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Globally, the majority of dairy cows are milked twice a day (TAD); however, in pasture-based production systems, such as in Ireland, the idea of milking once a day (OAD) is being considered for reasons such as improved work-life balance. The immediate effects within a lactation, as well as the multilactation consequences of OAD, compared with TAD milking, require understanding. The objective of this randomized experiment was to compare OAD and TAD milking, over a 3-yr period, by examining the differences in milk production and composition, body weight (BW), body condition score (BCS), dry matter intake (DMI), udder characteristics, locomotion score, and milking time. Over the 3-yr period, 83 cows were enrolled in the experiment; 32, 44, and 48 cows in yr 1, 2, and 3 of the experiment, respectively. Each year, 23% of the herds were primiparous animals, while the remainder were second lactation or greater in parity. All cows were milked in the morning at 0700 h; only cows milked TAD were milked a second time each day at 1600 h. Cows rotationally grazed pastures for the duration of the lactating period and were housed during the nonlactating period. Milking cows OAD reduced cumulative milk yield by 26%, and milk solids yield (kg of fat + kg of protein) by 21%, across the 3 yr of the experiment when compared with cows milked TAD which produced 4,126 and 365 kg/cow, respectively. A contributory factor to the reduced production was a shorter lactation length (9.7 d) of the cows milked OAD compared with TAD (294 d). Milk fat percent of cows milked TAD was similar for all 3 yr of the study (5.05%), whereas milk fat percent of the cows milked OAD increased year on year, with each year being greater than the previous year (5.02%, 5.32%, and 5.70% for yr 1, 2, and 3; respectively). Milk protein percent was greater (+0.19%) for cows milked OAD compared with TAD which was 3.78%. Compared with cows milked TAD, total DMI for cows milked OAD was 22% less at the start of lactation (<167 d), but as the lactation progressed (>167 d) we observed no difference in DMI between treatments. Similar to the literature, milking cows OAD significantly increased average somatic cell score, both during (+16%) and at the end of lactation (+19%), compared with milking cows TAD which were 4.69 and 4.79, respectively. We detected positive aspects associated with OAD milking such as greater BW, BCS, and fertility performance. Milking OAD reduced both milking time per cow per day (reductions ranged from 34% in the first 4 mo of lactation to 43% during mo 5–9 of lactation) and milking time per liter of milk (−3.5 s/L) throughout lactation, leading to less labor inputs on-farm which can have positive implications for farmer work-life balance. The significant time saving and potential savings in costs (e.g., electricity) need to be considered in conjunction with the milk production reduction when considering OAD milking for the entire lactation. [ABSTRACT FROM AUTHOR]

Silk is an important communication medium for spiders with roles in species recognition, sex identification, and mating status assessment. Spiders may benefit by discriminating between their own or another same‐sex conspecific's silk. Silk‐mediated self‐recognition could allow spiders to identify areas that they have previously visited, competitively block silk advertisements from sexual rivals or minimize redundant signaling in an area. Silk deposition behavior may also be contingent upon silk cues detected from same‐sex conspecifics. We tested if males and females of the wolf spider Pardosa milvina show different silk deposition patterns when encountering their own silk versus the silk of another spider of the same sex. Using a within‐between‐subjects design, we quantified male and female deposition of three silk types: draglines, cord silk, and attachment disks on substrates containing either their own silk or the silk of an adult same‐sex conspecific (N = 23 males, 28 females). Both males and females significantly increased dragline and cord silk deposition on substrates containing conspecific rather than their own silk with males producing more cord silk than females. Males significantly increased attachment disk deposition on conspecific male silk compared to their own while females showed the opposite response, decreasing attachment disk deposition on conspecific female silk. Both male and female P. milvina can recognize their own silk, but we found significant qualitative and quantitative sex differences in silk deposition suggesting sex‐specific functions for attachment disks compared to cord or dragline silk. [ABSTRACT FROM AUTHOR]

Random alloy fluctuations significantly affect the electronic, optical, and transport properties of (In,Ga)N-based optoelectronic devices. Transport calculations accounting for alloy fluctuations currently use a combination of modified continuum-based models, which neglect to a large extent atomistic effects. In this work, we present a model that bridges the gap between atomistic theory and macroscopic transport models. To do so, we combine atomistic tight-binding theory and continuum-based drift–diffusion solvers, where quantum corrections are included via the localization landscape method. We outline the ingredients of this framework in detail and present first results for uni-polar electron transport in single and multi- (In,Ga)N quantum well systems. Overall, our results reveal that both random alloy fluctuations and quantum corrections significantly affect the current–voltage characteristics of uni-polar electron transport in such devices. However, our investigations indicate that the importance of quantum corrections and random alloy fluctuations can be different for single and multi-quantum well systems. [ABSTRACT FROM AUTHOR]

Understanding the impact of the alloy micro-structure on carrier transport becomes important when designing III-nitride-based light emitting diode (LED) structures. In this work, we study the impact of alloy fluctuations on the hole carrier transport in (In,Ga)N single and multi-quantum well systems. To disentangle hole transport from electron transport and carrier recombination processes, we focus our attention on uni-polar (p-i-p) systems. The calculations employ our recently established multi-scale simulation framework that connects atomistic tight-binding theory with a macroscale drift-diffusion model. In addition to alloy fluctuations, we pay special attention to the impact of quantum corrections on hole transport. Our calculations indicate that results from a virtual crystal approximation present an upper limit for the hole transport in a p-i-p structure in terms of the current-voltage characteristics. Thus we find that alloy fluctuations can have a detrimental effect on hole transport in (In,Ga)N quantum well systems, in contrast to uni-polar electron transport. However, our studies also reveal that the magnitude by which the random alloy results deviate from virtual crystal approximation data depends on several factors, e.g. how quantum corrections are treated in the transport calculations. [ABSTRACT FROM AUTHOR]

In the spinal cord, classes of interneurons have been studied in vitro to determine their role in producing or regulating locomotion. It is unclear whether all locomotor behaviors are produced by the same circuitry or engage different subsets of neurons. Here, in neonatal mice of either sex, we test this idea by comparing the actions of a class of spinal, inhibitory interneuron (V1) expressing channelrhodopsin driven by the engrailed-1 transcription factor on the rhythms elicited by different methods. We find that, although the overall locomotor activities in vitro are similar, V1 interneuron depolarization produces opposite effects depending of the mode of activation of the locomotor circuitry. The differential behavior of V1 neurons suggests that their function depends on how the locomotor rhythm is activated and is consistent with the idea that the functional organization of the corresponding locomotor networks also differs. [ABSTRACT FROM AUTHOR]

In the mouse spinal cord, V1 interneurons are a heterogeneous population of inhibitory spinal interneurons that have been implicated in regulating the frequency of the locomotor rhythm and in organizing flexor and extensor alternation. By introducing archaerhodopsin into engrailed-1-positive neurons, we demonstrate that the function of V1 neurons in locomotor-like activity is more complex than previously thought. In the whole cord, V1 hyperpolarization increased the rhythmic synaptic drive to flexor and extensor motoneurons, increased the spiking in each cycle, and slowed the locomotor-like rhythm. In the hemicord, V1 hyperpolarization accelerated the rhythm after an initial period of tonic activity, implying that a subset of V1 neurons are active in the hemicord, which was confirmed by calcium imaging. Hyperpolarizing V1 neurons resulted in an equalization of the duty cycle in flexor and extensors from an asymmetrical pattern in control recordings in which the extensor bursts were longer than the flexor bursts. Our results suggest that V1 interneurons are composed of several subsets with different functional roles. Furthermore, during V1 hyperpolarization, the default state of the locomotor central pattern generator (CPG) is symmetrical, with antagonist motoneurons each firing with an approximately 50% duty cycle. We hypothesize that one function of the V1 population is to set the burst durations of muscles to be appropriate to their biomechanical function and to adapt to the environmental demands, such as changes in locomotor speed. [ABSTRACT FROM AUTHOR]

We show the importance of using a thermodynamically consistent flux discretization when describing drift–diffusion processes within light emitting diode simulations. Using the classical Scharfetter–Gummel scheme with Fermi–Dirac statistics is an example of such an inconsistent scheme. In this case, for an (In,Ga)N multi quantum well device, the Fermi levels show an unphysical hump within the quantum well regions. This result originates from neglecting diffusion enhancement associated with Fermi–Dirac statistics in the numerical flux approximation. For a thermodynamically consistent scheme, such as the SEDAN scheme, the humps in the Fermi levels disappear. We show that thermodynamic inconsistency has far reaching implications on the current–voltage curves and recombination rates. [ABSTRACT FROM AUTHOR]

The expansion of the Worsley Alumina refinery in Western Australia from an annual output of 3.5–4.6 million tonnes of alumina per annum provided the incentive for increased efficiencies in both the refinery process and the steam raising plant. The multi-fuel cogeneration (MFC) power station was installed to meet the additional steam requirement and to improve the use of energy per unit of alumina produced. The power station is capable of providing 605 t/h of process steam at two pressure levels while developing 113.6 MW of electrical power from two boiler/turbine units. A reheat steam cycle was implemented by integrating the high-pressure cylinder of a utility steam turbine with an industrial back-pressure extraction machine. When compared to the capability of the older coal-fired (CF) power station, the cycle and plant configuration selected provides a 37% increase in the electrical power generated per tonne of process steam supplied to the refinery. The main source of fuel is a local semi-bituminous coal that prescribes the installation of efficient plant to limit carbon dioxide emissions. Fuel flexibility is provided by circulating fluidised bed boiler units that enable the provision of up to 30% of the heat input from biomass. Greenhouse gas emissions from the MFC power station are some 10% less per unit of process steam than those from the older CF power station. Firing biomass in the MFC power station further reduces the carbon foot print. Boiler feed water is provided by condensate returned from the process that has total organic carbon levels some two orders of magnitude greater than that permitted by international boiler water standards for the 16.0 MPa(g) units. Boiler water chemistry is based on caustic treatment. Amine dosing is applied to the feed water obtained from selected condensate streams. [ABSTRACT FROM AUTHOR]

In this podcast, we talk to Professor Michael O'Donovan about the latest genetic advances in schizophrenia based on research data from the Schizophrenia Working Group of the Psychiatric Genomics Consortium. Functional and prediction studies from the identified genetic loci are described together with future directions in psychiatric genetics and its interplay with the environment. [ABSTRACT FROM AUTHOR]

Nitrous oxide (N2O) has been widely used as a dental and surgical anaesthetic for over 150 years. However, results from a recent study suggested that increased DNA damage was seen in lymphocytes from surgical patients and this led to its continued clinical use to be questioned. The data can be challenged on technical grounds and must be considered with other studies in order to assess any possible risk. There are other studies indicating that N2O has weak genotoxicity in man, but these are confused by exposure of the populations to other anaesthetic gases including isoflurane and sevoflurane, both of which have also been reported to increase DNA damage. It should be noted that the suggested genotoxic mechanisms are all indirect, including folate deficiency, oxidative stress and homocysteine toxicity. Further, results from in vitro studies indicate that N2O has no direct DNA reactivity as negative results were obtained in a bacterial mutation (Ames) test and an assay for mutation at the hprt locus in Chinese hamster lung cells. Although not performed to definitive study designs, no evidence of carcinogenicity was seen in two long-term tests in mice and another in rats. Although there is some evidence that N2O is weakly genotoxic in humans, this appears to be similar to that reported for isoflurane and sevoflurane and all the postulated mechanisms have clear thresholds with no evidence of direct DNA reactivity. Because any potential genotoxic mechanism would have a threshold, it seems reasonable to conclude that neither occasional high exposure to patients as an anaesthetic nor low-level exposure to staff within published recommended exposure limits presents any significant carcinogenic risk. [ABSTRACT FROM AUTHOR]

The fluorescent tracer Fluoro-Gold has been widely used to label neurons retrogradely. Here we show that Fluoro-Gold can also enter neurons through AMPA receptor endocytosis. We found that a 30 minute application of Fluoro-Gold to the isolated spinal cord labeled neurons under control conditions and in the presence of glutamatergic agonists including NMDA and AMPA. The labeling was abolished or greatly reduced by glutamatergic antagonists and the endocytic inhibitors Dynasore and dynamin inhibitory peptide. Whole cell recordings from spinal neurons exposed to extracellular AMPA revealed large inward currents that spontaneously decayed in the presence of the agonist but were maintained when a dynamin inhibitory peptide was included in the electrode. These findings suggest that Fluoro-Gold enters spinal neurons through AMPA-mediated receptor internalization. Drugs used to induce locomotor-like activity in the spinal cord also increased and decreased Fluoro-Gold labeling in a drug and lamina specific manner, indicating that AMPAR endocytosis is altered in the presence of the locomotor cocktail. Our findings suggest that endocytosis of Fluoro-Gold could potentially complicate the interpretation of experiments in which the tracer is used to label neurons retrogradely. Moreover, they also demonstrate that many drugs, including the locomotor cocktail, can modulate the number and/or the composition of AMPA receptors on spinal neurons and thereby affect network excitability. [ABSTRACT FROM AUTHOR]

It has been several decades since synaptic dysfunction was first suggested to play a role in schizophrenia, but only in the last few years has convincing evidence been obtained as progress has been made in elucidating the genetic underpinnings of the disorder. In the intervening years much has been learned concerning the complex macromolecular structure of the synapse itself, and genetic studies are now beginning to draw upon these advances. Here we outline our current understanding of the genetic architecture of schizophrenia and examine the evidence for synaptic involvement. A strong case can now be made that disruption of glutamatergic signalling pathways regulating synaptic plasticity contributes to the aetiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Recently, we described a new method for representing and analyzing the connectivity of a motoneuronal network. We used it to deduce a connectivity model for the neuromuscular network that generates locomotion in the nematode Caenorhabditis elegans. The network regulates muscle contraction and for this reason we used the location or function of body wall muscles to map every element (neuron or muscle cell) in a new framework, namely the peri-motor space. The previously published connectivity data for C. elegans locomotion network are incomplete; in particular, the connectivity of motoneurons in the posterior half of the animal is missing or partial. When we analyzed the connectivity data for motoneurons in the anterior half, we detected repeating patterns which we named iterativity. We analyzed the iterativity of each class of motoneuron and statistically validated that it is higher than expected by chance. We could then extrapolate the iteration into the posterior half. Here we will explain the new terms and elaborate on the process of analysis and the features of the new connectivity model. [ABSTRACT FROM AUTHOR]

The neuronal connectivity dataset of the nematode Caenorhabditis elegans attracts wide attention from computational neuroscientists and experimentalists. However, the dataset is incomplete. The ventral and dorsal nerve cords of a single nematode were reconstructed halfway along the body and the posterior data are missing, leaving 21 of 75 motoneurons of the locomotor network with partial or no connectivity data. Using a new framework for network analysis, the perimotor space, we identified rules of connectivity that allowed us to approximate the missing data by extrapolation. Motoneurons were mapped into perimotor space in which each motoneuron is located according to the muscle cells it innervates. In this framework, a pattern of iterative connections emerges which includes most (0.90) of the connections.Weidentified a repeating unit consisting of 12 motoneurons and 12 muscle cells. The cell bodies of the motoneurons of such a unit are not necessarily anatomical neighbors and there is no obvious anatomical segmentation. A connectivity model, composed of six repeating units, is a description of the network that is both simplified (modular and without noniterative connections) and more complete (includes the posterior part) than the original dataset. The perimotor framework of observed connectivity and the segmented connectivity model give insights and advance the study of the neuronal infrastructure underlying locomotion in C. elegans. Furthermore, we suggest that the tools used herein may be useful to interpret, simplify, and represent connectivity data of other motor systems. [ABSTRACT FROM AUTHOR]

Abstract: Boronic acids and their esters are important building blocks in organic syntheses including those for drug substances and for which, as far as it can be determined, there are no published reports of testing for genotoxicity. A number of boronic acids have now been tested in this laboratory using Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA(pKM101). Twelve of the 13 structures presented here were found to be mutagenic. All the compounds except one were active only in TA100 and/or WP2uvrA(pKM101), did not require S9 activation and produced relatively weak responses, i.e. no more than seven times the concurrent solvent-control values at >1000μg/plate. The single exception was also weakly mutagenic for TA1537 in the presence of S9. Results with two compounds mutagenic for both TA100 and WP2uvrA(pKM101) showed no evidence of DNA-adduct formation detectable by 32P-postlabelling. It appears that boronic acids represent a novel class of bacterial mutagen that may not act by direct covalent binding to DNA. However, their mechanism of action remains to be elucidated and it cannot yet be determined whether or not they present a real genotoxic hazard. [Copyright &y& Elsevier]

Abstract: At the laboratories of AstraZeneca, Alderley Park, UK the reference genotoxic agents etoposide (a topoisomerase II inhibitor), cadmium chloride (an inorganic carcinogen), colchicine (an aneugen that inhibits tubulin polymerisation), benzo[a]pyrene (a metabolism dependent reference genotoxin) and cyclophosphamide (a metabolism dependent reference genotoxin) were tested in the in vitro micronucleus assay (MNvit), using mouse lymphoma L5178Y cells, with and without cytokinesis block. Further, 2-aminoanthracene (a metabolism dependent weak clastogen) was tested in the MNvit, using TK6 cells, without cytokinesis block. This was done in support of the toxicity (cell death and cytostasis) measures recommended in the late 2007 version of the draft OECD Test Guideline 487 for the testing of chemicals. All six reference agents were positive in the MNvit without cytokinesis block at concentrations giving approximately 50% toxicity or less as defined by draft Test Guideline 487 recommended measures, relative population doublings and relative increase in cell counts. Furthermore, the five agents tested with cytokinesis block were positive in the MNvit at concentrations giving approximately 50% toxicity or less as assessed by replicative index. Accordingly, this work supports the premise that relative population doublings and relative increase in cell counts are appropriate measures of toxicity for the non-cytokinesis-blocked in vitro micronucleus assay. [ABSTRACT FROM AUTHOR]

Multifunctional motoneurons and muscles, which are active during forward and backward locomotion are ubiquitous in animal models. However, studies in the nematode Caenorhabditis elegans suggest that some locomotor motoneurons are necessary only for forward locomotion (dorsal B-motoneurons, DB), while others (dorsal A-motoneurons, DA) are necessary only for backward locomotion. We tested this hypothesis directly by recording the activity of these motoneurons during semirestrained locomotion. For this purpose, we used epifluorescence imaging of the genetically encoded calcium sensor cameleon, expressed in specific motoneurons, while monitoring locomotor behavior through the microscope condenser using a second camera. We found that ventral and dorsal B-motoneurons (DB and VB) were coactive during forward locomotion while ventral A-motoneurons (VA) were only active during backward locomotion. The signals we recorded correlated with the direction of locomotion but not with the faster undulatory cycles. To our knowledge, these are the first recordings of motoneuron activity in C. elegans and the only direction-dedicated motoneurons described to date. [ABSTRACT FROM AUTHOR]

It has recently been demonstrated that motoneurons in neonatal rodents release an excitatory amino acid, in addition to acetylcholine, from their central terminals onto Renshaw cells. Although the function of this amino acid release is not understood, it may mediate the excitatory actions of motor axon stimulation on spinal motor networks. Stimulation of motor axons in the ventral roots or muscle nerves can activate the locomotor central pattern generator or entrain bursting in the disinhibited cord. Both of these effects persist in the presence of cholinergic antagonists and are abolished or diminished by ionotropic and metabotropic glutamate antagonists. Calcium imaging in the disinhibited cord shows that a ventral root stimulus evokes ventrolateral activity initially, which subsequently propagates to the rest of the cord. This finding suggests that excitatory interneurons excited by motoneuron recurrent collaterals are located in this region. However, motoneurons do not exhibit short latency excitatory potentials in response to ventral root stimulation indicating that the excitatory effects are mediated polysynaptically. We discuss the significance of these findings. [ABSTRACT FROM AUTHOR]

The major psychotic illnesses, schizophrenia and bipolar disorder (BD), are among the most heritable common disorders, but finding specific susceptibility genes for them has not been straightforward. The reasons are widely assumed to include lack of valid phenotypic definition, absence of good theories of pathophysiology for candidate gene studies, and the involvement of many genes, each making small contributions to population risk. Within the last year or so, a number of genome wide association (GWAS) of schizophrenia and BD have been published. These have produced stronger evidence for association to specific risk loci than have earlier studies, specifically for the zinc finger binding protein 804A (ZNF804A) locus in schizophrenia and for the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) and ankyrin 3, node of Ranvier (ANK3) loci in bipolar disorder. The ZNF804A and CACNA1C loci appear to influence risk for both disorders, a finding that supports the hypothesis that schizophrenia and BD are not aetiologically distinct. In the case of schizophrenia, a number of rare copy number variants have also been detected that have fairly large effect sizes on disease risk, and that additionally influence risk of autism, mental retardation, and other neurodevelopmental disorders. The existing findings point to some likely pathophysiological mechanisms but also challenge current concepts of disease classification. They also provide grounds for optimism that larger studies will reveal more about the origins of these disorders, although currently, very little of the genetic risk of either disorder is explained. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci. [ABSTRACT FROM AUTHOR]

Abstract: Appropriate measures of cytotoxicity need to be used when selecting test concentrations in in vitro genotoxicity assays. Underestimation of toxicity may lead to inappropriately toxic concentrations being selected for analysis, with the potential for generation of irrelevant positive results. As guidance for the in vitro micronucleus test is being developed, it is clearly important to compare the different measures of cytotoxicity that can be used both with and without cytokinesis blocking. Therefore, relative cell counts (RCC), relative increase in cell counts (RICC) and relative population doubling (RPD) for treatments without cytokinesis block were compared with replication index (RI) for treatments with cytokinesis block, and the corresponding induction of micronucleated cells was evaluated. A wide range of chemicals and gamma irradiation were used, and in almost all cases, RCC underestimated cytotoxicity when compared with all other measures such that RCC would have resulted in the selection of inappropriately high concentrations for micronuclei analysis. In the absence of cytokinesis block, RICC or RPD is more comparable with RI with cytokinesis block, and therefore considered more appropriate measure of survival. Furthermore, using these estimations of cytotoxicity and the limit of 50% survival, all the mutagens and aneugens tested were appropriately identified as positive in the in vitro micronucleus assay. Accordingly, it was clear that testing beyond 50% survival was not necessary to identify the potential of these agents to induce micronuclei. [Copyright &y& Elsevier]

Abstract: The objective of this study is to investigate the effect of contrasting spring grazing dates (GD) and stocking rate (SR) on sward characteristics, grass dry matter intake and milk production performance of autumn calving dairy cows during the spring period. Two swards were created by grazing in March (early grazing; E) or by delaying first grazing until mid-April (late grazing; L). Two stocking rates, high (H; 5.5) and medium (M; 4.5) were applied across each sward. Forty eight autumn calving Holstein cows (160±35 days in milk) were assigned to one of four (n =12) different grazing treatments. The experiment began on April 17th and finished after 2 grazing rotations on June 20th. Later spring grazing significantly increased herbage mass (kg DM/ha) above ground level (+933, P <0.05) and >50 mm (+738, P <0.05). Compressed sward height (+22.1 mm, P <0.05), extended tiller height (+73 mm, P <0.001) and pseudostem height (+35 mm, P <0.001) were also significantly higher for later grazed swards. In the grazing horizon (>80 mm— extended tiller height), later grazed swards had significantly lower leaf proportion (−0.09, P <0.05) and higher dead material (+0.05, P <0.001). Daily herbage allowance (>50 mm) was on average 12.7, 15.9, 18.2 and 21.9 kg DM/cow for EH, EM, LH and LM, respectively. Daily leaf allowance (>80 mm) was 10.1, 12.3, 13.3 and 14.5 kg DM/cow for EH, EM, LH and LM, respectively. The EM (16.2 kg DM/cow), LH (+0.1 kg) and LM (0.8 kg) treatments all had similar grass DM intake, however there was evidence of an interaction (P <0.10) between GD and SR, this was due to the low grass DM intake of the EH (13.9 kg DM/cow) treatment. When expressed as UFL (Fill unit) intake the EM treatment recorded the highest value. There was a significant interaction between GD and SR (P <0.01) for milk, protein yield, 4% fat corrected milk yield (P <0.05) and protein concentration (P <0.001). Cows grazing the EM treatment produced 23.9 kg of milk, 876 and 685 g of fat and protein yield. The difference in milk production (cow/day) between EM and EH treatments was +3.6 kg milk, +98 g fat and +107 g protein. The production yield difference between LM and LH treatments was +1.1 kg milk, +27 g fat and +29 g protein in favour of the LM treatment (23.9 kg of milk, 877 and 687 g fat and protein yield). Herbage quality and morphological characteristics are clearly improved with early spring grazing as herbage mass is reduced on subsequent rotations. Swards grazed in early spring allow higher grass utilisation and high milk production performance when grazed at a medium stocking rate. Improved milk production from herbage can be achieved provided herbage mass and allowance are maintained at levels where herbage quality decreases are minimised. [Copyright &y& Elsevier]

Abstract: Screen-printed carbon electrodes (SPCEs) have been investigated as possible sensors to identify γ-irradiation induced oxidative damage in double stranded (ds) DNA. Studies were undertaken to explore the possibility of using both cyclic voltammetry and differential pulse voltammetry to identify changes due to oxidative damage. Initially, guanine, adenine and 8-oxoguanosine were examined and it was found possible to differentiate them from their voltammetric responses. The voltammetric response of 8-oxoguanosine was found to be linear over the concentration range 1–400μM, with a slope of 0.0296μAμM−1 (R 2 value of 0.9984), in the presence of 2mM concentrations of guanine and adenine. Investigations were made into harnessing these findings to identify oxidative damage in γ-irradiated dsDNA. The presence of oxidative damage in these samples was readily identifiable, and the magnitude of the voltammetric response was found to be dose dependant (R 2 =0.9919). A simple sample preparation step involving only the dissolution of double stranded DNA sample in the optimised electrolyte (0.1M acetate buffer pH 4.5) was required. This report appears to be first describing the use of a SPCE to detect DNA damage which can be related to the dose of γ-radiation used. [Copyright &y& Elsevier]

Reading reflects the complex integration of several cognitive processes and proves more difficult to achieve for a significant proportion of the population. Developmental dyslexia (DD), or specific reading disability, is influenced by genes, a fact that has led several research groups to attempt to identify susceptibility genes through the sequential analysis of genetic linkage and association. Strong evidence has now emerged for the presence of genes influencing DD at several chromosomal loci and for at least one of these, there is evidence implicating specific genes. In this review, we present the evidence for a genetic contribution to DD and its component processes and review the current status of molecular genetic research aimed at identifying susceptibility genes for this common, complex disorder.European Journal of Human Genetics (2006) 14, 681–689. doi:10.1038/sj.ejhg.5201575 [ABSTRACT FROM AUTHOR]

B Background: b MicroRNAs (miRNAs) are a class of small (18-25 nucleotide) non-coding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translational repression. Given the importance of miRNAs in brain development, identifying sex biased miRNA expression may be highly informative for understanding both brain sex differences and mechanisms underpinning psychiatric disorders. B Discussion: b This study begins to disentangle sex differences in microRNA expression in the fetal brain, which could contribute to sexual dimorphism in brain function and risk for neurodevelopmental disorders. [Extracted from the article]

People with schizophrenia are more likely to develop type 2 diabetes than the general population. Although an increased risk of diabetes has been attributed to environmental determinants such as diet, lifestyle and antipsychotic drugs, the association between these two disorders was noticed well before the advent of current lifestyles and pharmacological interventions, raising the possibility of a shared genetic basis. Schizophrenia and type 2 diabetes are common diseases with a complex mode of inheritance which includes both genetic factors and environmental determinants. As susceptibility genes for both type 2 diabetes and schizophrenia are beginning to be identified there is increasing interest in the possibility of shared susceptibility loci between the two conditions. This article reviews the genetic basis to schizophrenia and type 2 diabetes and discusses the potential for shared loci between both conditions. [ABSTRACT FROM PUBLISHER]

The article reviews the current genetic evidence linking two of the mostly widely studied genes, namely, dysbindin-1 and neuregulin-1, to schizophrenia. Research suggest dysbindin might influence schizophrenia risk through presynaptic mechanisms that are independent of the dystrophin-associated protein complex and involve glutamatergic neurotransmission, defects in which have been implicated in schizophrenia. Meanwhile, it has been proposed that neuregulin might influence disease susceptibility by changing the expression and activities of a wide range of neurotransmitter receptors, particularly N-methyl-D-aspartate glutamatergic receptors.

Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified a number of potential regions of linkage and 2 associated chromosomal abnormalities, and accumulating evidence favors several positional candidate genes. These findings are grounds for optimism that insight into genetic factors associated with schizophrenia will help further our understanding of this disease and contribute to the development of new ways to treat it. [ABSTRACT FROM AUTHOR]

Genes that encode synaptic proteins or messenger RNA targets of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein) have been linked to schizophrenia and autism spectrum disorder (ASD) through the enrichment of genetic variants that confer risk for these disorders. FMRP binds many transcripts with synaptic functions and is thought to regulate their local translation, a process that enables rapid and compartmentalized protein synthesis required for development and plasticity. We used summary statistics from large-scale genome-wide association studies of schizophrenia (74,776 cases, 101,023 controls) and ASD (18,381 cases, 27,969 controls) to test the hypothesis that the subset of synaptic genes that encode localized transcripts is more strongly associated with each disorder than nonlocalized transcripts. We also postulated that this subset of synaptic genes is responsible for associations attributed to FMRP targets. Schizophrenia associations were enriched in genes encoding localized synaptic transcripts compared to the remaining synaptic genes or to the remaining localized transcripts; this also applied to ASD associations, although only for transcripts observed after stimulation by fear conditioning. The genetic associations with either disorder captured by these gene sets were independent of those derived from FMRP targets. Schizophrenia association was related to FMRP interactions with messenger RNAs in somata, but not in dendrites, while ASD association was related to FMRP binding in either compartment. Our data suggest that synaptic transcripts capable of local translation are particularly relevant to the pathogenesis of schizophrenia and ASD, but they do not characterize the associations attributed to current sets of FMRP targets. [ABSTRACT FROM AUTHOR]

The purpose of this study was to characterise the metabolome of bovine colostrum and milk in the initial days of lactation. Colostrum and milk samples were collected from 18 cows representing an even spread of 1st, 2nd and 3rd lactation (n = 6) over the first 6 days of lactation. Samples were subsequently analysed using 1H-NMR. The metabolome of defatted colostrum and milk in the days immediately post parturition was demonstrated to be complex and changed significantly over time. The colostrum was rich in nutrients beneficial for growth and development of the new-born mammal with significantly higher levels of essential branched chain amino acids and choline and orotic acid that decreased in the subsequent days as milk composition evolved to that of regular milk. Multivariate analysis of metabolome profiles using PLS-DA was demonstrated to clearly distinguish between colostrum and subsequent milk samples. [ABSTRACT FROM AUTHOR]

Milk was collected from each of 18 cows (presenting an even spread of 1st, 2nd and 3rd lactation): colostrum on the day of calving and subsequent morning milk 1–5 days post parturition. Days post parturition significantly affected the fatty acid profile of colostrum and transition milk samples. The colostrum fatty acid profile was distinctly different from that of mature milk, with significantly higher levels of polyunsaturated and saturated fatty acids. Parity of the cow had a significant effect on the fatty acid profile of colostrum and transition milk samples; conjugated linoleic acid was significantly higher in cows entering their 1st lactation than in those in their 3rd lactation, while multiparous cows produced significantly higher concentrations of C16:0. The changing composition of the fatty acid profile can be classed into three distinct phases: colostrum (D0), transition milk (D1 and D2 post parturition) and mature milk (D3–D5). [ABSTRACT FROM AUTHOR]

This study investigated the effects of once‐a‐day (OAD) and twice‐a‐day (TAD) milking strategies on Cheddar cheese properties, within an Irish pasture‐based system. Cheese derived from OAD milk was more yellow, with significantly higher b* values and a significantly higher β‐carotene content. A significantly higher cheese yield also resulted from OAD milk. Compositional data were largely consistent with previously reported results, and no meaningful differences were found in texture, proteolysis, pH, volatile‐organic‐compounds and free‐fatty‐acid profile. Indications are that OAD milking does not negatively impact Cheddar quality, providing valuable insights for those considering milking frequency impacts on this key dairy product. [ABSTRACT FROM AUTHOR]

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (β = −0.054, SE = 0.019, P -value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2 , which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (β = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles. [ABSTRACT FROM AUTHOR]

Investigates whether synaptic depression can endow networks with novel and unexpected dynamic properties. Effect of release probability on transient and steady response; Minimal model for synaptic depression; Depression and temporal coding over rate encoding; Synaptic depression as a rhythmogenic mechanism.

Colostrum, the first postpartum secretion of the mammary gland, plays a vital role in the nutrition, development, and immunity of a newborn calf. We characterised the protein profile as milk transitions from colostrum to transition milk over the first 5 days of lactation, collecting samples on d0, d2 and d5 after calving. Protein concentration decreased significantly after d0 (colostrum) before stabilising. Principal component analysis revealed samples clustered by day postpartum, with a limited effect from parity. In total, 471 proteins were identified across all samples; 199 protein groups showed altered relative abundance by day of lactation (fold change ≥2, P < 0.05), but none were altered significantly by parity. Higher relative levels of immune proteins were found in colostrum, and milk fat globule membrane proteins were found to increase over early lactation. Our findings provide a better understanding of the dynamics of the protein profile of bovine milk in early lactation. [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety are the most common mental health problems in young people. Currently, clinicians are advised to wait before initiating treatment for young people with these disorders as many spontaneously remit. However, others develop recurrent disorder but this subgroup cannot be identified at the outset. We examined whether psychiatric polygenic scores (PGS) could help inform stratification efforts to predict those at higher risk of recurrence. Methods: Probable emotional disorder was examined in two UK population cohorts using the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ). Those with emotional disorder at two or more time points between ages 5 and 25 years were classed as 'recurrent emotional disorder' (n = 1,643) and those with emotional disorder at one time point as having 'single episode emotional disorder' (n = 1,435, controls n = 8,715). We first examined the relationship between psychiatric PGS and emotional disorders in childhood and adolescence. Second, we tested whether psychiatric PGS added to predictor variables of known association with emotional disorder (neurodevelopmental comorbidity, special educational needs, family history of depression and socioeconomic status) when discriminating between single‐episode and recurrent emotional disorder. Analyses were conducted separately in individuals of European and South Asian ancestry. Results: Probable emotional disorder was associated with higher PGS for major depressive disorder (MDD), anxiety, broad depression, ADHD and autism spectrum disorder (ASD) in those of European ancestry. Higher MDD and broad depression PGS were associated with emotional disorder in people of South Asian ancestry. Recurrent, compared to single‐episode, emotional disorder was associated with ASD and parental psychiatric history. PGS were not associated with episode recurrence, and PGS did not improve discrimination of recurrence when combined with clinical predictors. Conclusions: Our findings do not support the use of PGS as a tool to assess the likelihood of recurrence in young people experiencing their first episode of emotional disorder. [ABSTRACT FROM AUTHOR]

Low-heat skim milk powder (LHSMP) was manufactured on 3 separate occasions in mid lactation (ML, July 4–20) and late lactation (LL, September 27 to October 7) from bulk milk of 3 spring-calving dairy herds on different feeding systems: grazing on perennial ryegrass (Lolium perenne L.) pasture (GRO), grazing on perennial ryegrass and white clover (Trifolium repens L.) pasture (GRC), and housed indoors and offered total mixed ration (TMR). The resultant powders (GRO-SMP, GRC-SMP, and TMR-SMP) were evaluated for composition and color and for the compositional, physicochemical, and processing characteristics of the reconstituted skim milk (RSM) prepared by dispersing the powders to 10% (wt/wt) in water. Feeding system significantly affected the contents of protein and lactose, the elemental composition, and the color of the LHSMP, as well as the rennet gelation properties of the RSM. The GRO and GRC powders had a higher protein content; lower levels of lactose, iodine, and selenium; and a more yellow-green color (lower a* and higher b* color coordinates) than TMR powder. On reconstitution, the GRO-RSM had higher concentrations of protein, casein, and ionic calcium, and lower concentrations of lactose and nonprotein nitrogen (% of total N). It also produced rennet gels with a higher storage modulus (G′) than the corresponding TMR-RSM. These effects were observed over the combined ML and LL period but varied somewhat during the separate ML and LL periods. Otherwise, feeding system had little or no effect on proportions of individual caseins, concentration of serum casein, casein micelle size, casein hydration, heat coagulation time, or ethanol stability of the RSM at pH 6.2 to 7.2, or on the water-holding capacity, viscosity, and flow behavior of stirred yogurt prepared by starter-induced acidification of RSM. The differences in the functionality of the LHSMP may be of greater or lesser importance depending on the application and the conditions applied during the processing of the RSM. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the impact of increasing proportions of grazed pasture in the diet on the composition, quality, and functionality of bovine milk across a full lactation. Fifty-four spring-calving cows were randomly assigned to 1 of 3 groups (n = 18), blocked on the basis of mean calving date (February 15, 2020 ± 0.8 d), pre-experimental daily milk yield (24.70 ± 3.70 kg), milk solids yield (2.30 ± 0.27 kg), lactation number (3.10 ± 0.13), and economic breeding index (182 ± 19). Raw milk samples were obtained weekly from each group between March and November 2020. Group 1 (GRS) consumed perennial ryegrass and was supplemented with 5% concentrates (dry matter basis); group 2 was maintained indoors and consumed a total mixed ration (TMR) diet consisting of maize silage, grass silage, and concentrates; and group 3 consumed a partial mixed ration diet (PMR), rotating between perennial ryegrass during the day and indoor TMR feeding at night. Raw milk samples consisted of a pooled morning and evening milking and were analyzed for gross composition, free amino acids, fatty acid composition, heat coagulation time, color, fat globule size, and pH. The TMR milks had a significantly higher total solids, lactose, protein, and whey protein as a proportion of protein content compared with both GRS and PMR milks. The GRS milks demonstrated a significantly lower somatic cell count (SCC), but a significantly higher pH and b*-value than both TMR and PMR milks. The PMR milks exhibited significantly lower total solids and fat content, but also demonstrated significantly higher SCC and total free amino acid content compared with GRS and TMR. Partial least squares discriminant analysis of fatty acid profiles displayed a distinct separation between GRS and TMR samples, while PMR displayed an overlap between both GRS and TMR groupings. Variable importance in projection analysis identified conjugated linoleic acid cis -9, trans -11, C18:2n-6 cis , C18:3n-3, C11:0, and C18:2n-6 trans as the largest contributors to the variation between the diets. Milk fats derived from GRS diets exhibited the highest proportion of unsaturated fats and higher unsaturation, health-promoting, and desaturase indices. The lowest proportions of saturated fats and the lowest atherogenic index were also exhibited by GRS-derived milk fats. This work highlights the positive influence of grass-fed milk for human consumption through its more nutritionally beneficial fatty acid profile, despite the highest milk solid percentages derived from TMR feeding systems. Furthermore, this study demonstrates the proportional response of previously highlighted biomarkers of pasture feeding to the proportion of pasture in the cow's diet. [Display omitted] [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is caused by an interplay of polygenic risk and environmental factors, which may alter regulators of gene expression leading to pathogenic misexpression of SCZ risk genes. The CPEB family of RNA-binding proteins (CPEB1–4) regulates translation of target RNAs (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD) because its neuronal-specific microexon (exon 4) is mis-spliced in ASD brains, causing underexpression of numerous ASD risk genes. The genetic factors and pathogenic mechanisms shared between SCZ and ASD led us to hypothesize CPEB4 mis-splicing in SCZ leading to underexpression of multiple SCZ-related genes. We performed MAGMA-enrichment analysis on Psychiatric Genomics Consortium genome-wide association study data and analyzed RNA sequencing data from the PsychENCODE Consortium. Reverse transcriptase polymerase chain reaction and Western blot were performed on postmortem brain tissue, and the presence/absence of antipsychotics was assessed through toxicological analysis. Finally, mice with mild overexpression of exon 4–lacking CPEB4 (CPEB4Δ4) were generated and analyzed biochemically and behaviorally. First, we found enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased usage of CPEB4 microexon in SCZ probands, which was correlated with decreased protein levels of CPEB4-target SCZ-associated genes only in antipsychotic-free individuals. Interestingly, differentially expressed genes fit those reported for SCZ, specifically in the SCZ probands with decreased CPEB4-microexon inclusion. Finally, we demonstrated that mice with mild overexpression of CPEB4Δ4 showed decreased protein levels of CPEB4-target SCZ genes and SCZ-linked behaviors. We identified aberrant CPEB4 splicing and downstream misexpression of SCZ risk genes as a novel etiological mechanism in SCZ. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including the genetic aspects of human intelligence by Deary et al., aggression by Craig and Halton, and attention-deficit hyperactivity disorder (ADHD) by Franke and colleagues.

Copy number variation has emerged as an important type of genetic risk factor for developmental disorders, including the neurodevelopmental disorders schizophrenia, autism and mental retardation. The highly pleiotropic effects observed for specific copy number variants (CNVs) challenge current classification of these disorders, but also provide opportunities to understand their origins and the relationships between them. [ABSTRACT FROM AUTHOR]

Presents an editorial about schizophrenia. Speculation on the causes of schizophrenia; Discussion of a recent study; Hypotheses regarding dopamine and neurodevelopment; Assertion that the fundamental causes of schizophrenia are exerted from early in life and well before the changes in neurotransmission at the onset of acute psychosis; Vagueness of the hypotheses regarding schizophrenia; Need for the specific mechanisms to be identified by which the current crop of genes alters risk of schizophrenia and the molecular processes that link these primary events to altered function.

Reports the suspension of triazolam drug in Great Britain. Issues on the use of benzodiazepines; Occurrence of rebound insomnia; Association of the drug with psychiatric disturbances during treatment.

Background: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD. [ABSTRACT FROM AUTHOR]

PastureBase Ireland (PBI) is a web-based grassland management application incorporating a dual function of grassland decision support and a centralized national database to collate commercial farm grassland data. This database facilitates the collection and storage of vast quantities of grassland data from grassland farmers. The database spans across ruminant grassland enterprises – dairy, beef and sheep. To help farmers determine appropriate actions around grassland management, we have developed this data informed decision support tool to function at the paddock level. Individual farmers enter data through the completion of regular pasture cover estimations across the farm, allowing the performance of individual paddocks to be evaluated within and across years. To evaluate the PBI system, we compared actual pasture cut experimental data (Etesia cuts) to PBI calculated outputs. We examined three comparisons, comparing PBI outputs to actual pasture cut data, for individual DM yields at defoliation ( Comparison 1 ), for cumulative annual DM yields including silage data ( Comparison 2 ) and, for cumulative annual DM yields excluding silage data ( Comparison 3 ). We found an acceptable accuracy between PBI outputs and pasture cut data when statistically analyzed using relative prediction error and concordance correlation coefficients for the measurement of total annual DM yield ( Comparison 2 ), with a relative prediction error of 15.4% and a concordance correlation coefficient of 0.85. We demonstrated an application of the PBI system through analysis of commercial farm data across two years (2014–2015) for 75 commercial farms who actively use the system. The analysis showed there was a significant increase in DM yield from 2014 to 2015. The results indicated a greater variation in pasture growth across paddocks within farms than across farms. [ABSTRACT FROM AUTHOR]

Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework. We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high. After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p =.001), CLOZUK3 (β = 12.73, SE = 5.99, p =.034), and the Norwegian cohort (β = 46.45, SE = 18.83, p =.014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p =.006). The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia. [ABSTRACT FROM AUTHOR]

While a variety of evidence supports a prenatal component in schizophrenia, there are few data regarding the cell populations involved. We sought to identify cells of the human prenatal brain mediating genetic risk for schizophrenia by integrating cell-specific gene expression measures generated through single-nuclei RNA sequencing with recent large-scale genome-wide association study (GWAS) and exome sequencing data for the condition. Single-nuclei RNA sequencing was performed on 5 brain regions (frontal cortex, ganglionic eminence, hippocampus, thalamus, and cerebellum) from 3 fetuses from the second trimester of gestation. Enrichment of schizophrenia common variant genetic liability and rare damaging coding variation was assessed in relation to gene expression specificity within each identified cell population. Common risk variants were prominently enriched within genes with high expression specificity for developing neuron populations within the frontal cortex, ganglionic eminence, and hippocampus. Enrichments were largely independent of genes expressed in neuronal populations of the adult brain that have been implicated in schizophrenia through the same methods. Genes containing an excess of rare damaging variants in schizophrenia had higher expression specificity for developing glutamatergic neurons of the frontal cortex and hippocampus that were also enriched for common variant liability. We found evidence for a distinct contribution of prenatal neuronal development to genetic risk for schizophrenia, involving specific populations of developing neurons within the second-trimester fetal brain. Our study significantly advances the understanding of the neurodevelopmental origins of schizophrenia and provides a resource with which to investigate the prenatal antecedents of other psychiatric and neurologic disorders. [ABSTRACT FROM AUTHOR]