bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Cytokeratin 9 in the bovine hoof sole
Authors: Meyer K. , Lomax M.A. , Galbraith H. , Hazlerigg D.G.
Published: November 2021

Lameness in the dairy cow results in large financial losses to the industry and severely compromises the welfare of the cows affected. A large proportion of lameness involves haemorrhage and lesions of the solar horn of the hoof. Deterioration of hoof horn quality may involve inadequate keratinisation, with differences in the amount of specific keratins present in the horn. Few studies of the keratin composition of solar horn have been carried out. The present study examines specifically the expression of the type I, acidic cytokeratin 9 (CK9). since this protein appears to be a major constituent of hardened epidermal structures. In human epidermal studies, CK9 has only been identified in the calloused palmar and plantar sites (Langbein et al, 1993). A comparable cytokeratin has been demonstrated in the epidermis of the bovine heel pad, but not at other body sites studied (Knapp et al, 1986). CK9 has not previously been reported in the solar horn.

Bovine hoof soles from adult cows were obtained from abattoirs. Samples of cornified Stratum comeum material from below the pedal bone (the commonest site of solar lesions) were taken and the proteins extracted in 8M urea.
Relationships between muscle fibre traits with meat and eating quality in pigs
Authors: Cameron N.D. , Oksbjerg N. , Henckel P. , Nute G. , Brown S. , Wood J.D.
Published: November 2021

Knowledge of the genetic and phenotypic relationships for muscle fibre characteristics with meat and eating quality in pigs is required by the pig breeding industry for two reasons. Muscle fibre traits, determined from muscle biopsy, could be used as genetic predictors of meat and eating quality traits and, secondly, if responses in meat and eating quality traits are partially due to changes in muscle fibre traits, then selection criteria can be designed to compensate for such responses. The current study estimated the genetic and phenotypic relationships for muscle fibre traits with meat and eating quality traits.

The study consisted of 160 Large White pigs from lines divergently selected for lean growth rate on ad-libitum or restricted feeding regimes, lean food conversion ratio and daily food intake for seven generations in the Edinburgh lean growth selection experiment. Within each selection line, there were 10 pairs of full-sibs. Boars and gilts were tested from 30 kg, individually penned and fed a diet consisting of 224 g CP/kg DM and 15.9 MJ DE/kg DM.
Voluntary feed intake and apparent digestibility in vivo in ponies given ad libitum access to de-hydrated grass or hay harvested from the same grass crop
Authors: Hyslop J. J. , Bayley A. , Tomlinson A. L. , Cuddeford D.
Published: November 2021

De-hydrated forages are often fed to equids in the UK in place of more traditional grass hay, particularly where individual animals are known to have a sensitivity to dusty, mouldy hay which may play a part inducing respiratory problems such as chronic obstructive pulmonary disease (COPD). One such alternative forage is short-chop de-hydrated grass. However, there is very little information available on voluntary feed intake (VFI), apparent digestibility and nutrient intake parameters when de-hydrated grass is offered to equids compared with traditional grass hay. This study examines the VFI and apparent digestibility in vivo of a short-chop de-hydrated grass compared with a traditional grass hay and determines their ability to meet the predicted energy and protein needs of mature ponies.

Six mature Welsh-cross pony geldings with a mean liveweight (LW) of 281 kg (s.e.d. 0.89) were individually housed and offered ad libitum access to either short-chop de-hydrated grass (DHG) or traditional grass hay (HAY) plus 60 g/h/d minerals. The DHG and HAY were made from the same 2nd cut perennial ryegrass sward cut on the same day.
Photoperiodic entrainment of seasonal changes in appetite and growth in pony colts
Authors: Fuller Z. , Cox J.E. , Argo C. McG.
Published: November 2021

During winter, voluntary food intake (VFI) and growth decreased in light horse weanlings given ad libitum access to a forage/concentrate diet (Cymbaluk et al, 1989). These changes were attributed to decreased ambient temperatures. However, photoperiodically entrained seasonal changes in VFI and growth are documented in other Northern ungulates (Moen, 1978) and may comprise an adaptation to changes in forage availability. Throughout their evolution, horses experienced similar environmental pressures and may demonstrate similar photoperiodic adaptations. This study characterised changes in VFI and growth in pony colts maintained under an artificial photoperiodic regime.

Seven, 2 year-old pony colts of Welsh Mountain type (182.4 ± 5.4 kg), were obtained from pasture (53°N). Animals were individually housed in loose-boxes, within a light-proof building. Measured quantities of a complete pelleted diet (gross energy = 16.7 MJ.kgDM-1), calculated to exceed appetite by at least 1 kg, were offered daily.
Comparison of a range of NE systems with data obtained from slaughter balance studies on 8-12 week old pigs
Authors: Beattie V.E. , Weatherup R.N. , McCracken K.J. , McIlroy S.G. , Henry R.W.
Published: November 2021

The gross energy of any pig feed is not completely available to the animal with losses occurring in faeces, urine, methane and heat. The NE system of feed evaluation should be more accurate in predicting animal performance since it takes into account these energy losses and the metabolic utilisation of energy. The NE system ascribes a relatively higher value to energy from fat and a lower value to energy from protein sources than the DE system. One method of deriving NE is to multiply DE by a factor of 0.71 (Noblet, 1996a). A wide range of more complex NE systems are currently in use involving individual feed ingredient data collected at various European research centres. This study was designed to compare a range of NE systems with data obtained from slaughter balance studies on 8-12 week old pigs using a range of diets for growing pigs differing in CP and DE levels.
Effects of sow, udder section and time on colostrum immunoglobulin G (IgG) concentrations and piglet colostrum intake
Authors: Bland I. , Rooke J.A.
Published: November 2021

An adequate intake of colostrum by the newborn piglet allows the piglet to acquire passive immunity and develop active immunity. However there is relatively little information on the composition of colostrum from sows of modern genotypes. The purpose of the study was therefore to investigate the changes in IgG concentration of colostrum and the uptake of colostrum by piglets.

A total of 9 muciparous sows (Newsham - Large White x Landrace) were observed whilst farrowing naturally. Colostrum was sampled, without using oxytocin, at 0, 3, 6, 9, 12, 15, 18, 21 and 24 h post partum from the anterior, middle and rear thirds of the udder and frozen at -20 °C. Colostrum intake was measured as soon as piglets began to suckle after being born, by removing three piglets/sow from the sow and weighing the piglets before and after a period of suckling, the mean weight change over eight consecutive weighings (corrected for urinary losses) being taken as colostrum intake. Piglets were observed to determine on which udder section the piglet was suckling. IgG concentration was measured using an ELISA technique (Varley et al, 1985). Statistical analysis was carried out using analysis of variance.
Effect of time post-surgery on the measurement of ileal digestibility in ileal rectal anastomosed pigs.
Authors: Bodin J.C. , McMillan E. , Maillard R. , van Kempen T. , Williams P.E.V.
Published: November 2021

The measurement of ileal digestibility of amino acids is recognized to be a valid tool for the estimation of availability of amino acids. One of the techniques used to obtain this measure - ileal rectal anastomosis - has, however, received a lot of criticism since it has been claimed that the removal of the colon from the active digestive tract leads to the development of a colon-like microflora in the ileum (Köhler et al, 1991). The aim of this experiment was to evaluate if the possible development of microflora affected the ileal digestibility results obtained.
Inhibition of Listeria monocytogenes by Lactobacillus plantarum is abolished by food intake, in an in vitro simulation of the pig colon
Authors: Hillman K. , Khaddour R. , Fenlon D. R.
Published: November 2021

Probiotics are live microbial cultures fed to animals with the intention of promoting intestinal health. However, one of the problems with these preparations is the variability in their effectiveness, reasons for which include genetic and physiological differences between herds of animals or between individuals, and the type of feed presented to the animals. This study has examined the effects of different food types on the efficacy of a strain of Lactobacillus plantarum as an inhibitor of Listeria monocytogenes. The strain of L. plantarum used (PF31) has been previously shown to inhibit the growth of the porcine enteric pathogen Escherichia coli O 149:K88:K91 in coculture (Hillman and Fox, 1994). In a subsequent series of tests, L. plantarum PF31 was also shown to inhibit the growth of List, monocytogenes in coculture.
Effect of exposure to oestrous ewes on rams’ sexual behaviour, testosterone secretion and ability to stimulate ovulation in seasonal anoestrous ewes
Authors: Rosa H. J. D. , Bryant M. J.
Published: November 2021

The proportion of seasonal anoestrous ewes that ovulate in response to the introduction of rams has long been thought to be influenced by pheromone production by the rams (Watson and Radford, 1960). More recently the role of the sexual behaviour of the rams as a source of ewe stimulation has been demonstrated (Perkins and Fitzgerald, 1994). The present study investigated the hypothesis that the exposure of rams to ewes in oestrus can enhance rams’ sexual behaviour and consequently improve the efficacy of the ram effect.

Sixteen groups of 16 anoestrous ewes, described as the experimental ewes, were randomly allocated to 4 treatments and 4 periods. Treatments were as follows; ewes introduced to 2 rams (R), ewes introduced to 2 rams and 4 oestrous ewes (RE), ewes introduced to 2 rams recendy exposed to 4 oestrous ewes (ER) and ewes introduced to 2 rams recently exposed to 4 oestrous ewes plus a further 4 oestrous ewes (ERE). Treatments were replicated 4 times (4 periods) with 2-week intervals starting on 4 July. Another group of 16 ewes remained isolated from rams during the course of the experiment (C).
Genetic and phenotypic trends in production traits in the United Kingdom (UK) dairy herd
Authors: Lindberg C. M. , Swanson G. J. T. , Mrode R. A.
Published: November 2021

It is important for the dairy industry to be aware of the consequences of past selection policies. This can provide guidance on how to improve or change current breeding schemes. In addition it is important to know how much of current progress is due to breeding and how much to management. The objective of the study was to analyse genetic and phenotypic trends for the production traits (milk, fat and protein) using the results from the latest UK Individual Animal Model evaluations.
Effect of nutrient demand and level of supplement on the intake and feeding behaviour of dairy cows offered grass silage
Authors: Romney D.L. , Blunn V. , Leaver J.D.
Published: November 2021

The nutrient demand of dairy cattle varies with milk yield level and is greater in early than in later lactation. This is likely to influence forage feeding behaviour and intake, although the mechanisms are not well understood. The objectives of this experiment were to examine the feeding behaviour of dairy cows in early and late lactation (representing two levels of nutrient demand), and at three levels of concentrate supplement (representing three dietary influences on demand for forage).
The effects of concentrate composition on silage intake and feeding behaviour of lactating dairy cattle offered a range of grass silages differing in intake characteristics
Authors: Keady T.W.J. , Mayne C.S.
Published: November 2021

A previous study at this Institute (Keady and Mayne, 1997) indicated that concentrate energy source did not alter silage intake or feeding behaviour of lactating dairy cattle offered one of a diverse range of grass silages differing in fermentation and intake characteristics, but of similar digestibility. Digestibility is the most important variable in grass silages at farm level and also has a considerable influence on silage intake. The aim of the present study was to examine the effects of concentrate energy source and effective rumen degradable protein (ERDP):digestible undegradable protein (DUP) ratio on silage intake and feeding behaviour of lactating dairy cows offered a range of grass silages differing in digestibility and intake characteristics.
Influence of source of methionine and protection technology on the post ruminal delivery and supply to the blood of dairy cows of an oral supplement of methionine
Authors: Robert J-C. , Williams P.E.V. , Bouza B.
Published: November 2021

Rumen protected forms of methionine have been developed to facilitate rationing of dairy cows in term of digestible methionine. It is essential for rumen protected products that the proportion of the amino acid that resists ruminal degradation as well as the proportion available in the intestine is known. Methods based on the concentration of amino acid in blood have been developed to provide fast and effective assessment of protection / release coefficients. The objective of this trial was to test the efficiency with which four different sources of methionine could deliver methionine to the blood of dairy cows.

Two multiparous Friesian Holstein cows fitted with rumen and duodenal canulae and in their 10th week of lactation were used. They received a ration composed of corn silage ad libitum, soybean meal (2.5 kg/head/day) and concentrate (6.5 kg/head/day).
Plasma copper and cobalt metabolism of guanacos (Lama guanicoe) and sheep grazing the same upland pasture
Authors: Illingworth D.V. , Jackson D.W. , Fraser M.D. , Telfer S.B.
Published: November 2021

Previous work has suggested that assessing the trace element status of South American camelids (llamas) using cattle or sheep plasma values as reference norms could lead to incorrect diagnoses of sufficiency /deficiency (Illingworth et al.,1997). However there are no previous accounts of a direct comparison of the trace mineral status between a species of camelid and a conventional ruminant. This study directly compares the blood copper and cobalt status of guanacos and sheep grazing the same typical upland Agrostis / Festuca spp. dominated pasture.

Blood samples were obtained in May 1996 from the tail vessels of 10 mature, captive bred guanaco castrates and 9 mature barren ewes (Merino x Welsh Mountain) which had grazed the same upland pasture for 6 weeks with ad libitum access to trace mineral blocks (Wright Block - Standard) which both species were observed to consume.
The effect of feeding high levels of fish oil and additional vitamin E on intake, milk yield, composition and fatty acid content in high yielding dairy cows
Authors: Mansbridge R J , Blake J S , Collins C
Published: November 2021

The COMA report on The Nutritional Aspects of Cardiovascular Disease (1994) recommended that the intake of long chain n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by the UK population should double. EPA and DHA in the human diet are derived principally from oily fish. The aim of this experiment was to determine the effect of increasing levels of fish oil in the diet at two levels of vitamin E supplementation, on intake, milk production, the extent of uptake of EPA and DHA into milk fat at levels exceeding those investigated to date, and the effect of a dietary supplement of vitamin E on fatty acid content.
Effect of various feedstuffs rich in fat or tannin content on rumen methanogenesis in vitro - using the Hohenheim Gas Test (HFT)
Authors: Finger T. , Hayler R. , Steingaß H. , Drochner W.
Published: November 2021

Methane is an unavoidable product of rumen fermentation. Reduction of rumen methanogenesis can lead to an improved exploitation of nutrient energy and a decrease of methane emissions in the environment. The objective of this study was to investigate the effect of several fat and tannin containing feedstuffs on the production of CH4 and concommitant CO2 using the in vitro system „Hohenheim Gas Test” (STEINGAß & MENKE 1986). Special emphasis was directed to the suitability of the method to measure the effect of various substrates on rumen methanogenesis. Another objective was to investigate to what extent increasing fat or tannin contents in the diet of the donor sheep affect methanogenesis in vitro.
Ionospheric Electrodynamic Response to Solar Flares in September 2017
Authors: Chen Junjie , Lei Jiuhou , Wang Wenbin , Liu Jing , Maute Astrid , Qian Liying , Zhang Ruilong , Dang Tong
Published: November 2021

Abstracts

In this work, the Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model is used to investigate the responses of ionospheric electrodynamic processes to the solar flares at the flare peaks and the underlying physical mechanisms on September 6 and 10, 2017. Simulations show that solar flares increased global daytime currents and reduced the eastward electric fields during the daytime from the equator to middle latitudes. Furthermore, westward equatorial electric fields and equatorial counter electrojets occurred in the early morning. At the flare peak, these electrodynamic responses are predominantly related to the enhanced E‐region conductivity by flares, as the responses of neutral winds and F‐region conductivity to flares are negligible. Specifically, the Cowling conductance enhancement is not the major process causing the reduction of zonal electric fields. This electric field reduction is primarily associated with the decrease of the ratio between the field line‐integrated wind‐driven currents and the conductance. The flare‐induced conductivity enhancement is larger but the background wind speed is smaller in the E‐region than in the F‐region, as a result, the increase of total integrated wind‐driven currents is less than the conductance enhancement.
The Magmatic Architecture of Continental Flood Basalts I: Observations From the Deccan Traps
Authors: Mittal Tushar , Richards Mark A. , Fendley Isabel M.
Published: November 2021

Flood basalts are some of the largest magmatic events in Earth history, with intrusion and eruption of millions of km3 of basaltic magma over a short time period (∼1–5 Ma). A typical continental flood basalt (CFB) is emplaced in hundreds of individual eruptive episodes lasting decades to centuries with lava flow volumes of 103–104 km3. These large volumes have logically led to CFB models invoking large magma reservoirs (–105 km3) within the crust or at Moho depth. Since there are currently no active CFB provinces, we must rely on observations of past CFBs with varying degrees of surface exposure to develop and test models. In the last few decades, significant improvements in geochronological, geochemical, paleomagnetic, volcanological, and paleo‐proxy measurements have provided high‐resolution constraints on CFB eruptive tempo ‐ the volume, duration, and frequency of individual eruptive episodes. Using the well‐studied Deccan Traps as an archetype for CFB systems, we compile multiple lines of evidence–geochronology, eruption tempo, dike spatial distribution, intrusive‐extrusive ratio, geochemical variations, and volcanological observations–to assess the viability of previous models. We find that the presence of just a few large crustal magma reservoirs is inconsistent with these constraints. Although observations from the Deccan Traps primarily motivate our model, we discuss constraints from other CFBs to illustrate that this conclusion may be broadly applicable for CFB magmatic systems in general.
Carbonate Mineralogy in Mantle Peridotites of the Atlantis Massif (IODP Expedition 357)
Authors: Ternieten Lotta , Früh‐Green Gretchen L. , Bernasconi Stefano M.
Published: November 2021

Petrographic and major element investigations of carbonates from seven drill cores recovered during IODP Expedition 357 on the Atlantis Massif (AM) provide information on the genesis of carbonate minerals in the oceanic lithosphere. Textural sequences and mineralogical assemblages reveal three distinct types of carbonate occurrences in ultramafic rocks that are controlled by (a) fluid composition and flow, (b) temperature, and (c) the presence of mafic intrusions. The first occurrence of carbonate consists of different generations of calcite that formed syn‐ to post‐ serpentinization. These calcites formed at temperatures between 30 and 184°C (based on clumped isotope thermometry) and from a fluid influenced by interaction with mafic intrusions. The second occurrence consists of magnesite, dolomite, calcite, and aragonite veins that also formed syn‐ to post serpentinization. These carbonates formed at temperatures between ambient and 196°C, from fluids with highly variable FeO, MnO, and SrO composition and Mg/Ca ratios, but overall high CO2 and moderate SiO2 concentrations. High FeO (3.3 wt%) and MnO (7.3 wt%) contents indicate high temperatures, high water/rock ratios, and low oxygen fugacity for both carbonate assemblages. The third occurrence consists solely of aragonite veins formed at low temperatures (<9°C) within the uplifted serpentinized peridotites. Major element analyses suggest that aragonite precipitated from seawater, which experienced little interaction with the basement. Combining these results, we propose a model that positions different carbonate occurrences in a conceptual framework considering mafic domains in the peridotites and fluid heterogeneities during progressive exhumation and alteration of the AM.
Seasonal Variations and Driving Factors of the Eastern Maine Coastal Current
Authors: Li Denghui , Wang Zhengui , Xue Huijie , Thomas Andrew C. , Pettigrew Neal , Yund Philip O.
Published: November 2021

To investigate the coastal current in the Gulf of Maine (GoME) and its relation to forcing from outside of the gulf, a high‐resolution circulation model was developed and validated. Our model shows that the Eastern Maine Coastal Current (EMCC) possesses two cores, an offshore and a nearshore core that peak in summer and spring, respectively. The two cores can be traced back to outflows from the Bay of Fundy from opposite sides of Grand Manan Island, and both cores are deeper and slightly more onshore in summer and fall in response to tidal mixing, surface thermal stratification and wind. The two cores merge south of Pleasant Bay, then split into two branches again east of Mount Desert Rock, where the nearshore branch flows along the coast, while the offshore branch turns southward to recirculate in the eastern GoME. Subject to variations of Scotian Shelf Water and Slope Water (SW) inflows, the offshore veering occurs further upstream (northeastward) in late winter and summer, but gradually shifts downstream (southwestward) from summer to winter. Diagnosis of momentum balance demonstrates that the EMCC is primarily driven by the pressure gradient force (PG), of which the barotropic PG is dominant and offshore, while the baroclinic PG is onshore and increases with depth. The large baroclinic PG at depths, modulated by SW, that is, blended by tidal mixing, offsets the barotropic PG. Near the surface, the barotropic PG is nearly balanced by the Coriolis force, forming the geostrophic EMCC.
Prediction of Streamflow Recession Curves in Gauged and Ungauged Basins
Authors: Singh Shailesh Kumar , Griffiths George A.
Published: November 2021

Prediction of the time for perennial outflow from a natural basin to recede from the mean to some low flow value is an important practical and difficult problem in water resource management. This study aims to gain further understanding of this complex problem and to put forward new practical and accurate methods for predicting flow recessions between nominated limits in both gauged and ungauged basins. For a gauged basin, a three parameter recession model is employed to estimate the recession time, from day‐to‐day, as flow recedes from mean flow using previously measured site recession curves and a library of recession curve shapes generated by the RObust Parameter Estimation algorithm. The model is tested using data from 10 New Zealand basins which are diverse in low flow hydrological behavior and yields a Median Absolute Error (MAE) of 1 day. Another new model is also developed to predict recession time in an ungauged basin using catchment characteristics and information from master recession curves in a suite of 10 reference basins geologically and hydrologically similar to the ungauged basin, as assessed by a Random Forest model. Model performance is robust with a MAE of 1 day and the models advance the use of past flow records to enable more accurate predictions to be obtained. They can be applied elsewhere with confidence although further testing is desirable.
Intertwined Eco‐Morphodynamic Evolution of Salt Marshes and Emerging Tidal Channel Networks
Authors: Geng Liang , D'Alpaos Andrea , Sgarabotto Alessandro , Gong Zheng , Lanzoni Stefano
Published: November 2021

The formation and development of tidal channels and salt marshes are controlled by complex interactions between hydrodynamics, sediment transport, and vegetation dynamics. Tidal channels affect and, at the same time, are affected by the growth of salt marshes fringing them. The coupled evolution of these morphological units, mediated by vegetation growth, is thus a key ingredient for simulating the behavior of tidal environments. Considering these two factors, we developed a mathematical model to investigate the eco‐morphodynamic evolution of intertidal areas fringing a main channel and of the tidal creeks cutting through them. Model results indicate that vegetation promotes the development of channel networks, leading to more complex channel structures and higher drainage efficiency. Vegetation encroachment influences sediment deposition patterns by trapping sediment in the seaward and middle intertidal areas, while reducing the amount of sediment delivered to landward areas. In the presence of sea level rise, this deficit of sediment enhances the landward‐decreasing trend of the intertidal platform and leads to more isolated vegetation patches. Overall, sea level rise restricts the extension of salt marshes and consequently reduces the effect of vegetation on channel network form and function.
A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease
Authors: Asanomi Yuya , Shigemizu Daichi , Akiyama Shintaro , Miyashita Akinori , Mitsumori Risa , Hara Norikazu , Ikeuchi Takeshi , Niida Shumpei , Ozaki Kouichi
Published: November 2021

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.
Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice
Authors: Hiramoto Takeshi , Sumiyoshi Akira , Yamauchi Takahira , Tanigaki Kenji , Shi Qian , Kang Gina , Ryoke Rie , Nonaka Hiroi , Enomoto Shingo , Izumi Takeshi , Bhat Manzoor A. , Kawashima Ryuta , Hiroi Noboru
Published: November 2021

Copy number variants (CNVs) have provided a reliable entry point to identify the structural correlates of atypical cognitive development. Hemizygous deletion of human chromosome 22q11.2 is associated with impaired cognitive function; however, the mechanisms by which the CNVs contribute to cognitive deficits via diverse structural alterations in the brain remain unclear. This study aimed to determine the cellular basis of the link between alterations in brain structure and cognitive functions in mice with a heterozygous deletion of Tbx1, one of the 22q11.2-encoded genes. Ex vivo whole-brain diffusion-tensor imaging (DTI)–magnetic resonance imaging (MRI) in Tbx1 heterozygous mice indicated that the fimbria was the only region with significant myelin alteration. Electron microscopic and histological analyses showed that Tbx1 heterozygous mice exhibited an apparent absence of large myelinated axons and thicker myelin in medium axons in the fimbria, resulting in an overall decrease in myelin. The fimbria of Tbx1 heterozygous mice showed reduced mRNA levels of Ng2, a gene required to produce oligodendrocyte precursor cells. Moreover, postnatal progenitor cells derived from the subventricular zone, a source of oligodendrocytes in the fimbria, produced fewer oligodendrocytes in vitro. Behavioral analyses of these mice showed selectively slower acquisition of spatial memory and cognitive flexibility with no effects on their accuracy or sensory or motor capacities. Our findings provide a genetic and cellular basis for the compromised cognitive speed in patients with 22q11.2 hemizygous deletion.
Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia
Authors: Campeau Anaamika , Mills Robert H. , Stevens Toer , Rossitto Leigh-Ana , Meehan Michael , Dorrestein Pieter , Daly Rebecca , Nguyen Tanya T. , Gonzalez David J. , Jeste Dilip V. , Hook Vivian
Published: November 2021

Schizophrenia is a devastating psychiatric illness that detrimentally affects a significant portion of the worldwide population. Aging of schizophrenia patients is associated with reduced longevity, but the potential biological factors associated with aging in this population have not yet been investigated in a global manner. To address this gap in knowledge, the present study assesses proteomics and metabolomics profiles in the plasma of subjects afflicted with schizophrenia compared to non-psychiatric control patients over six decades of life. Global, unbiased analyses of circulating blood plasma can provide knowledge of prominently dysregulated molecular pathways and their association with schizophrenia, as well as features of aging and gender in this disease. The resulting data compiled in this study represent a compendium of molecular changes associated with schizophrenia over the human lifetime. Supporting the clinical finding of schizophrenia’s association with more rapid aging, both schizophrenia diagnosis and age significantly influenced the plasma proteome in subjects assayed. Schizophrenia was broadly associated with prominent dysregulation of inflammatory and metabolic system components. Proteome changes demonstrated increased abundance of biomarkers for risk of physiologic comorbidities of schizophrenia, especially in younger individuals. These findings advance our understanding of the molecular etiology of schizophrenia and its associated comorbidities throughout the aging process.
Assigning the right credit to the wrong action: compulsivity in the general population is associated with augmented outcome-irrelevant value-based learning
Authors: Shahar Nitzan , Hauser Tobias U. , Moran Rani , Moutoussis Michael ,   NSPN consortium,   Principal investigators, Bullmore Edward , Dolan Raymond J. , Goodyer Ian , Fonagy Peter , Jones Peter ,   NSPN (funded) staff, Moutoussis Michael , Hauser Tobias , Neufeld Sharon , Romero-Garcia Rafael , Clair Michelle St , Vértes Petra , Whitaker Kirstie , Inkster Becky , Prabhu Gita , Ooi Cinly , Toseeb Umar , Widmer Barry , Bhatti Junaid , Villis Laura , Alrumaithi Ayesha , Birt Sarah , Bowler Aislinn , Cleridou Kalia , Dadabhoy Hina , Davies Emma , Firkins Ashlyn , Granville Sian , Harding Elizabeth , Hopkins Alexandra , Isaacs Daniel , King Janchai , Kokorikou Danae , Maurice Christina , McIntosh Cleo , Memarzia Jessica , Mills Harriet , O’Donnell Ciara , Pantaleone Sara , Scott Jenny , Kiddle Beatrice , Polek Ela ,   Affiliated scientists, Fearon Pasco , Suckling John , van Harmelen Anne-Laura , Kievit Rogier , Chamberlain Sam , Bullmore Edward T. , Dolan Raymond J.
Published: November 2021

Compulsive behavior is enacted under a belief that a specific act controls the likelihood of an undesired future event. Compulsive behaviors are widespread in the general population despite having no causal relationship with events they aspire to influence. In the current study, we tested whether there is an increased tendency to assign value to aspects of a task that do not predict an outcome (i.e., outcome-irrelevant learning) among individuals with compulsive tendencies. We studied 514 healthy individuals who completed self-report compulsivity, anxiety, depression, and schizotypal measurements, and a well-established reinforcement-learning task (i.e., the two-step task). As expected, we found a positive relationship between compulsivity and outcome-irrelevant learning. Specifically, individuals who reported having stronger compulsive tendencies (e.g., washing, checking, grooming) also tended to assign value to response keys and stimuli locations that did not predict an outcome. Controlling for overall goal-directed abilities and the co-occurrence of anxious, depressive, or schizotypal tendencies did not impact these associations. These findings indicate that outcome-irrelevant learning processes may contribute to the expression of compulsivity in a general population setting. We highlight the need for future research on the formation of non-veridical action−outcome associations as a factor related to the occurrence and maintenance of compulsive behavior.
Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis
Authors: Theorell Jakob , Ramberger Melanie , Harrison Ruby , Mgbachi Victor , Jacobson Leslie , Waters Patrick , Erhardt Sophie , Sellgren Carl M. , Cervenka Simon , Piehl Fredrik , Irani Sarosh R.
Published: November 2021

Patients with autoimmune encephalitides, especially those with antibodies to theN-methyl-d-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from aforme frusteof autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these—and other—limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher’s test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion,formes frustesof autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.
Functional annotation of breast cancer risk loci: current progress and future directions
Authors: Romualdo Cardoso Shirleny , Gillespie Andrea , Haider Syed , Fletcher Olivia
Published: November 2021

Genome-wide association studies coupled with large-scale replication and fine-scale mapping studies have identified more than 150 genomic regions that are associated with breast cancer risk. Here, we review efforts to translate these findings into a greater understanding of disease mechanism. Our review comes in the context of a recently published fine-scale mapping analysis of these regions, which reported 352 independent signals and a total of 13,367 credible causal variants. The vast majority of credible causal variants map to noncoding DNA, implicating regulation of gene expression as the mechanism by which functional variants influence risk. Accordingly, we review methods for defining candidate-regulatory sequences, methods for identifying putative target genes and methods for linking candidate-regulatory sequences to putative target genes. We provide a summary of available data resources and identify gaps in these resources. We conclude that while much work has been done, there is still much to do. There are, however, grounds for optimism; combining statistical data from fine-scale mapping with functional data that are more representative of the normal “at risk” breast, generated using new technologies, should lead to a greater understanding of the mechanisms that influence an individual woman’s risk of breast cancer.
Dihydroartemisinin is potential therapeutics for treating late-stage CRC by targeting the elevated c-Myc level
Authors: Hu Xianjing , Fatima Sarwat , Chen Minting , Huang Tao , Chen Yuen Wa , Gong Ruihong , Wong Hoi Leong Xavier , Yu Rongmin , Song Liyan , Kwan Hiu Yee , Bian Zhaoxiang
Published: November 2021

Currently, no frontline treatment is effective for the late-stage colorectal cancer (CRC). Understanding the molecular differences in different stages of CRC can help us to identify the critical therapeutic targets for designing therapeutic strategy. Our data show that c-Myc protein is highly expressed in late-stage CRC when compared with early-stage CRC in both clinical samples and in cell lines representing different cancer stages. Given that c-Myc is a well-known oncogenic driver in CRC, its high expression in the late-stage CRC may represent a critical therapeutic target for treating the cancer. Dihydroartemisinin treatment significantly increases c-Myc protein degradation and hence reduces its expression in CRC. The treatment also reduces CRC cell viability. Interestingly, dihydroartemisinin exhibits a more potent growth-inhibitory effect in late-stage CRC than the early-stage CRC. The treatment also possesses potent growth-inhibitory effects in mouse models bearing c-Myc-overexpressed CRC. The reduced c-Myc level and its reduced transcriptional activity reduce the expressions of acetyl-CoA carboxylase, fatty acid synthase, carnitine–palmitoyltransferase-1, and medium-chain acyl-CoA dehydrogenase in the cancer cells. Lipidomics study also shows that dihydroartemisinin treatment changes the metabolic phenotypes in CRC, reduces oxygen consumption, respiration, and ATP production, hence reduces the cell proliferation and induces apoptosis. Our study provides strong pharmacological evidence to support the translation of dihydroartemisinin for the treatment of late-stage CRC by targeting c-Myc.
Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma
Authors: Zeng Huishan , Yang Huiru , Song Yifan , Fang Dong , Chen Liang , Zhao Zhijun , Wang Chaojie , Xie Songqiang
Published: November 2021

Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.
Mitigation potential of global ammonia emissions and related health impacts in the trade network
Authors: Ma Rong , Li Ke , Guo Yixin , Zhang Bo , Zhao Xueli , Linder Soeren , Guan ChengHe , Chen Guoqian , Gan Yujie , Meng Jing
Published: November 2021

Ammonia (NH3) emissions, mainly from agricultural sources, generate substantial health damage due to the adverse effects on air quality. NH3 emission reduction strategies are still far from being effective. In particular, a growing trade network in this era of globalization offers untapped emission mitigation potential that has been overlooked. Here we show that about one-fourth of global agricultural NH3 emissions in 2012 are trade-related. Globally they induce 61 thousand PM2.5-related premature mortalities, with 25 thousand deaths associated with crop cultivation and 36 thousand deaths with livestock production. The trade-related health damage network is regionally integrated and can be characterized by three trading communities. Thus, effective cooperation within trade-dependent communities will achieve considerable NH3 emission reductions allowed by technological advancements and trade structure adjustments. Identification of regional communities from network analysis offers a new perspective on addressing NH3 emissions and is also applicable to agricultural greenhouse gas emissions mitigation.
BEAR reveals that increased fidelity variants can successfully reduce the mismatch tolerance of adenine but not cytosine base editors
Authors: Tálas András , Simon Dorottya A. , Kulcsár Péter I. , Varga Éva , Krausz Sarah L. , Welker Ervin
Published: November 2021

Adenine and cytosine base editors (ABE, CBE) allow for precision genome engineering. Here, Base Editor Activity Reporter (BEAR), a plasmid-based fluorescent tool is introduced, which can be applied to report on ABE and CBE editing in a virtually unrestricted sequence context or to label base edited cells for enrichment. Using BEAR-enrichment, we increase the yield of base editing performed by nuclease inactive base editors to the level of the nickase versions while maintaining significantly lower indel background. Furthermore, by exploiting the semi-high-throughput potential of BEAR, we examine whether increased fidelity SpCas9 variants can be used to decrease SpCas9-dependent off-target effects of ABE and CBE. Comparing them on the same target sets reveals that CBE remains active on sequences, where increased fidelity mutations and/or mismatches decrease the activity of ABE. Our results suggest that the deaminase domain of ABE is less effective to act on rather transiently separated target DNA strands, than that of CBE explaining its lower mismatch tolerance.
Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM
Authors: Radamaker Lynn , Karimi-Farsijani Sara , Andreotti Giada , Baur Julian , Neumann Matthias , Schreiner Sarah , Berghaus Natalie , Motika Raoul , Haupt Christian , Walther Paul , Schmidt Volker , Huhn Stefanie , Hegenbart Ute , Schönland Stefan O. , Wiese Sebastian , Read Clarissa , Schmidt Matthias , Fändrich Marcus
Published: November 2021

Systemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Authors: Kumar Manish , Molkentine David , Molkentine Jessica , Bridges Kathleen , Xie Tongxin , Yang Liangpeng , Hefner Andrew , Gao Meng , Bahri Reshub , Dhawan Annika , Frederick Mitchell J. , Seth Sahil , Abdelhakiem Mohamed , Beadle Beth M. , Johnson Faye , Wang Jing , Shen Li , Heffernan Timothy , Sheth Aakash , Ferris Robert L. , Myers Jeffrey N. , Pickering Curtis R. , Skinner Heath D.
Published: November 2021

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.