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SummaryMany animals rely on vision to navigate through their environment. The pattern of changes in the visual scene induced by self-motion is theoptic flow1, which is first estimated in local patches by directionally selective (DS) neurons2–4. But how should the arrays of DS neurons, each responsive to motion in a preferred direction at a specific retinal position, be organized to support robust decoding of optic flow by downstream circuits? Understanding this global organization is challenging because it requires mapping fine, local features of neurons across the animal’s field of view3. InDrosophila, the asymmetric dendrites of the T4 and T5 DS neurons establish their preferred direction, making it possible to predict DS responses from anatomy4,5. Here we report that the preferred directions of fly DS neurons vary at different retinal positions and show that this spatial variation is established by the anatomy of the compound eye. To estimate the preferred directions across the visual field, we reconstructed hundreds of T4 neurons in a full brain EM volume6and discovered unexpectedly stereotypical dendritic arborizations that are independent of location. We then used whole-head μCT scans to map the viewing directions of all compound eye facets and found a non-uniform sampling of visual space that explains the spatial variation in preferred directions. Our findings show that the organization of preferred directions in the fly is largely determined by the compound eye, exposing an intimate and unexpected connection between the peripheral structure of the eye, functional properties of neurons deep in the brain, and the control of body movements.

openaire: EC/H2020/713645/EU//BioMEP Funding Information: We thank Drs. Kristian Donner, Greg Schwartz, Gabriel Peinado, and Christophe Ribelayga for valuable comments on the manuscript; Matthew Dunkerley and Sathish Narayanan for the design of the data acquisition software; Dr. Martta Viljanen for technical assistance with the design of the water maze; and Mr. Sami Minkkinen for technical assistance with the design of the patch rig. Support was provided by the Academy of Finland (296269 and 305834 to P.A.-L.); the Aalto Brain Centre (J.W.); Svenska kulturfonden (J.W.); the Finnish Society of Sciences and Letters (J.W.); the European Union's Horizon 2020 research and innovation programme (Marie Sklodowska-Curie grant 713645 to N.M.); the Doctoral programme Brain & Mind, University of Helsinki (S.K.); the Finnish Cultural Foundation (S.K.); the Ella and Georg Ehrnrooth Foundation (T.T.); the Oskar Öflund Foundation (T.T.); and the Finnish Foundation for Technology Promotion (T.T.). We acknowledge the computational resources provided by the Aalto Science-IT Project. Parts of Figure 1 and 4 were adapted from https://biorender.com. J.W. S.K. and P.A.-L. designed the experiments. T.T. developed the methodology for markerless mouse tracking. T.T. and S.K. set up the water maze used for behavioral experiments, and S.P carried out behavioral experiments. S.K. and S.P. collected and analyzed pupil data. N.M. carried out RGC experiments. J.W. S.K. and S.P. analyzed data. J.W. S.K. and P.A.-L wrote the MS. P.A.-L. is a founder and shareholder of Quantal Vision Technologies. T.T. and P.A.-L. have the following patents related to “a method for performing behavioral experiments with rodents”: FI127666B & US10706287B2. Perception of light in darkness requires no more than a handful of photons, and this remarkable behavioral performance can be directly linked to a particular retinal circuit—the retinal ON pathway. However, the neural limits of shadow detection in very dim light have remained unresolved. Here, we unravel the neural mechanisms that determine the sensitivity of mice (CBA/CaJ) to light decrements at the lowest light levels by measuring signals from the most sensitive ON and OFF retinal ganglion cell types and by correlating their signals with visually guided behavior. We show that mice can detect shadows when only a few photon absorptions are missing among thousands of rods. Behavioral detection of such “quantal” shadows relies on the retinal OFF pathway and is limited by noise and loss of single-photon signals in retinal processing. Thus, in the dim-light regime, light increments and decrements are encoded separately via the ON and OFF retinal pathways, respectively.

The aim of this study was to assess the occurrence and nature of retained dental roots and their associations with demographics in the Finnish adult population. From the cross-sectional nationwide Health 2000 Survey of the Finnish population aged 30 years and older, 6005 participants with clinical oral examination and panoramic radiographs were included. Occurrence and characteristics of all retained dental roots were examined. Statistical analyses included chi(2), Kruskal-Wallis and Mann-Whitney U tests, and SAS-SUDAAN calculations. The mean age of the 6005 participants (46% men and 54% women) was 53 (SD 14.6) years. At least one retained dental root was observed in 13% (n = 754) of the participants. The 1350 retained roots included 461 (34%) roots retained entirely in bone and 889 (66%) partly in bone. The most common location of a retained dental root was the third molar region. Occurrence of retained roots partly in bone was associated with male sex and lower education. Occurrence of retained third molar roots entirely in bone was associated with female sex, younger age, higher education, and living in a city. Among all retained dental roots, the preponderance of third molars emphasized the demanding nature of extracting the third molar in women.

SUMMARYPerception of light in darkness requires no more than a handful of photons and this remarkable behavioral performance can be directly linked to a particular retinal circuit – the retinal ON pathway. However, the neural limits to shadow detection in very dim light have remained unresolved. Here, we unravel the neural mechanisms that determine the sensitivity of mice to the dimmest light decrements by measuring signals from the most sensitive ON and OFF retinal ganglion cell types and by correlating their signals with visually guided behavior. We show that mice can detect shadows when only a few photon absorptions are missing among thousands of rods. Behavioral detection of “quantal” shadows relies only on the retinal OFF pathway and is limited by noise and losses of single-photon signals in retinal processing. Thus, in the dim-light regime, light increments and decrements are encoded separately via the ON and OFF retinal pathways, respectively.

At the sensitivity limit of vision, the quantal fluctuations of light and neural noise in the retina and the brain limit the detection of light signals. The challenge for vision, as for all senses, lies in separating the weakest signals from the neural noise originating within the sensory system. In this thesis, I studied sparse signal detection in the vertebrate visual system (mouse and frog) at low light levels from single retinal neurons to behavioral performance. First, we determined the sensitivity limit of amphibian color vision at low light levels. Unlike most vertebrates, amphibians are potential dichromats even at night, with two spectrally distinct classes of rod photoreceptors: common vertebrate rods (peak sensitivity at 500 nm) and an additional class called “green rods” (peak sensitivity at 430 nm). We showed that frogs in a phototaxis experiment can distinguish blue from green down to their absolute visual threshold, meaning that they have wavelength discrimination as soon as they start seeing anything. Remarkably, the behavioral blue/green discrimination approached theoretical limits set by photon fluctuations and rod noise, highlighting the sensitivity of the system comparing signals from the two different photoreceptors. Additionally, we show that the amphibian threshold for color discrimination is task- and context-dependent, underlining that sensory discrimination is not universally driven to absolute physical limits, but depends on evolutionary trade-offs and flexible brain states. In the second paper, we studied the impact of the circadian rhythm on the sensitivity limit of mouse vision. The retina has its own intrinsic circadian rhythms, which has led to the hypothesis that the sensitivity limit of vision would be under circadian control. We used a simple photon detection task, which allowed us to link well-defined retinal output signals to visually guided behavior. We found that mice have strikingly better performance in the visual task at night, so that they can reliably detect 10-fold dimmer light in the night than in the day. Interestingly, and contrary to previous hypotheses, this sensitivity difference did not arise in the retina, as assessed by spike recordings from retinal ganglion cells. Instead, mice utilize a more efficient search strategy in the task during the night. They are even able to apply the more efficient strategy at day once they have first performed the task during the night. Measured differences in search strategy explain only part of the day/night difference, however. We hypothesize that in addition there are diurnal changes in the state of brain circuits reading out the retinal input and making decisions. In the third paper, we determined the sensitivity limit of decrement (shadow) detection of mouse vision. Compared with the question of ultimate limit for detecting light, the question of sensitivity limits for detecting light decrements (negative contrast) has been remarkably neglected. We recorded the OFF responses of the most sensitive retinal ganglion cells at dim background light levels and correlated the thresholds to visually guided behavior in tightly matched conditions. We show that compared with an ideal-observer model most of the losses happen in the retina and remarkably, the behavioral performance is very close to an optimal read-out of the retinal ganglion cells. I have shown across visual tasks and in two different species how closely behavior in specific conditions can approach the performance limit set by physical constraints, rejecting noise and making use of every available photon. However, the actual performance strongly depends on the behavioral context and relevance of the task and state of the brain. Näön herkkyyden rajalla valokvanttien vähäinen määrä asettaa erityisen suuren haasteen näköjärjestelmän toiminnalle. Tällöin näköjärjestelmän on kyettävä erottamaan heikoimmatkin signaalit aistijärjestelmän sisäisestä kohinasta. Väitöskirjassani kysyn miten biologiset mekanismit vastaavat näihin haasteisiin. Selvitän hermoverkkojen signaalinkäsittelykykyä käyttäytymistä määrittävänä tekijänä, käyttäen mallina selkärankaisen (sammakko, hiiri) silmän verkkokalvon suorituskykyä lähellä näönherkkyyden rajaa. Tutkin näköaistin suorituskykyä yksittäisten verkkokalvon hermosolujen tasolta koko eläimen näönvaraiseen käyttäytymiseen. Ensimmäisessä osaprojektissa määritin heikoimman valointensiteetin missä sammakko pystyy erottamaan värejä. Toisin kuin muilla selkärankaisilla, sammakkoeläimillä on kaksi erityyppistä hämäränäköön erikoistunutta sauva-valoreseptoria: vihreän valon aallonpituutta parhaiten absorboiva viherherkkä sauvareseptori (kuten meillä) sekä lyhyempiä, sinisiä aallonpituuksia absorboiva siniherkkä sauva. Osoitimme, että sammakot pystyvät erottamaan värejä valaistuksessa, missä ihmiset eivät pysty. Tämä sini/viher-erotuskyky lähestyi teoreettisia fysikaalisia raja-arvoja. Lisäksi näytimme, että sammakkoeläinten värinäön kynnysherkkyys riippuu käyttäytymistehtävästä, korostaen kuinka aistinvarainen erotuskyky riippuu myös evolutiivisista valinnoista ja eläimen käyttäytymistilasta. Toisessa osatyössä tutkin vuorokausirytmin vaikutusta hiiren näönherkkyyteen. On oletettu, että verkkokalvon sopeutuu ennakoivasti valtaviin valon intensiteettimuutoksiin yön ja päivän välillä. Tässä työssä käytimme yksinkertaista, himmeiden valojen havaitsemistehtävää, joka mahdollisti verkkokalvon aivoihin lähettämän signaalin yhdistämisen näönvaraiseen käyttäytymiseen tiukan kvantitatiivisesti. Havaitsimme, että yöllä hiiret erottivat hyvin heikkoja valoja pimeässä jopa kymmenen kertaa paremmin kuin päivällä. Yllätykseksemme tämä ei johtunut muutoksista verkkokalvon maksimaalisessa herkkyydessä, vaan parempi suorituskyky yöllä johtui tehokkaammasta käyttäytymisstrategiasta sekä tarkemmasta näkötiedon käsittelystä aivoissa. Näytimme lisäksi, että hiiret pystyvät hyödyntämään tehokkaampaa strategiaa myös päiväsaikaan, jos ovat ensin suorittaneet tehtävän yöllä. Näkeminen vaatii sekä valojen että varjojen havaitsemista. Kolmannessa osaprojektissa määritin kuinka paljon fotoneja pitää poistaa heikosta taustavalosta, jotta hiiri havaitsee eron. Tämä kysymys on jäänyt verrattain huomiotta, verrattuna kymmenien vuosien tutkimukseen pienimmästä havaittavasta valomäärästä. Vertasimme herkimpien verkkokalvosolujen suorituskykyä näönvaraiseen käyttäytymiseen vastaavissa olosuhteissa. Näytimme verkkokalvon prosessointiin perustuvaa mallinnusta hyväksi käyttäen, että verrattuna teoreettisesti täydelliseen suorituskykyyn suurin osa informaationmenetyksistä tapahtuu verkkokalvolla fotonien pyydystämisessä ja verkkokalvon signaalinkäsittelyssä. Käyttäytyminen sen sijaan on huomattavan lähellä tilannetta, jossa aivot lukevat verkkokalvon lähettämää signaalia lähes täydellisesti. Väitöskirjassani näytän kahdella selkärankaisella, kuinka näkösuoritus pääsee useassa tehtävässä erittäin lähelle fysikaalisten reunaehtojen määräämiä raja-arvoja. Suorituskyky riippuu kuitenkin kontekstista ja käyttäytymistehtävän merkityksestä eläimelle sekä aivojen sen hetkisestä tilasta.

The aim of this study was to analyze malpractice claims related to tooth extractions in order to identify areas requiring emphasis and eventually to reduce the number of complications. We compiled a file of all malpractice claims related to tooth extractions (EBA code) between 1997 and 2010 from the Finnish Patient Insurance Centre. We then examined the data with respect to date, tooth, surgery, injury diagnosis, and the authority's decision on the case. The material consisted of 852 completed patient cases. Most of the teeth were third molars (66 %), followed by first molars (8 %), and second molars (7 %). The majority of claims were related to operative extraction (71 %) followed by ordinary extraction (17 %) and apicoectomy of a single-rooted tooth (7 %) or multi-rooted tooth (2 %). The most common diagnosis was injury of the lingual or inferior alveolar nerve. According to the authority's decision, the patient received compensation more often in cases involving a third molar than other teeth (56 vs. 46 %, P

Circadian clocks predictively adjust the physiology of organisms to the day/night cycle. The retina has its own clock, and many diurnal changes in its physiology have been reported. However, their implications for retinal functions and visually guided behavior are largely unresolved. Here, we study the impact of diurnal rhythm on the sensitivity limit of mouse vision. A simple photon detection task allowed us to link well-defined retinal output signals directly to visually guided behavior. We show that visually guided behavior at its sensitivity limit is strongly under diurnal control, reaching the highest sensitivity and stability at night. The diurnal differences in visual sensitivity did not arise in the retina, as assessed by spike recordings from the most sensitive retinal ganglion cell types: ON sustained, OFF sustained, and OFF transient alpha ganglion cells. Instead, we found that mice, as nocturnal animals, use a more efficient search strategy for visual cues at night. Intriguingly, they can switch to the more efficient night strategy even at their subjective day after first having performed the task at night. Our results exemplify that the shape of visual psychometric functions depends robustly on the diurnal state of the animal, its search strategy, and even its diurnal history of performing the task. The results highlight the impact of the day/night cycle on high-level sensory processing, demonstrating a direct diurnal impact on the behavioral strategy of the animal.

Ovarian adult-type granulosa cell tumors (AGCTs) require prolonged follow-up, but evidence regarding the optimal follow-up marker is lacking. The objective of our study was to validate the clinical usefulness of serum anti-Mullerian hormone (AMH) and the current marker inhibin B as single and combined markers of AGCTs. We conducted a longitudinal, partially prospective cohort study of 123 premenopausal and postmenopausal AGCT patients with a median follow-up time of 10.5 years (range 0.3-50.0 years). Serum AMH and inhibin B levels were measured from 560 pretreatment and follow-up serum samples by using immunoenzymometric assays. We found that serum AMH and inhibin B levels were significantly elevated in patients with primary or recurrent AGCTs. The levels of both markers positively correlated to tumor size (p

Anti-Müllerian hormone (AMH), also known as Müllerian inhibitory substance, is a useful marker of ovarian function. Granulosa cells of growing follicles secrete AMH, and its serum levels reflect the remaining follicular pool and thus the remaining length of a woman's reproductive lifespan. Serum AMH measurement can be used as a marker of ovarian dysfunction such as primary ovarian insufficiency, polycystic ovarian syndrome and granulosa cell tumors. Furthermore, it helps to estimate ovarian damage due to chemotherapy or surgery and can be used as a tool in infertility treatment. The use of AMH in clinical practice will likely become more common in the future as the new automatic assay methods become available.

The genitourinary tract is considered to be a target for the actions of sex steroid hormones. Decreased ovarian function and lack of estrogen after menopause are associated with lower genitourinary tract symptoms as well as bladder dysfunctions such as incontinence. Estrogen may also affect urothelial cells. The estrogen receptors (ERs) are found in the mucosa of the urinary tract. The purpose of this study was to culture human urothelial cells (HUCs) originating from urothelial tissue biopsies and to use them as a reproducible test platform to evaluate the effect of 17beta-estradiol (E2).Urothelial tissue biopsies were obtained from 95 patients undergoing gynaecological open surgery for urinary incontinence, paediatric vesicoureteral reflux or transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. HUCs originating from biopsies were cultured in vitro in the absence or in the presence of 0.1 nmol, 0.01 micromol and 1 micromol of E2. ER expression of the cultured HUCs was examined by Western analysis and immunofluorescence microscopy, which was also used for HUC characterization. The effect of E2 in the proliferation of the HUCs was determined by tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-assay.HUCs were cultured successfully in four to six passages but there was variation between samples. The cultured cells showed expression of beta(4)-integrin, E-cadherin and cytokeratins 7, 8, 9 and 19, indicating the epithelial origin of the cells. Both types of ERs, ERalpha and ERbeta, were found in the in vitro cultured HUCs. E2 treatment of HUCs did not affect remarkably the expression of ERalpha but cell proliferation was induced. However, no concentration-dependent effect was seen.This study indicates that HUCs originating from small tissue biopsies can be cultured in several passages in vitro and could have potential in repairing or restoring urinary tract tissue by tissue engineering therapy. HUCs serve as a good in vitro test platform, as shown by analysing E2-treated HUCs. E2 induced the proliferation of cultured HUCs even though concentration dependency was not observed. The findings of this study may have relevance in determining the mechanisms of estrogen therapy in postmenopausal urinary tract symptoms and in the future development of tissue engineering technology.

Calcium wave propagation and connexin 26, 32 and 43 expression were studied in normal and malignant urothelial cells.Human urothelial cell cultures were established from tissue biopsies obtained from three healthy control persons and compared to human transitional cell carcinoma (TCC) cell line 5637. Fluo-3 was used to study intercellular calcium signaling in urothelial cells. The cells were stimulated mechanically in the presence of inhibitors of gap-junctional or ATP-mediated communication to determine which pathways are operative in intercellular calcium signaling. In addition, Gö6976 was used to determine the effects of PKC alpha and betaI inhibition on intercellular calcium signaling.In normal urothelial cells, the primary pathway for intercellular calcium mediated cell signaling was gap junctional intercellular communication (GJIC), but the paracrine ATP-mediated signaling was also operative. In 5637 TCC cells, GJIC and ATP-mediated signaling routes were altered when compared to normal urothelial cells. More specifically, inhibition of GJIC resulted in a complete block of intercellular calcium signaling, while inhibition of ATP-mediated signaling decreased signal transduction in 5637 TCC cells. The results of the present study also demonstrated that connexin 26 was the most abundant gap junction plaque protein in cultured normal human urothelial cells and that it did not form gap junction plaques in 5637 TCC cell culture. Treatment with Gö6976 induced gap junction plaque formation by connexin 26 in 5637 TCC cells. In addition, the exposure to Gö6976 enhanced intercellular calcium mediated signaling in 5637 TCC cells, but not in normal cells.The results of the present study suggest that gap junctions play a major role in intercellular calcium signaling in urothelial cells. In addition, intercellular calcium signaling is altered in urinary bladder carcinoma cells, and it can be improved by PKC alpha and betaI inhibition. (Supplementary materials are available for this article. Go to the publisher's online edition of Cell Communication and Adhesion for the following free supplemental resources; Movie files of Fig. 2normal Gö6976-, normal Gö6976+, TCC Gö6976-, TCC Gö6976+ and image of Supplementary Figure 1).

Changes in activation balance of different protein kinase C (PKC) isoenzymes have been linked to cancer development. The current study investigated the effect of different PKC inhibitors on cellular contacts in cultured high-grade urinary bladder carcinoma cells (5637 and T24). Exposure of the cells to isoenzyme-specific PKC inhibitors yielded variable results: Go6976, an inhibitor of PKCα and PKCβ isoenzymes, induced rapid clustering of cultured carcinoma cells and formation of an increased number of desmosomes and adherens junctions. Safingol, a PKCα inhibitor, had similar but less pronounced effects. In contrast, a PKCδ inhibitor, rottlerin, had an opposite effect on cell clustering and caused dissociation of cell junctions. A broad-spectrum PKC inhibitor bisindolylmaleimide I did not have any apparent effect on the morphology of the cultures or on the number of cell junctions. Additional studies with Go6976 demonstrated that inhibition of PKCα and β isoenzymes induced translocation of β1-integrin from the cell-matrix junctions and that β4-integrin was translocated to face the culture substratum. Go6976 was also highly effective in inhibiting migration of carcinoma cells and inhibited invasion through artificial basement membrane. Our results on urinary bladder carcinoma cells emphasize that Go6976 is a potential anticancer drug due to its effects on cell-cell and cell-matrix junctions, migration, and invasion. Furthermore, the results may be explained by changes in PKC activation balance promoted by inhibition of PKCα/β.

The presence of two spectrally different kinds of rod photoreceptors in amphibians has been hypothesized to enable purely rod-based colour vision at very low light levels. The hypothesis has never been properly tested, so we performed three behavioural experiments at different light intensities with toads (Bufo) and frogs (Rana) to determine the thresholds for colour discrimination. The thresholds of toads were different in mate choice and prey-catching tasks, suggesting that the differential sensitivities of different spectral cone types as well as task-specific factors set limits for the use of colour in these behavioural contexts. In neither task was there any indication of rod-based colour discrimination. By contrast, frogs performing phototactic jumping were able to distinguish blue from green light down to the absolute visual threshold, where vision relies only on rod signals. The remarkable sensitivity of this mechanism comparing signals from the two spectrally different rod types approaches theoretical limits set by photon fluctuations and intrinsic noise. Together, the results indicate that different pathways are involved in processing colour cues depending on the ecological relevance of this information for each task.This article is part of the themed issue ‘Vision in dim light’.

Background Shoulder disorders are common problems in primary health care. The course of disease of patients consulting for a new episode of a shoulder problem has been thought to be benign. In this prospective cohort study, we assessed the one-year consumption of medical resources and clinical outcome of shoulder disorders inclusive of all disease episodes. Methods All individuals consulting primary health care for shoulder disorder in a catchment area of more than 120 000 people were included. A composite questionnaire including the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) was used to measure use of resources as well as shoulder pain and function. A follow-up assessment was performed after one year. Results A total of 128 individuals responded to the questionnaire. Only 24% of the patients had recovered after one year. Mean shoulder pain (Visual analogue scale, VAS, max 100 mm) decreased from 38.9 mm to 28.6 mm (95% CI -16.3 to -4.2 mm). The ASES score (max 100) improved significantly from 59.9 to 70.2 (95% CI 5.3 to 15.3). Mean one-year consumption of medical resources after the index consultation was 1.5 consultations, 0.5 radiological examinations, and 3.3 visits to physiotherapist. Mean resource-weighted direct costs were €543/patient/year (95% CI €351 to 735). Conclusions Shoulder disorders are often chronic and require a significant amount of resources from the health care system. The clinical outcome of the management of shoulder disorders in our study population including also individuals who have consulted previously for a shoulder problem is notably poorer than the one reported by previous studies on new episodes. However, despite the relatively modest outcome, subjective disability is low.