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ObjectiveThe diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment (‘STIM’ classification).DesignWe applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease.ResultsiCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical(~10%) and inflammatory stroma(~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stromashowing T cell exhaustion, abundant stroma and KRASmutations (p<0.001). Analysis of cell–cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class(~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-likeclass (~35%) is enriched in ‘M2-like’ macrophages, mutations in IDH1/2and BAP1,and FGFR2fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19murine model and the inflammatory stromaclass (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS-mutant iCCA murine model to anti-PD1 therapy.ConclusionsWe describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

Basal forebrain cholinergic neurons (BFCNs) modulate synaptic plasticity, cortical processing, brain states and oscillations. However, whether distinct types of BFCNs support different functions remains unclear. Therefore, we recorded BFCNs in vivo, to examine their behavioral functions, and in vitro, to study their intrinsic properties. We identified two distinct types of BFCNs that differ in their firing modes, synchronization properties and behavioral correlates. Bursting cholinergic neurons (Burst-BFCNs) fired synchronously, phase-locked to cortical theta activity and fired precisely timed bursts after reward and punishment. Regular-firing cholinergic neurons (Reg-BFCNs) were found predominantly in the posterior basal forebrain, displayed strong theta rhythmicity and responded with precise single spikes after behavioral outcomes. In an auditory detection task, synchronization of Burst-BFCNs to the auditory cortex predicted the timing of behavioral responses, whereas tone-evoked cortical coupling of Reg-BFCNs predicted correct detections. We propose that differential recruitment of two basal forebrain cholinergic neuron types generates behavior-specific cortical activation.

Organisms have evolved diverse behavioural strategies that enhance the likelihood of encountering and assessing mates1. Many species use pheromones to communicate information about the location, sexual and social status of potential partners2. In mice, the major urinary protein darcin—which is present in the urine of males—provides a component of a scent mark that elicits approach by females and drives learning3,4. Here we show that darcin elicits a complex and variable behavioural repertoire that consists of attraction, ultrasonic vocalization and urinary scent marking, and also serves as a reinforcer in learning paradigms. We identify a genetically determined circuit—extending from the accessory olfactory bulb to the posterior medial amygdala—that is necessary for all behavioural responses to darcin. Moreover, optical activation of darcin-responsive neurons in the medial amygdala induces both the innate and the conditioned behaviours elicited by the pheromone. These neurons define a topographically segregated population that expresses neuronal nitric oxide synthase. We suggest that this darcin-activated neural circuit integrates pheromonal information with internal state to elicit both variable innate behaviours and reinforced behaviours that may promote mate encounters and mate selection.

Individual neurons in many cortical regions have been found to encode specific, identifiable features of the environment or body that pertain to the function of the region1–3. However, in frontal cortex, which is involved in cognition, neural responses display baffling complexity, carrying seemingly disordered mixtures of sensory, motor and other task-related variables4–13. This complexity has led to the suggestion that representations in individual frontal neurons are randomly mixed and can only be understood at the neural population level14,15. Here we show that neural activity in rat orbitofrontal cortex (OFC) is instead highly structured: single neuron activity co-varies with individual variables in computational models that explain choice behaviour. To characterize neural responses across a large behavioural space, we trained rats on a behavioural task that combines perceptual and value-guided decisions. An unbiased, model-free clustering analysis identified distinct groups of OFC neurons, each with a particular response profile in task-variable space. Applying a simple model of choice behaviour to these categorical response profiles revealed that each profile quantitatively corresponds to a specific decision variable, such as decision confidence. Additionally, we demonstrate that a connectivity-defined cell type, orbitofrontal neurons projecting to the striatum, carries a selective and temporally sustained representation of a single decision variable: integrated value. We propose that neurons in frontal cortex, as in other cortical regions, form a sparse and overcomplete representation of features relevant to the region’s function, and that they distribute this information selectively to downstream regions to support behaviour.

Systems neuroscience seeks explanations for how the brain implements a wide variety of perceptual, cognitive and motor tasks. Conversely, artificial intelligence attempts to design computational systems based on the tasks they will have to solve. In artificial neural networks, the three components specified by design are the objective functions, the learning rules and the architectures. With the growing success of deep learning, which utilizes brain-inspired architectures, these three designed components have increasingly become central to how we model, engineer and optimize complex artificial learning systems. Here we argue that a greater focus on these components would also benefit systems neuroscience. We give examples of how this optimization-based framework can drive theoretical and experimental progress in neuroscience. We contend that this principled perspective on systems neuroscience will help to generate more rapid progress.

The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR−CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis. Although the plasma concentrations of CXCL9 and CXCL11 were similar, those of CXCL10 were markedly lower in diabetic db/db mice compared with control db/m mice. In cell culture, CXCL10 inhibited kidney fibroblast collagen production in response to high glucose and the prosclerotic growth factor, transforming growth factor-β. In vivo, recombinant murine CXCL10 reduced mesangial and peritubular matrix expansion, albuminuria, and glomerular hypertrophy in db/db mice. In bone marrow, a major source of circulating chemokines, the concentration of CXCL10 was lower in cells derived from diabetic mice than from their nondiabetic counterparts. Silencing of CXCR3, the cognate receptor for CXCL10, abrogated the antifibrotic effects of bone marrow–derived secretions. In conclusion, experimental diabetes is a state of CXCL10 deficiency and that restoration of CXCL10 abundance prevented fibrosis and the development of diabetic kidney disease in mice.

Most forms of chronic, progressive kidney disease are characterized by fibrosis whereby the prototypical prosclerotic growth factor, transforming growth factor β (TGF-β), is thought to play a pivotal role. With the recent understanding that TGF-β's canonical signaling pathway may be modified by acetylation as well as phosphorylation, we explored the role of the NAD+-dependent lysine deacetylase, sirtuin 1 (SIRT1) in fibrogenesis in the cell culture, animal model, and human settings. In vitro, the increase in collagen production that results from TGF-β1 stimulation was ameliorated by the allosteric modifier of Sirt1 deacetylase, SRT3025, in association with a reduction in Smad3 reporter activity. In the remnant kidney model (subtotally or 5/6 nephrectomized rats) that develops progressive kidney disease in association with TGF-β overexpression, administration of SRT3025 attenuated glomerular filtration rate decline and proteinuria without affecting blood pressure. Glomerulosclerosis and tubulointerstitial fibrosis were similarly reduced with Sirt1 activation as were cardiac structure and function in this rodent model of primary kidney and secondary cardiac disease. Relating these findings to the human setting, we noted a reduction in SIRT1mRNA in kidney biopsies obtained from individuals with focal glomerulosclerosis. Together these studies highlight the potential of SIRT1 activation as a therapeutic strategy in progressive, fibrotic kidney disease.

When facing uncertainty, adaptive behavioral strategies demand that the brain performs probabilistic computations. In this probabilistic framework, the notion of certainty and confidence would appear to be closely related, so much so that it is tempting to conclude that these two concepts are one and the same. We argue that there are computational reasons to distinguish between these two concepts. Specifically, we propose that confidence should be defined as the probability that a decision or a proposition, overt or covert, is correct given the evidence, a critical quantity in complex sequential decisions. We suggest that the term certainty should be reserved to refer to the encoding of all other probability distributions over sensory and cognitive variables. We also discuss strategies for studying the neural codes for confidence and certainty and argue that clear definitions of neural codes are essential to understanding the relative contributions of various cortical areas to decision making.

Emotional processes are central to behavior, yet their deeply subjective nature has been a challenge for neuroscientific study as well as for psychiatric diagnosis. Here we explore the relationships between subjective feelings and their underlying brain circuits from a computational perspective. We apply recent insights from systems neuroscience—approaching subjective behavior as the result of mental computations instantiated in the brain—to the study of emotions. We develop the hypothesis that emotions are the product of neural computations whose motor role is to reallocate bodily resources mostly gated by smooth muscles. This “emotor” control system is analagous to the more familiar motor control computations that coordinate skeletal muscle movements. To illustrate this framework, we review recent research on “confidence.” Although familiar as a feeling, confidence is also an objective statistical quantity: an estimate of the probability that a hypothesis is correct. This model-based approach helped reveal the neural basis of decision confidence in mammals and provides a bridge to the subjective feeling of confidence in humans. These results have important implications for psychiatry, since disorders of confidence computations appear to contribute to a number of psychopathologies. More broadly, this computational approach to emotions resonates with the emerging view that psychiatric nosology may be best parameterized in terms of disorders of the cognitive computations underlying complex behavior.

Cell-based regenerative therapies offer a new alternative approach to the treatment of chronic disease. Specifically, studies by our laboratory and others have shown that a subpopulation of cells derived from the bone marrow, known as early outgrowth cells (EOCs), are able to attenuate the progression of chronic kidney disease (CKD). In this study we examined the efficacy of a tissue engineering system, in which EOCs were embedded into submillimeter-sized collagen cylinders. These small individual units are referred to as modules and together form a functional microtissue. Due to their resemblance to endothelial cells, late outgrowth cells (LOCs) were used to coat the module surface, hypothesizing that as such they would promote vascularization and enhance engraftment of the encapsulated EOCs. These coated modules were transplanted subcutaneously into the subtotally nephrectomized rat model of CKD. While coated module therapy significantly improved both renal structure and function, noncoated modules with embedded EOCs were unable to reproduce these salutary effects on the kidney. Nevertheless, in both treatments, the embedded EOCs quickly degraded the modular environment and were seen to migrate to the liver, spleen, and bone marrow as early as 6 days after transplantation. With the efflux of EOCs, and unexpectedly no evidence of vascularization, we hypothesized that the LOCs did not enhance EOC engraftment, but rather augmented the renoprotection provided by EOCs by secretion of their own soluble and potent antifibrotic factors. To the best of our knowledge, this is the first study to document an effective subcutaneous approach for renoprotection.

Adult bone marrow‐derived cells can improve organ function in chronic disease models, ostensibly by the release of paracrine factors. It has, however, been difficult to reconcile this prevailing paradigm with the lack of cell retention within injured organs and their rapid migration to the reticuloendothelial system. Here, we provide evidence that the salutary antifibrotic effects of bone marrow‐derived early outgrowth cells (EOCs) are more consistent with an endocrine mode of action, demonstrating not only the presence of antifibrotic factors in the plasma of EOC‐treated rats but also that EOC conditioned medium (EOC‐CM) potently attenuates both TGF‐β‐ and angiotensin II‐induced fibroblast collagen production in vitro. To examine the therapeutic relevance of these findings in vivo, 5/6 subtotally nephrectomized rats, a model of chronic kidney and heart failure characterized by progressive fibrosis of both organs, were randomized to receive i.v. injections of EOC‐CM, unconditioned medium, or 106EOCs. Rats that received unconditioned medium developed severe kidney injury with cardiac diastolic dysfunction. In comparison, EOC‐CM‐treated rats demonstrated substantially improved renal and cardiac function and structure, mimicking the changes found in EOC‐treated animals. Mass spectrometric analysis of EOC‐CM identified proteins that regulate cellular functions implicated in fibrosis. These results indicate that EOCs secrete soluble factor(s) with highly potent antifibrotic activity, that when injected intravenously replicate the salutary effects of the cells themselves. Together, these findings suggest that an endocrine mode of action may underlie the effectiveness of cell therapy in certain settings and portend the possibility for systemic delivery of cell‐free therapy. StemCells2013;31:2408–2419

Neurons compute and communicate by transforming synaptic input patterns into output spike trains. The nature of this transformation depends crucially on the properties of voltage-gated conductances in neuronal membranes. These intrinsic membrane conductances can enable neurons to generate different spike patterns including brief, high-frequency bursts that are commonly observed in a variety of brain regions. Here we examine how the membrane conductances that generate bursts affect neural computation and encoding. We simulated a bursting neuron model driven by random current input signal and superposed noise. We consider two issues: the timing reliability of different spike patterns and the computation performed by the neuron. Statistical analysis of the simulated spike trains shows that the timing of bursts is much more precise than the timing of single spikes. Furthermore, the number of spikes per burst is highly robust to noise. Next we considered the computation performed by the neuron: how different features of the input current are mapped into specific output spike patterns. Dimensional reduction and statistical classification techniques were used to determine the stimulus features triggering different firing patterns. Our main result is that spikes, and bursts of different durations, code for different stimulus features, which can be quantified without a prioriassumptions about those features. These findings lead us to propose that the biophysical mechanisms of spike generation enables individual neurons to encode different stimulus features into distinct spike patterns.

Burst firing is a prominent feature of cortical pyramidal cells and is thought to have significant functional roles in reliable signaling and synaptic plasticity. Modeling studies have successfully elucidated possible biophysical mechanisms underlying complex bursting in pyramidal cells. Based on these results (Pinsky, Rinzel, J. Comput. Neurosci. 1 (1994) 39–60), we have built a simplified two-compartment burst model. Using the fast- and slow-variable analysis method, we show that complex bursting is an instance of square-wave bursting, where the dendritic slow potassium conductance is the single slow variable. The coupling parameters between the two compartments change the topological class of bursting thereby altering the firing patterns of the neuron. These results explain the diverse set of firing patterns seen with different dendritic morphologies (Mainen, Sejnowski, Nature 382 (1996) 363–366).

Since the 1960s it has become an established practice to perform microcensuses between population censuses. Prior to the latest survey on 1 October 1984, the Central Statistical Office had carried out microcensuses three times: twice between 1960 and 1970 and once between 1970 and 1980. The microcensus of 1984 differed from the previous ones in respect of its method which, to a certain extent already pointed to the future. For the first time, on the basis of designated addresses, available personal data had been preprinted from the register of the National Population Registration Office of Hungary and enumerators visiting the population had the thus prepared questionnaires already in their hands. In October and November 1984, almost simultaneously with the microcensus, a trial population census was held in the county of Gyór. One of the major aims of this trial census was to establish what practical results could be obtained from the use and print-out of data stored in the data base of the National Population Registration Office and from conducting the survey with the help of such preprinted questionnaires for future population censuses.

A 1973 mailed survey of all psychiatrists practicing in Chicago utilized many questions identical to those used in a 1962 survey of this same population. By 1973, more psychiatrists were working in the public sector than in 1962, but by 1973, their interest in a social and community therapeutic orientation had decreased. The psychoanalytic orientation remained strong, though interest in analytic training had declined. In both private and organizational practice, the average Chicago psychiatrist was seeing more Blacks, poor people and Catholics, and fewer Jews, in 1973 than in 1962. Societal changes associated with these changes in psychiatric practice are discussed.

This monograph demonstrates a new method for describing crime stalistics reported in the Uniform Crime Reports. After discussing the methods currently used to present these dam, we explain a scaling modcl based on the scaling of inlelligence uscd in differential psychology and apply that model to a rescaling of reported crime occurences in 76 of the largest cities in the United Stales. A profile of victimization quotients was generated for these cities that allows for more detailed analyses of crime patterns and covariances than do otlm reporting methods. The crime quotients are still examined in relation to four structural characteristics of the 76 cities (municipal expendituscs, police service expenditures, percent of the population that is minority, and population density) as an example of the potential uses of the new scaling system. Psychometric and practical issues associated with the new scaling system are discussed.

Abstract: Researchers interested in developing long-term social histories are faced with myriad difficulties rising from the biased and fragmentary nature of various available sources of information on the distant past. Understanding the crucial centuries surrounding the Spanish invasion of the northern Maya lowlands is hindered by uncritical mixing of the written and material records. This case study from the Chikinchel region in northeast Yucatán is focused on economic issues. Relevant data from each register first are considered separately in order to preserve the integrity of each source. The resulting synthesis offers a new, well-informed interpretation of late prehispanic economic organization and its alteration under Spanish authority.

We have identified two forms of a major histocompatibility complex (MHC) class I molecule, H-2Kb, distinguishable by specific antibodies through a study of a genetically engineered mouse cell line that overexpresses these molecules. One form, a complex associated with beta 2-microglobulin (native, beta 2m+ class I), is detectable by conformation-dependent antibodies. The other form, which remains after preclearing cell lysates of native class I, is only poorly, if at all, associated with beta 2-microglobulin (beta 2m- class I) and is detectable by an antiserum against the cytoplasmic tail region of H-2K molecules. Both forms are also present in normal cell lines. The affinity-purified native class I molecules bind short peptides (8 or 9 residues) and assemble tightly with beta 2-microglobulin. In striking contrast, the beta 2m- class I molecules bind peptides that are longer (> 15 residues) than those bound to native class I molecules. This finding is consistent with the recent evidence that peptides longer than 8-10 amino acid residues are transported into the endoplasmic reticulum and suggests the possibility of a control step for peptide presentation by MHC in which the incompletely processed peptides bind to the heavy chain and a selected fraction undergoes final processing and presentation on the cell surface.

Groups of patients suffering from asthma, atopic or localized neurodermatitis, arthritis, and hypertension were tested. Each subject received three types of sensory stimulationcutaneous, muscular, and olfactory, in modified random order.

Atopic dermatitis, a disease which causes severe itching and scratching, often begins in the first few months of life, and may continue to the adult period, with exacerbations and remissions. The presence of an itching eruption from early life raises such questions as: How does this affect maturation of defenses against irritation? Does early itch-scratch lead to fixation, and of what does this consist? By careful observation of reactions to skin stimulation, it is possible to obtain some information pertinent to these and related problems.Earlier studies10,11,16 of responses of subjects to stroking the forehead with cotton for two minutes have proved to be useful indicators of how a person reacts to mild irritation, of how this irritation is a source of erotic pleasure, and of how irritation is finally mastered.We found that people who are emotionally volatile and labile tended to

INTRODUCTION In his paper on repression11 Freud states that "the essence of repression lies simply in the function of rejecting and keeping something out of consciousness." This function is implemented in a number of ways. These differing ways complement and combine with one another to produce repression, but a few of them may be separately appraised in order to investigate their particular roles in the total process. REPRESSION WITHOUT PRIMARY PSYCHOLOGICAL CONTENT. —Here the subject may become aware of an inability to think about or approach a certain area of feeling. Sometimes, as in trying to remember a forgotten name, there is awareness of something which cannot be reached, or can be reached only partially. The feeling of the sound of the name, the number of syllables, the inflection in its pronunciation, may be felt before the actual word is recalled. In some active states of repression the mind

An attempt has been made to set down some general observations and formulations concerning somatic displacements in man which are influenced by psychological events. Emphasis has been laid on the usual psychological and physiological characteristics of the various areas and functional systems of the body in influencing somatic displacements. These factors must be considered in addition to the individual events of patients' lives.

The skin is a particularly fortunate site for studying certain peripheral manifestations of the functioning of the psychic structures originally described by Freud. Indeed, we might say that in a phylogenetic sense the skin is the mother structure of both the id and the ego. "The skin, which in particular parts of the body has become differentiated into sense organs or modified into mucous membrane, and is thus the erotogenic zone par excellence."5 "The ego is first and foremost a body-ego; it is not merely a surface entity, but is itself the projection of a surface."4 An authorized note by the translator amplifies this statement: "The ego is ultimately derived from bodily sensations, chiefly from those springing from the surface of the body."The study of sensory and perceptual phenomena in their bearing on the total functioning of the organism is by no means new.1 The aim

THE PAST decade has been a period of rapid social change. The effects of this are perhaps no more evident than in the areas of sexual and social role expectations and behavior. There is much evidence (visual and graphic) that we may be moving in an androgynous direction-toward a "unisex." This would seem to have many psychiatric implications.1-4 In discussing these trends, Winick5 concludes:Multivalent, amorphous, and depolarized roles might theoretically lead to increased flexibility and options in behavior, but in actuality may tend to invoke uncertainty. Such tolerance of ambiguity is desirable for a healthy personality, but today's environment and culture are ambiguous enough to tax the adaptability of even the healthiest personalities (p 24). We attempted to empirically document the psychological byproducts of these societal changes by studying the Minnesota Multiphasic Personality Inventory (MMPI) scale scores of patients during two time periods 1958 to 1960 and 1967

PSYCHOANALYSIS in the United States is today suffering a decline in prestige and popularity, having reached the high point of its influence in American psychiatry in the 1950's. Many young psychiatrists then believed to be really first class one had to become an analyst. In many residency programs, particularly in analytic training centers, almost all the residents applied to psychoanalytic institutes. Acceptance was a great event and rejection was treated as shameful. Young candidates who had been dropped from training because they were regarded as not suitable felt stigmatized and a pall of second-class citizenship was cast over their careers. Some psychoanalysts, by this turn of events placed in positions of great power over the careers of others, became afflicted by a distressing spirit of arrogance and pride. By certain sectors of urban, middle class society, psychoanalysis was also regarded with great respect and often illusory hopes existed about its

The skin, we have observed, is not limited to functioning as an isolated organic system. Rather, it participates intimately in the functioning of the whole person. Inferences based on behavior or concepts applicable to psychological processes may be used to understand the functioning of the skin. And conversely, observations regarding dermal processes may lead to confirmation, extension, or modification of concepts derived from psychological observations. In his Three Essays on the Theory of Sexuality Freud refers to the skin as the erotogenic zone per excellence, and in The Ego and The Id he describes the ego as first and foremost a body ego, derived from sensations arising chiefly from the body surface.Observations of skin sensation at various ages are used here to throw light on such subjects as the stimulus barrier; stages of defense against irritation; development of adaptation, control, and integration.Stimulation of the skin

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

There is increasing evidence that the social and cultural characteristics of psychiatric patients have been changing over time. 1,2 It is important from a professional and public policy point of view to understand better the nature of these changes, and to what they are related. This paper presents data showing that: 1) psychiatric care is increasingly reaching patients of lower socio economic status, and 2) changes in patient characteristics are related to the growth in the pro portion of psychiatric care given in organisationally based non-private practice settings.

On 20 October 2017, John Lisman passed away at the age of 73. Neuroscience lost a great luminary.

Dr. Ainslie Meares is clearly a gifted psychotherapist. In this work on hypnosis, he repeatedly demonstrates sensitivity to the nuances of relationships, and awareness of the interactions between the two participants in the hypnotic process. Written in a notably lucid and felicitous style, the varying therapeutic uses of hypnosis are described, based on the author's own method of practice. His book is informed throughout by his purpose of presenting "Medical hypnosis ... as a system of treatment in which various practices are linked each to each by their clear relation to underlying psychodynamic theory." In the main by psychodynamic theory he means psychoanalytic theory. As befits a "system," the entire range of therapeutic applications of hypnosis is covered. Detailed descriptions of the doctor-patient interactions in hypnosis are offered. Different methods of induction (relaxation, arm levitation, repetitive movement, direct stare, and a dynamic method directly geared to the individual

In addition to the main current of psychoanalysis and the most popular divagations from it, backwaters and eddies exist in which development has been going on in ways quite different from one's habitual conceptual set. Alexander Lowen, a follower of Wilhelm Reich, describes what might be considered an attempt at synthesis of Reich's vegetotherapy and psychoanalytic theory. A general theory and its application to a variety of disorders is propounded. Impulse originates in the center of the organism, from whence it moves to the periphery, where it has two functions: charging the organism by intake, and discharging, especially through the sex act and reproduction. In man, the upper part of the body, including arms and hands, is devoted to energy intake. Discharge tends to be relegated to the lower half of the body. Consciousness and higher ego functions tend to be set in opposition to the body, from which, however,