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William H. Welch, ca. 1915
No full textWilliam H. Welch, circa 1915. Photograph by Bachrach
Detail of the exhibit JEM: The Beginnings
Idea, design - Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1016/thumbnail.jp
Details of the Exhibit
No full textDetails of the exhibit JEM: The Beginning
Idea, design: Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepankhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1023/thumbnail.jp
Details of the Exhibit
No full textDetails of the exhibit JEM: The Beginnings
Idea, design: Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1024/thumbnail.jp
The Taste of Blood
Get PDFHuman blood and floral nectar are both appetizing meals to a hungry female mosquito, yet each meal fulfills a distinct nutritional requirement. While protein obtained from blood is required for females to develop eggs and successfully reproduce, carbohydrates supplied from plant nectar are sufficient for energy metabolism in both females and males. To procure essential nutrients from these distinct food sources, females employ two mutually exclusive feeding programs with unique sensory appendages, meal sizes, digestive tract targets, and metabolic fates. When a female is ready to reproduce, she must selectively seek the taste of blood and ignore the sweet taste of nectar. How does she flexibly modify her preference for the taste of blood to select the feeding program that satisfies her current metabolic needs? Here we investigated the syringe-like blood-feeding appendage, the stylet, and discovered a population of sexually dimorphic chemosensory neurons that are the first neurons to contact blood as a mosquito bites her victim. Using pan-neuronal GCaMP calcium imaging, we found that stylet neurons robustly respond to blood and its components but are insensitive to nectar-specific sugars. The complex mixture of blood is detected by four functionally distinct stylet neuron classes, each tuned to specific blood components associated with diverse taste qualities. Surprisingly, one subset contained polymodal Integrator neurons that responded only to mixtures of blood components belonging to distinct taste qualities. What functional role does taste quality integration play in Ae. aegypti? We discovered that Integrator neurons selectively respond to physiological levels of blood glucose only in the presence of additional blood components like NaCl and NaHCO3. Integrator neurons, like all remaining stylet neurons, are insensitive to nectar-specific sugars. Since glucose is the only redundant cue in blood and nectar, this unconventional taste coding mechanism confers context-specific information to distinguish between glucose present in blood versus nectar. Together these experiments reveal that specialized stylet neurons innately encode the distinction between blood and nectar at the very first level of sensory detection. This innate ability to recognize blood is the basis of global vector-borne disease transmission and is a remarkable example of how specialists can adopt exceptional neural coding strategies to thrive in their niche
Tension Propagation Along Tip-Link Cadherins: Regulation and Implications for the Auditory System
Get PDFHair bundles detect sound by shearing in response to vibrations spanning orders of magnitude in intensity and frequency. Their responsiveness stems from mechanosensitive ion channels that sit atop the stereocilia and are gated by tension in tip links. Experimental evidence and theoretical arguments implicate a soft compliant element, with a stiffness of 1-4 mN/m, as necessary for mechanotransduction. Although the identity of this element remains an open question, direct measurements of a component of the tip link have highlighted entropic elasticity as one relevant characteristic. A tip link comprises a heterotetremer of protocadherin-15 and cadherin-23, arranged in a loose helical configuration and joined at their amino-terminals through a calcium ion dependent interaction. As for many other biopolymers, the tip link\u27s stiffness is several times greater than that of the empirically measured gating spring. To remain a viable candidate as a compliant element, entropic elasticity in the tip link must therefore be shown to support the full frequency and intensity range of auditory stimuli. In the present work, we model the tip link as a worm-like chain and evaluate its fast dynamic response using theoretical and numerical calculations. Our analysis uncovers frequencies at which the tip link exhibits viscoelastic behavior, and we evaluate how this behavior might alter auditory function. Critical to modulating the tip link\u27s frequency-dependent response is the resting tension, which controls both the frequency above which the tip link behaves viscoelastically and the tip-link\u27s local nonlinear stiffness. Under low resting tensions, we find that tension pools at the ends of the tip link and propagates poorly into the bulk of the chain. Upon application of high resting tensions, the frequency above which the tip link shows non-equilibrium behavior shifts beyond the range of human hearing
The Role of DNA Methylation in Defining the Vocal Learning Transcriptome of the Zebra Finch
Get PDFVocal learning is a rare, complex behavior which is a critical component of human spoken language acquisition. It is convergent across several independent lineages of birds and mammals, including songbirds and humans. The development of speech and song production in humans and songbirds is strikingly similar, though the molecular mechanisms underlying these similarities are not yet understood. Our lab has previously found convergently differentially expressed genes in the vocal learning circuitry of humans and song-learning birds relative to adjacent non-vocal motor circuits. Most notably, the RA song nucleus in the songbird is molecularly convergent with the human laryngeal motor cortex. What remains unknown, however, is how such striking molecular convergences came to be. One likely mechanism by which differential expression can be established in the brain is DNA methylation, an epigenomic signature that is canonically associated with transcriptional repression. In my thesis work, I examined whether this differential specialized gene expression in the zebra finch, one of the most well-studied songbirds, is associated with differential DNA methylation. To do so, I performed whole-genome bisulfite sequencing in the RA song nucleus and its adjacent non-vocal motor region. I found that the convergent specialized transcriptome in this nucleus is in part defined by DNA methylation in a subset of these genes. A significant proportion of downregulated genes in RA exhibit increased gene body methylation relative to the adjacent non-vocal motor region. I additionally profiled the potential writers and readers of DNA methylation in the zebra finch brain to explore mechanisms for establishing the methylome over development. Strikingly, I found that the de novo writer of DNA methylation, DNMT3A, is specifically upregulated in the RA relative to the surrounding arcopallium only at post-hatch day ~60, not earlier or in adulthood. These findings indicate that differential DNA methylation could be contributing to specialization of gene down regulation, and thereby influence circuit specializations of vocal learning brain circuits. This study represents the first unbiased, basepair-resolution, genome-wide analysis of DNA methylation in the songbird as well as one of the first brain methylome studies in a non-mammalian vertebrate. Understanding the genomic mechanisms for vocal learning in the songbird will expand our understanding of speech and language disorders in humans, especially those that are congenital
Interactions Between Microbial, Neuronal, and Immune Cells in the Digestive System
Get PDFThe intestine is the largest continuous environmental interface of the body. As such, it exerts homeostatic tissue functions, including digestion, sensing and absorption of nutrients, and excretion of waste products. In performing these roles, the intestine faces the unique challenge of remaining tolerant to harmless or beneficial diet- and microbederived stimuli, while simultaneously protecting against pathogen invasion. To tackle these challenges, the intestine houses both the body\u27s largest immune compartment, as well as a vast neuronal network, the enteric nervous system (ENS). In concert with the commensal intestinal microbiota, the enteric immune and nervous systems communicate with one another, and this crosstalk was the focus of my thesis work. The studies as presented here are divided into two parts: The first part will focus on the influence of gut microbes on the murine ENS and its functions in host physiology. The second part will investigate the dynamic interplay between gut microbes, neurons and immune cells in the murine intestine during homeostasis and upon microbial perturbations. The human intestinal tract is home to ~10 trillion commensal microbes (Sender et al., 2016). The microbiota influences key physiological processes including nutrient absorption and lipid metabolism. Further, it has been demonstrated to influence the basal activity of intestine-associated cells, including the excitability of enteric neurons (Furness et al., 2013). Alterations to the composition of the gut microbiota have a potential role in systemic disorders including obesity and diabetes (Ridaura et al., 2013). Yet, the mechanisms underlying these effects of the microbiota, and whether they are mediated by components of the ENS, are still poorly understood. In addition, the cellular circuits and molecular components that mediate gut-to-enteric neuron or gut-to-brain communication remain largely unknown. We thus aimed to determine how commensal microbes influence enteric neurons and their functions to better characterize their role in tissue function and further sought to investigate how disturbances to the microbial composition – during microbial dysbiosis and enteric infections – impact the ENS and host physiology. Using translating ribosomal affinity purification (TRAP)-sequencing, coupled with confocal microscopy, we found that enteric neurons are functionally adapted to the intestinal segment they occupy. By utilizing germ-free mice, we uncovered a stronger influence of the microbiota on distal intestine neurons, correlating with the region\u27s higher bacterial density. Chronic antibiotic-mediated microbial depletion reinstated our findings in germ-free mice, establishing that specific subsets of enteric neurons, including those expressing the neuropeptide cocaine and amphetamine-regulated transcript (CART), are dependent on the microbiota for their survival. Notably, these changes were not permanent, as colonization of germ-free mice and replenishment of the microbiota of antibiotic-treated mice restored neuronal numbers and neuropeptide levels. We found that murine enteric infections with different pathogens led to lasting intestinal inflammation, functional disturbances and most notably, rapid and persistent enteric neuron loss driven by a persistent alteration to the microbial composition postinfection; however, restoration of a healthy microbiota was sufficient to induce tissue recovery. Mechanistically, neuronal loss post-infection and following microbial depletion was mediated by a novel form of enteric neuronal cell death, involving the non-canonical inflammasome components NLRP6 and caspase 11. In further characterizing enteric neuronal populations, we identified a subset of intestinal CART+ neurons that were enriched in the distal intestine and modulated by the microbiota. Through microbial modulation strategies and chemogenetic targeting, we found that these enteric CART+ neurons regulate metabolic parameters including blood glucose and insulin levels. Retro- and anterograde tracing studies revealed that a subset of enteric CART+ neurons send axons to the gut sympathetic ganglion and are synaptically connected to the liver and pancreas. Together, we uncovered a gutpancreas- liver circuit that regulates glucose metabolism by sensing microbial cues. This peripherally-restricted circuit offers unique neuronal targets for the treatment of metabolic disorders, such as type 2 diabetes, which would bypass central nervous system effects. We further aimed to better characterize the role of neuro-immune interactions in the context of enteric pathologies, including post-infectious intestinal dysfunction and neuronal damage observed upon enteric infections. We further sought to determine whether a state of tolerance could be induced upon exposure to enteric pathogens, preventing tissue damage during subsequent infections. Finally, we aimed to characterize the role of extrinsic gut-projecting neurons to understand their role in sensing and responding to luminal cues, including enteric infections. Using cell sorting-independent transcriptomics, confocal imaging, genetic gainand loss-of-function approaches, surgical lesioning, chemogenetic manipulations, as well as multiple microbial manipulation strategies, we identified a critical role for enteric neuron-macrophage crosstalk in limiting ENS damage induced by a single enteric infection. A population of tissue-resident macrophages residing in close proximity to enteric neurons responded to luminal cues by upregulating a tissue-protective signature, and mediated enteric neuronal protection through adrenergic receptor signaling, and an arginase 1-polyamine program. Notably, we found engagement of macrophage adrenergic receptor signaling to be dependent on local catecholamine release by gutinnervating sympathetic neurons. We further uncovered that these sympathetic neurons on their end are tuned by enteric microbes and microbial products, in that a healthy microbiota suppresses, and absence of a microbiota, dysbiosis and infection enhance their activity. Finally, we found that previous infection with unrelated pathogens prevented infection-induced neuronal loss during subsequent, heterologous infections, suggesting a form of innate immune memory, or trained tolerance . Of note, while enteric bacterial and helminth infections induced distinct immune responses, these converged at the level of tissue-protective intestinal macrophages, which mediated enteric neuronal protection, aiding host fitness. Together, this work identified a functional role for interactions between sympathetic neurons, tissue-resident macrophages and enteric neurons in limiting infection-induced tissue damage. Overall, the research presented in this work uncovered that the ENS relies on the gut-resident microbiota for its homeostatic tissue function, with influence for local intestinal function and systemic metabolism. Furthermore, through communication with gut-extrinsic sympathetic neurons, tissue-resident macrophages upregulate and maintain a tissue-protective program, which protects enteric neurons from excessive damage during primary enteric infections and prevents cumulative damage during subsequent perturbations
A-to-I RNA Editing in Human Cells
Get PDFRNA editing is a means of diversifying the transcriptome and regulating innate immunity. Among the different classes of enzymes that modify RNA, adenosine deaminase acting on RNA (ADAR) is a type that catalyzes adenosine-to-inosine editing on double-stranded RNA molecules to regulate cellular responses to endogenous and exogenous RNA. Of the three ADAR homologs in humans, dysregulation of ADAR1 editing due to inherited mutations leads to disorders such as Aicardi-Goutieres syndrome, an inflammatory disease that manifests in the brain and skin, and dyschromatosis symmetrica hereditaria, a skin pigmentation disorder. ADAR1 is the primary A-to-I editor of RNA in humans, and the majority of edit sites are found in a class of repetitive elements called Alu, many of which are located in introns and 3\u27 untranslated regions of RNA. The functional consequences of A-to-I editing are varied, although a complete lack of functional ADAR1 is usually not tolerated, as revealed by the MDA5-mediated embryonic lethality in mice lacking functional ADAR1. In human neural progenitor cells, loss of ADAR1 causes spontaneous upregulation of interferon and cell death, although the RNA triggers remain unknown. Given the importance of ADAR1-editing in maintaining homeostasis in various contexts, there is a need to understand in more detail how ADAR1 isoforms are regulated and how they individually contribute to the A-to-I RNA editome. Two ADAR1 protein isoforms, p110 (110 kDa) and p150 (150 kDa), are expressed constitutively and in response to interferon, respectively, but the contribution of each isoform to the editing landscape remains incompletely characterized, largely because of the challenges in expressing p150 without p110. We revealed that the p110 isoform can be expressed from the canonical p150-encoding mRNA due to leaky ribosome scanning downstream of the p150 start codon. Synonymous mutations introduced in the region between the p150 and p110 start codons reduce leaky scanning and usage of the p110 start codon, and cells expressing p150 constructs with these mutations produce significantly reduced levels of p110. With the ability to express p150 with significantly reduced levels of p110, the A-to-I editome can be classified in terms of p150-selective and p110-selective sites, allowing evaluation of the relative contributions of either isoform to global editing levels. Our editing analysis revealed that the majority of ADAR1-edit sites are p150-selective, although a significant proportion of ADAR1-edit sites are also shared between p150 and p110, being not dependent on presence of either isoform for editing to occur. Of the sites that are putatively p110- selective, the majority are located in introns. Finally, the ability of p150 mRNA to give rise to p110 means that p110 is also an interferon-inducible protein alongside the canonical interferon-stimulated ADAR1 isoform: p150. During the interferon response, the transcriptome changes, and many new mRNA structures, perhaps some immunogenic ones, will enter the nucleus and cytoplasm. The distribution of ADAR1 isoforms is such that p110 is mostly present in the nucleus, and p150 mostly in the cytoplasm. We propose that optimal editing in the nucleus and cytoplasm during the interferon response is achieved by the inducibility of p110 and p150, both of which share a large number of target sites
William H. Welch with Dr. Christian Herter and S. D. Herter
No full textWilliam H. Welch with Dr. Christian Herter and S. D. Herter and poliomyelitis rabbit, at Charlton Hall, in Irvington-on-Hudson, New York, 1887
Courtesy of Medical Archives of The Johns Hopkins Medical Institutionshttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1009/thumbnail.jp
William H. Welch With the First Graduating Class of The Johns Hopkins University School of Medicine
No full textWilliam H. Welch with the male members of the first graduating class of The Johns Hopkins University School of Medicine, 1897
Courtesy of Medical Archives of The Johns Hopkins Medical Institutions
To quantities of students and to a large part of Baltimore, the great distinguished Dr. Welch was known as Popsy . He was indeed an intellectual father to many of the greatest scientists in America, and he had many endearing foibles.
The anecdotes about Welch are touching and revealing. He was unable to refuse a request, however inconvenient. He followed the local baseball team, the famous Orioles , with the enthusiasm of a true fan, correcting learned articles between innings. Scorning scholarly retreats, he loved seaside resorts like Coney Island; he was an inveterate rider of roller-coasters, and so adventurous a swimmer that at the age of fifty-nine he was arrested in Germany for swimming out of bounds.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1010/thumbnail.jp