 41.7% with undiagnosed diabetes had CKD; 17.7% with prediabetes and 10.6% without diabetes had CKD. Age-, gender-, and race/ethnicity-adjusted prevalence of CKD was 32.9, 24.2, 17.1, and 11.8%, for diagnosed, undiagnosed, pre-, and no diabetes, respectively. Among those with CKD, 39.1% had undiagnosed or prediabetes.
CKD prevalence is high among people with undiagnosed diabetes and prediabetes. These individuals might benefit from interventions aimed at preventing development and/or progression of both CKD and diabetes.
Ixodes scapularis ticks transmit a wide array of human and animal pathogens including Borrelia burgdorferi; however, how tick immune components influence the persistence of invading pathogens remains ...unknown. As originally demonstrated in Caenorhabditis elegans and later in Anopheles gambiae, we show here that an acellular gut barrier, resulting from the tyrosine cross-linking of the extracellular matrix, also exists in I. scapularis ticks. This dityrosine network (DTN) is dependent upon a dual oxidase (Duox), which is a member of the NADPH oxidase family. The Ixodes genome encodes for a single Duox and at least 16 potential peroxidase proteins, one of which, annotated as ISCW017368, together with Duox has been found to be indispensible for DTN formation. This barrier influences pathogen survival in the gut, as an impaired DTN in Doux knockdown or in specific peroxidase knockdown ticks, results in reduced levels of B. burgdorferi persistence within ticks. Absence of a complete DTN formation in knockdown ticks leads to the activation of specific tick innate immune pathway genes that potentially resulted in the reduction of spirochete levels. Together, these results highlighted the evolution of the DTN in a diverse set of arthropod vectors, including ticks, and its role in protecting invading pathogens like B. burgdorferi. Further understanding of the molecular basis of tick innate immune responses, vector-pathogen interaction, and their contributions in microbial persistence may help the development of new targets for disrupting the pathogen life cycle.
How tick immune components influence persistence of pathogens remains unknown.
Impairment of dityrosine network formed by a dual oxidase and a peroxidase activates specific immune genes and reduces pathogen survival.
A dityrosine network influences persistence of Lyme disease pathogens.
Knowledge of a Duox system in protein cross-linking may offer new strategies to disrupt pathogen life cycle.
Background
Transgender and gender-diverse individuals are particularly vulnerable to healthcare discrimination and related health sequelae.
Objective
To demonstrate diversity in demographics and ...explore variance in needs at the time of intake among patients seeking care at a large, urban gender health program.
Design
We present summary statistics of patient demographics, medical histories, and gender-affirming care needs stratified by gender identity and sexual orientation.
Participants
We reviewed all intake interviews with individuals seeking care in our gender health program from 2017 to 2020.
Main Measures
Clients reported all the types of care in which they were interested at the time of intake as their “reason for call” (i.e., establish primary care, hormone management, surgical services, fertility services, behavioral health, or other health concerns).
Key Results
Of 836 patients analyzed, 350 identified as trans women, 263 as trans men, and 223 as non-binary. The most prevalent sexual identity was straight among trans women (34%) and trans men (38%), whereas most (69%) non-binary individuals identified as pansexual or queer; only 3% of non-binary individuals identified as straight. Over half of patients reported primary care, hormone management, or surgical services as the primary reason for contacting our program. Straight, transgender women were more likely to report surgical services as their primary reason for contacting our program, whereas gay transgender men were more likely to report primary care as their reason.
Conclusions
Individuals contacting our gender health program to establish care were diverse in sexual orientation and gender-affirming care needs. Care needs varied with both gender identity and sexual orientation, but primary care, hormone management, and surgical services were high priorities across groups. Providers of gender-affirming care should inquire about sexual orientation and detailed treatment priorities, as trans and gender-diverse populations are not uniform in their treatment needs or goals.
The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by ...internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.
Objective
The neuronal underpinnings of impaired consciousness during absence seizures remain largely unknown. Spike‐and‐wave (SW) activity associated with absences imposes two extremely different ...states in cortical neurons, which transition from suprathreshold synaptic depolarizations during spike phases to membrane hyperpolarization and electrical silence during wave phases. To investigate whether this rhythmic alternation of neuronal states affects the processing of sensory information during seizures, we examined cortical and thalamic responsiveness to brief sensory stimuli in the different phases of the epileptic cycle.
Methods
Electrocorticographic (ECoG) monitoring from the primary somatosensory cortex combined with intracellular recordings of subjacent pyramidal neurons, or extracellular recordings of somatosensory thalamic neurons, were performed in the Genetic Absence Epilepsy Rat From Strasbourg. Sensory stimuli consisted of pulses of compressed air applied to the contralateral whiskers.
Results
Whisker stimuli delivered during spike phases evoked smaller depolarizing synaptic potentials and fewer action potentials in cortical neurons compared to stimuli occurring during wave phases. This spike‐related attenuation of cortical responsiveness was accompanied by a reduced neuronal membrane resistance, likely due to the large increase in synaptic conductance. Sensory‐evoked firing in thalamocortical neurons was also decreased during ECoG spikes as compared to wave phases, indicating that time‐to‐time changes in the thalamocortical volley may also contribute to the variability of cortical responses during seizures.
Significance
These findings demonstrate that thalamocortical sensory processing during absence seizures is nonstationary and strongly suggest that the cortical impact of a given environmental stimulus is conditioned by its exact timing relative to the SW cycle. The lack of stability of thalamic and cortical responses along seizures may contribute to impaired conscious sensory perception during absences.
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