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Following the mutation screening of genes known to cause amyotrophic lateral sclerosis (ALS) in index cases from 107 familial ALS (FALS) kindred, a point mutation was identified in vesicle-associated membrane protein-associated protein B (VAPB), or VAMP-associated protein B, causing an amino acid change from threonine to isoleucine at codon 46 (T46I) in one FALS case but not in 257 controls. This is an important finding because it is only the second mutation identified in this gene that causes ALS. In order to investigate the pathogenic effects of this mutation, we have used a motor neuron cell line and tissue-specific expression of the mutant protein in Drosophila. We provide substantial evidence for the pathogenic effects of this mutation in abolishing the effect of wild type VAPB in the unfolded protein response, promoting ubiquitin aggregate formation, and activating neuronal cell death. We also report that expression of the mutant protein in the Drosophila motor system induces aggregate deposition, endoplasmic reticulum disorganization, and chaperone up-regulation both in neurons and in muscles. Our integrated analysis of the pathogenic effect of the T46I mutation and the previously identified P56S mutation indicate extensive commonalities in the disease mechanism for these two mutations. In summary, we show that this newly identified mutation in human FALS has a pathogenic effect, supporting and reinforcing the role of VAPB as a causative gene of ALS. [ABSTRACT FROM AUTHOR]

Degeneration of midbrain nigrostriatal dopaminergic neurons is a pathological hallmark of Parkinson's disease (PD). Peripheral delivery of a compound(s) to arrest or slow this dopaminergic degeneration is a key therapeutic goal. Pan-inhibitors of histone deacetylase (HDAC) enzymes, key epigenetic regulators, have shown therapeutic promise in PD models. However as there are several classes of HDACs (ClassI-IV), class-specific inhibition will be important to ensure target specificity. Here we examine the neuroprotective potential of the Class-IIa HDAC inhibitor, TMP269. We show that TMP269 protected against 6-hydroxydopamine (6-OHDA)-induced neurite injury in SH-SY5Y cells and cultured rat ventral mesencephalic dopaminergic neurons. We find that TMP269 upregulated the neurotrophic factor BMP2 and BMP-Smad dependent transcription signalling in SH-SY5Y cells, which was necessary for its neuroprotective effect against 6-OHDA-induced injury. Furthermore, peripheral continuous infusion of 0.5 mg/kg of TMP269 for 7 days via a mini-osmotic pump, reduced forelimb impairments induced by striatal 6-OHDA administration. TMP269 also protected dopaminergic neurons in the substantia nigra and their striatal terminals from striatal 6-OHDA-induced neurodegeneration and prevented the 6-OHDA-induced increases in the numbers of IBA1-positive microglia in the striatum and substantia nigra in vivo. TMP269 also prevented 6-OHDA-induced decreases in BMP2, pSmad1/5 and acetylated histone 3 levels, and it reversed 6-OHDA-induced increase in nuclear HDAC5 in dopaminergic neurons in the substantia nigra. These data add to the growing body of evidence that Class-IIa specific HDAC inhibitors may be pharmacological agents of interest for peripheral delivery with the goal of neuroprotection in PD., Competing Interests: Declaration of competing interest All authors have no competing interests to declare., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vitamin A/Retinoic Acid (Vit A/RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (i.e scRNAseq and snATACseq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP1 and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, in vivo analysis of control and conditionally YAP1 KO mouse embryos ( Sox2-cre ) revealed that the expression of atrial lineage genes, such as NR2F2 , is compromised by YAP1 deletion in the CPCs of the second heart field. Accordingly, we found that YAP1 is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.

Behaviour is often the fundamental driver of disease transmission, where behaviours of individuals can be seen to scale up to epidemiological patterns seen at the population level. Here we focus on animal behaviour, and its role in parasite transmission to track its knock-on consequences for parasitism, production and pollution. Livestock face a nutrition versus parasitism trade-off in grazing environments where faeces creates both a nutritional benefit, fertilizing the surrounding sward, but also a parasite risk from infective nematode larvae contaminating the sward. The grazing decisions of ruminants depend on the perceived costs and benefits of the trade-off, which depend on the variations in both environmental (e.g., amounts of faeces) and animal factors (e.g., physiological state). Such grazing decisions determine the intake of both nutrients and parasites, affecting livestock growth rates and production efficiency. This impacts on the greenhouse gas costs of ruminant livestock production via two main mechanisms: (1) slower growth results in longer durations on-farm and (2) parasitised animals produce more methane per unit food intake. However, the sensitivity of behaviour to host parasite state offers opportunities for early detection of parasitism and control. Remote monitoring technology such as accelerometers can detect parasite-induced sickness behaviours soon after exposure, before impacts on growth, and thus may be used for targeting individuals for early treatment. We conclude that livestock host x parasite interactions are at the centre of the global challenges of food security and climate change, and that understanding livestock behaviour can contribute to solving both.

Objectives. To describe the current financial health of syringe services programs (SSPs) in the United States and to assess the predictors of SSP budget levels and associations with delivery of public health interventions. Methods. We surveyed all known SSPs operating in the United States from February to June 2022 (n = 456), of which 68% responded (n = 311). We used general estimating equations to assess factors influencing SSP budget size and estimated the effects of budget size on multiple measures of SSP services. Results. The median SSP annual budget was $100 000 (interquartile range = $20 159‒$290 000). SSPs operating in urban counties and counties with higher levels of opioid overdose mortality had significantly higher budget levels, while SSPs located in counties with higher levels of Republican voting in 2020 had significantly lower budget levels. SSP budget levels were significantly and positively associated with syringe and naloxone distribution coverage. Conclusions. Current SSP funding levels do not meet minimum benchmarks. Increased funding would help SSPs meet community health needs. Public Health Implications. Federal, state, and local initiatives should prioritize sustained SSP funding to optimize their potential in addressing multiple public health crises. ( Am J Public Health. 2024;114(4):435-443. https://doi.org/10.2105/AJPH.2024.307583).

Background: Single injection ropivacaine interscalene anesthesia (ISA) is frequently used in Latarjet reconstruction to enhance post-operative analgesia. A potential limitation is the occurrence of severe rebound pain on block resolution. We investigated the effect of intravenous magnesium on post-operative pain, particularly at the transition of block resolution to multimodal analgesia., Methods: Elective patients ( n  = 40) having Latarjet open shoulder reconstruction were randomised to receive either intravenous magnesium sulphate 50 mg/kg (M) or normal saline (S) before induction. Post-operatively, a standardised analgesic regimen was used, and post-operative pain was recorded using a verbal numerical rating assessment (VNRA) score. Requirement for injected opioid analgesia was recorded., Results: ISA provided longstanding analgesia in all patients with block duration slightly prolonged in the magnesium group (16.7(1.0) (S), 17.8(1.3) h (M), p  = 0.049). Magnesium resulted in less rebound pain following ISA resolution (VNRA 4.0 (0.6) M, 6.2 (0.8) S, p  = 0.03) and lower pain intensity at 24 h. Four patients had nausea and two required rescue opioid injection., Conclusion: Magnesium before Latarjet surgery results in less rebound pain following ropivacaine block and improves post-operative analgesia. Magnesium may be indicated in major upper limb surgery, where significant pain intensity is anticipated., Level of Evidence: Treatment study; Randomised blinded; Level 2., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex ( p < 0.05). There was no effect of SLC30A3 genotype on BOLD activation during n-back or on cortical brain volume. This study supports the further investigation of SLC30A3 and its role in glutamatergic neurotransmission and in the neuropathology of mental illness., Competing Interests: In the last 3 years, JS has been principle investigator or sub-investigator on studies sponsored by Takeda, Janssen and Lundbeck Plc. He has attended an Investigators' meeting run by Allergan Plc. AY has given paid lectures and attended advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma. He is also a consultant to Johnson & Johnson and to Livanova. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jelen, Green, King, Morris, Zhang, Lythgoe, Young, De Belleroche and Stone.)

The ability of parasites to manipulate the behaviour of their hosts has evolved multiple times, and has a clear fitness benefit to the parasite in terms of facilitating growth, reproduction and transfer to suitable hosts. The mechanisms by which these behavioural changes are induced are poorly understood, but in many cases parasite manipulation of serotonergic signalling in the host brain is implicated. Here we report that Phasmarhabditis hermaphrodita, a parasite of terrestrial gastropod molluscs, can alter the behaviour of slugs. Uninfected slugs (Deroceras panormitanum, Arion subfuscus and Arion hortensis) avoid areas where P. hermaphrodita is present, but slugs infected with P. hermaphrodita are more likely to be found where the nematodes are present. This ability is specific to P. hermaphrodita and other nematodes (Steinernema carpocapsae and Heterorhabditis bacteriophora) do not induce this behavioural change. To investigate how P. hermaphrodita changes slug behaviour we exposed slugs to fluoxetine (a selective serotonin reuptake inhibitor) and cyproheptadine (a serotonin receptor antagonist). Uninfected slugs fed fluoxetine no longer avoided areas where P. hermaphrodita was present; and conversely, infected slugs fed cyproheptadine showed no increased attraction to areas with nematodes. These findings suggest that a possible mechanism by which P. hermaphrodita is able to manipulate parasite avoidance behaviour in host slugs is by manipulating serotonergic signalling in the brain, and that increased serotonin levels are potentially associated with a reduction in parasite avoidance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Protein disulfide isomerase (PDI) plays an important role in the endoplasmic reticulum (ER) by facilitating the exchange of disulfide bonds and, together with other ER stress proteins, is induced in amyotrophic lateral sclerosis (ALS). However, genetic polymorphisms in the P4HB gene, which encodes PDI, have not been thoroughly investigated in ALS cases. In this study, we determined whether single-nucleotide polymorphisms (SNPs) in the P4HB gene were associated with familial ALS (FALS) and sporadic ALS (SALS). We report significant genotypic associations for two SNPs in P4HB with FALS, rs876016 (P=0.0198) and rs2070872 (P=0.0046), all values being FDR corrected. Significant allelic associations were also obtained for rs876016 with FALS (P=0.0155) and ALS (FALS and SALS) (P=0.0148). Four SNP haplotypes, which included two additional flanking SNPs, rs876017 and rs8324, were examined and rare haplotypes were found to be more common in ALS cases compared to controls. Seven haplotypes were significantly associated with FALS and one haplotype was significantly associated with SALS. One rare haplotype, which was present in controls, was overrepresented in a group of SOD1-positive FALS cases. Reduced survival was observed in FALS cases possessing at least one copy of the minor allele of rs2070872 (P=0.0059) and rs8324 (P=0.0167) and in individuals lacking the homozygous AAAC/AAAC diplotype (P=0.011). The results suggest that P4HB is a modifier gene in ALS susceptibility and may represent a potential therapeutic target for ALS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.

Thioredoxin reductase 1 is a key enzyme in cellular redox processes, which are known to play a role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). The gene TXNRD1 was therefore screened for association with FALS. Resequencing of the exons and flanking regions identified 19 single-nucleotide polymorphisms (SNPs) of which 2, the intronic SNPs rs6539137 and rs4630362, were significantly associated with FALS. However, no association of rs6539137 with sporadic ALS was detected. The TXNRD1 haplotypes were reconstructed using the EH and PHASE 2.1 programs and also showed an association with FALS. Bayesian analysis of these SNP combinations, carried out using the BIMBAM program, indicated that rs10861192 strongly augmented this association. Indeed the haplotypes with minor alleles at both rs10861192 and rs6539137, although present in FALS, were totally absent from controls. Patients with the minor allele of rs6539137 were also associated with an early age at onset, which was decreased by 8 years. Furthermore the shift of onset was more pronounced in males and not significant in females. These results show that TXNRD1 may act as an important modifier gene of FALS and indicate that the additional thiol-redox system genes, thioredoxin and the peroxiredoxins, should also be investigated in FALS and other neurological disorders.

Background: Trinucleotide repeats have been associated with schizophrenia, but the evidence, based on cross-sectional clinical information, is equivocal., Aims: To examine the relationship between genomic CAG/CTG repeat size and premorbid development in schizophrenia., Method: Early development and premorbid functioning of 22 patients with DSM-IV diagnosis of schizophrenia were assessed by parental interviews. Repeat expansion detection (RED) technique was used to measure genomic CAG/CTG repeat size, and PCR for CAG repeat size at the ERDA-1 and CTG 18.1 loci., Results: There was an inverse association between CAG/CTG size and perinatal complications. Patients with speech and motor developmental delay had larger repeats. The results were not due to expansion in the ERDA-1 and CTG 18.1 genes., Conclusions: CAG/CTG repeat expansion is associated with speech and motor developmental delay in schizophrenia. We propose that the developmental model may be useful for research into the genetics of schizophrenia.

OPA1, the gene responsible for autosomal dominant optic atrophy, represents a good candidate gene for glaucoma, as there are similarities in the clinical phenotype and OPA1 is expressed in the optic nerve. Single nucleotide polymorphisms on intervening sequence (IVS) 8 of the OPA1gene (genotype IVS8+4 C/T;+32T/C) were recently found to be strongly associated with normal tension glaucoma (NTG). In order to investigate whether this association exists in patients with high-tension glaucoma (HTG), 90 well-characterized HTG patients were examined for the presence of these OPA1polymorphisms by PCR amplification followed by bi-directional sequencing. Five out of 90 HTG subjects (5.6%; 95% CI 1.8-12.5) were found to carry the OPA1 genotype IVS 8+4 C/T; +32 T/C, compared with 32/163 (19.6%; 95% CI 13.8-26.6) NTG subjects [chi(2)=9.2, P=0.002, OR 4.1 (95% CI 1.6-11.1)], and 7/186 (3.8%; 95% CI 1.5-7.6) control subjects [chi(2)=0.47, P=0.49, OR 1.5 (95% CI 0.5-4.9)]. These results indicate that unlike NTG, the OPA1 genotype IVS8+4 C/T,+32T/C is not significantly associated with high-tension primary open angle glaucoma, and suggest genetic heterogeneity between the conditions.

Normal tension glaucoma (NTG) is a major form of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. OPA1, the gene responsible for autosomal dominant optic atrophy represents an excellent candidate gene for NTG, as the clinical phenotypes are similar and OPA1 is expressed in the retina and optic nerve. Eighty-three well-characterized NTG patients were screened for mutations in OPA1 by heteroduplex analysis and bi-directional sequencing. Sequences found to be altered in NTG subjects were examined for variations in 100 population controls. A second cohort of 80 NTG patients and 86 population controls was subsequently screened to determine whether the initial findings could be replicated. A single nucleotide polymorphism (SNP) on intervening sequence (IVS) 8 (IVS8 + 4 C/T) was found to be strongly associated with the occurrence of NTG in both cohorts (chi(2)=7.97, P=0.005 in the first cohort, chi(2)=9.93, P=0.002 in the second cohort; odds ratio 3.1 (95% CI: 1.8-5.6). A second SNP (IVS8 + 32 T/C) appeared to be associated with disease in the first cohort (chi(2)=4.71, P=0.030), but this finding could not be replicated in the second cohort. In the combined cohort, the compound at-risk genotype IVS8 + 4 C/T, + 32 T/C was strongly associated with the occurrence of NTG (chi(2)=22.04, P=0.00001 after correcting for testing four genotypes). These results indicate that polymorphisms in the OPA1 gene are associated with NTG and may be a marker for the disease.