Professor Janine Kirby
Department of Neuroscience
Professor in Neurogenetics
+44 114 222 2247
Full contact details
Department of Neuroscience
385a Glossop Road
I first came to the University of Sheffield as an undergraduate, graduating with a First Class Honours in Genetics and the Alan Roper (Panlabs) Prize for Genetics. I then completed my PhD in Genetics at the MRC Human Biochemical Genetics Unit, University College London.
I subsequently joined the Motor Neurone Disease Research Group at the University of Newcastle-upon-Tyne, headed by Prof Pamela Shaw. During the intervening years, first at Newcastle and now at the University of Sheffield, I have focused on the genetic and transcriptomic analysis of ALS, in order to understand the molecular basis of this complex disorder and identify prognostic and diagnostic biomarkers.
I was awarded a New Blood Lectureship in the Academic Neurology Unit and I am now Professor of Neurogenetics. I am Deputy Head of Department for Learning and Teaching and the Faculty Director of Postgraduate Teaching.
- Research interests
My research interests are the genetics of MND and how gene expression profiling can be used to investigate the pathogenic mechanisms of neurodegeneration and to identify diagnostic and prognostic biomarkers. MND is genetically heterogeneous, with over 25 loci identified for the most common form of the disease, ALS, and the causative genes have been identified at most of these through the application of next generation sequencing.
Since individuals with known genetic variants of MND are generally indistinguishable from sporadic patients in the clinical setting, the disease is thought to progress along common pathways which result in the death of the motor neurones. Therefore, by understanding the pathogenic mechanisms in the genetic variants of the disease, it is hoped that the results will be widely applicable to other cases where the cause is currently unknown.
My research therefore focuses on obtaining gene expression profiles from experimental models of the disease and from patient and control samples, in order to both elucidate the reasons why the motor neurones are dying and to identify useful biomarkers of ALS. More recently, I am looking at the impact of therapeutic treatments on the blood transcriptome.
- Determining the transcriptional response in blood to riluzole and low dose interleukin-2 (IMODALS and MIROCALS Clinical Trials)
- Identification of novel genetic causes of ALS using next generation sequencing technology
- Elucidation of genotype / phenotype correlations in newly identified genetic variants of ALS
- Isolating motor neurones from MND and control post-mortem spinal cord to look for changes in gene expression specific to genetic and disease variants of MND
- Elucidation of age-related changes in RNA expression profiles of the spinal cord
- Establishing a gene signature of fast and slow disease progression in biosamples from ALS patients
- Elucidation of distinct ALS subgroups through large scale gene expression profiling of lymphoblastoid cell lines, with a specific focus on identifying signatures associated with genetic variants and disease progression.
- Establishing biomarkers for diagnosis and monitoring progression of the disease by detecting miRNAs in the serum and CSF of patients and controls
- The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential.. Amyotroph Lateral Scler Frontotemporal Degener, 1-10.
- TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis. Neuropathology and Applied Neurobiology. View this article in WRRO
- Neuropathological characterisation of a novel TBK1 loss of function mutation associated with amyotrophic lateral sclerosis. Neuropathology & Applied Neurobiology. View this article in WRRO
- Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis. Cell Reports, 26(9), 2298-2306.e5. View this article in WRRO
- Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia. Neurobiology of Aging, 73, 229.e5-229.e9. View this article in WRRO
- Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis. Annals of Neurology, 85(4), 470-481.
- Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6. View this article in WRRO
- Small RNA Sequencing of Sporadic Amyotrophic Lateral Sclerosis Cerebrospinal Fluid Reveals Differentially Expressed miRNAs Related to Neural and Glial Activity. Frontiers in Neuroscience, 11. View this article in WRRO
- ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of Aging, 71, 266.e1-266.e10. View this article in WRRO
- Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype. Frontiers in Molecular Neuroscience, 10, 370-370. View this article in WRRO
- SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nature Communications, 8. View this article in WRRO
- Serum miRNAs miR-206, 143-3p and 374b-5p as potential biomarkers for amyotrophic lateral sclerosis (ALS). Neurobiology of Aging, 55, 123-131. View this article in WRRO
- Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Science Translational Medicine, 9(388). View this article in WRRO
- A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.. Acta Neuropathol Commun, 5(1), 23-23. View this article in WRRO
- C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten. Human Molecular Genetics, 26(6), 1133-1145. View this article in WRRO
- Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 1-7. View this article in WRRO
- Motor neurone disease/amyotrophic lateral sclerosis associated with intermediate‐length CAG repeat expansions in Ataxin‐2 does not have 1C2‐positive polyglutamine inclusions. Neuropathology and Applied Neurobiology, 42(4), 377-389. View this article in WRRO
- The genetics of amyotrophic lateral sclerosis: current insights. Degenerative Neurological and Neuromuscular Disease, 6, 49-64. View this article in WRRO
- Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP‐43‐negative inclusions of C9ORF72‐ALS. Neuropathology, 36(2), 125-134. View this article in WRRO
- Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 17(5-6), 404-413. View this article in WRRO
- Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience, 9, 410-410. View this article in WRRO
- Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. FRONTIERS IN CELLULAR NEUROSCIENCE, 9. View this article in WRRO
- The CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients. Neurobiology of Aging, 36(10), 2908.e17-2908.e18. View this article in WRRO
- Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathologica, 130(1), 63-75. View this article in WRRO
- C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLOS ONE, 10(5), e0127376-e0127376. View this article in WRRO
- Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes. Neurobiology of Aging, 36(5), 2006.e1-2006.e9. View this article in WRRO
- The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis. Neurotherapeutics, 12(2), 326-339. View this article in WRRO
- Invited Review: Decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathology and Applied Neurobiology, 41(2), 109-134. View this article in WRRO
- Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response and RNA processing functions.. Neuropathol Appl Neurobiol, 41(2), 201-226. View this article in WRRO
- Intermediate length C9orf72 expansion in an ALS patient without classical C9orf72 neuropathology. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16(3-4), 249-251. View this article in WRRO
- Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones.. Neuropathol Appl Neurobiol, 40(6), 670-685.
- Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15(5-6), 344-350.
- Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions.. Brain, 137(Pt 7), 2040-2051. View this article in WRRO
- Axonal Preservation in Deep Subcortical White Matter Lesions in the Ageing Brain. Journal of Aging Science, 2(1). View this article in WRRO
- TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.. Acta Neuropathol, 127(3), 407-418. View this article in WRRO
- The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype.. Acta Neuropathol, 127(3), 333-345. View this article in WRRO
- Comparison of blood RNA extraction methods used for gene expression profiling in amyotrophic lateral sclerosis.. PLoS One, 9(1), e87508. View this article in WRRO
- C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles.. Neurology, 81(19), 1719-1721.
- ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN. Human Molecular Genetics, 22(18), 3690-3704.
- C9ORF72 expansions, parkinsonism, and Parkinson disease: a clinicopathologic study.. Neurology, 81(9), 808-811.
- S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis.. Free Radic Biol Med, 61, 438-452.
- Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation.. Mol Neurodegener, 8, 12. View this article in WRRO
- Investigating cell death mechanisms in amyotrophic lateral sclerosis using transcriptomics.. Front Cell Neurosci, 7, 259. View this article in WRRO
- Neuronal dark matter: the emerging role of microRNAs in neurodegeneration.. Front Cell Neurosci, 7, 178. View this article in WRRO
- Lack of unique neuropathology in amyotrophic lateral sclerosis associated with p.K54E angiogenin (ANG) mutation.. Neuropathol Appl Neurobiol, 39(5), 562-571. View this article in WRRO
- Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity.. Acta Neuropathol, 125(1), 95-109. View this article in WRRO
- Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72.. J Neurol Neurosurg Psychiatry, 84(1), 79-87.
- The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.. Eur J Hum Genet, 21(1), 102-108.
- Gene expression profiling in human neurodegenerative disease.. Nat Rev Neurol, 8(9), 518-530.
- Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72.. Brain, 135(Pt 3), 751-764.
- Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: A cross-sectional study. The Lancet Neurology, 11(4), 323-330.
- Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. The Lancet Neurology.
- Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology.. Acta Neuropathol, 122(6), 657-671.
- Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis.. Nat Rev Neurol, 7(11), 616-630.
- Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis.. Brain, 134(Pt 9), 2627-2641.
- HFE H63D, C282Y and AGTR1 A1166C Polymorphisms and Brain White Matter Lesions in the Aging Brain. J NEUROGENET, 25(1-2), 7-14.
- Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis.. Brain, 134(Pt 2), 506-517. View this article in WRRO
- Brain iron dysregulation and the risk of ageing white matter lesions. NeuroMolecular Medicine, 13(4), 289-299.
- Brain Iron Dysregulation and the Risk of Ageing White Matter Lesions. NeuroMolecular Medicine, 1-11.
- TARDBP mutations, amyotrophic lateral sclerosis and alternative splicing in human fibroblasts. BRAIN PATHOLOGY, 20, 32-32.
- Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis.. Neurogenetics, 11(2), 217-225. View this article in WRRO
- Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.. Arch Neurol, 67(4), 455-461.
- Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS).. PLoS One, 5(3), e9872. View this article in WRRO
- Molecular and evolutionary investigation of the phosphoglucomutase gene family..
- Transcriptional response of the neuromuscular system to exercise training and potential implications for ALS.. J Neurochem, 109(6), 1714-1724.
- New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP).. Neurogenetics, 10(2), 105-110.
- HSP60 is a rare cause of hereditary spastic paraparesis, but may act as a genetic modifier.. Neurology, 70(19), 1717-1718.
- Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS.. J Neurosci, 27(34), 9201-9219.
- Mutations in VAPB are not associated with sporadic ALS.. Neurology, 68(22), 1951-1953.
- Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.. Ann Neurol, 61(5), 427-434.
- Gene expression assays.. Adv Clin Chem, 44, 247-292.
- Clinical features of hereditary spastic paraplegia due to spastin mutation.. Neurology, 67(1), 45-51.
- Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen.. Brain, 129(Pt 7), 1693-1709.
- Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS.. Brain, 128(Pt 7), 1686-1706.
- Screening of the regulatory and coding regions of vascular endothelial growth factor in amyotrophic lateral sclerosis. NEUROGENETICS, 6(2), 101-104.
- No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders. AMYOTROPH LATERAL SC, 4(3), 150-157.
- Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND).. Amyotroph Lateral Scler Other Motor Neuron Disord, 4(2), 96-99.
- Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways.. J Biol Chem, 278(8), 6371-6383.
- Quantitative assessment of AMPA receptor mRNA in human spinal motor neurons isolated by laser capture microdissection.. Neuroreport, 13(14), 1753-1757.
- Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis.. J Neurochem, 82(5), 1118-1128.
- Differential gene expression in a cell culture model of SOD1-related familial motor neurone disease.. Hum Mol Genet, 11(17), 2061-2075.
- Mutation screening of manganese superoxide dismutase in amyotrophic lateral sclerosis.. Neuroreport, 12(11), 2319-2322.
- Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England.. Neurology, 56(4), 467-471.
- Screening of AP endonuclease as a candidate gene for amyotrophic lateral sclerosis (ALS).. Neuroreport, 11(8), 1695-1697.
- Mechanisms leading to cell death associated with mutations in Cu/Zn superoxide dismutase (SOD1): Insights from cellular models. EUR J NEUROSCI, 12, 226-226.
- Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS).. Neuroreport, 9(17), 3967-3970.
- Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of five new cases, and comparison with previous reports and 73 sporadic cases of ALS.. J Neuropathol Exp Neurol, 57(10), 895-904.
- Kennedy's disease: unusual molecular pathologic and clinical features.. Neurology, 51(1), 252-255.
- A phylogenetic approach to the identification of phosphoglucomutase genes. Molecular Biology and Evolution, 15(4), 456-462.
- CNS tissue Cu/Zn superoxide dismutase (SOD1) mutations in motor neurone disease (MND).. Neuroreport, 8(18), 3923-3927.
- Mutation analysis in CNS tissue from motor neurone disease (MND) patients. J MED GENET, 34, 1422-1422.
- Molecular and cytological investigations of phosphoglucomutase (PGM1) in the K562 cell line. Annals of Human Genetics, 61(2), 99-108.
- Oligodendrocyte pathology exceeds axonal pathology in white matter in human amyotrophic lateral sclerosis. The Journal of Pathology.
- Common Themes in the Pathogenesis of Neurodegeneration, Neurodegenerative Disorders (pp. 1-12). Springer International Publishing
- Insights Arising from Gene Expression Profiling in Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis InTech
- Genetics of Familial Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis InTech
Conference proceedings papers
- Nottingham Pathology 2016. 9th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland, 28 June - 1 July 2016. The Journal of Pathology, Vol. 240 (pp S1-S48) View this article in WRRO
- Investigating the mechanisms underlying oligodendrocyte dysfunction in C9ORF72 ALS. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 42(S1) (pp 28-28), 2 March 2016 - 4 March 2016. View this article in WRRO
- Investigating the mechanisms underlying oligodendrocyte dysfunction in C9ORF72 ALS. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 41 (pp 26-27)
- AMYOTROPHIC LATERAL SCLEROSIS ASSOCIATED WITH AN INTERMEDIATE LENGTH GGGGCC REPEAT EXPANSION HAS DISTINCT NEUROPATHOLOGY COMPARED TO PATIENTS WITH LARGER EXPANSIONS. Journal of Neurology, Neurosurgery & Psychiatry, Vol. 85(10) (pp e4.130-e4)
- A pathological basis for the association of parkinsonism and amyotrophic lateral sclerosis. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 39 (pp 51-51)
- Neurodegeneration caused by intronic expansions of C9ORF72 is a clinically heterogeneous but pathologically distinct disease. LANCET, Vol. 381 (pp 32-32)
- DYSREGULATION OF THE CROSS-TALK WITH ASTROCYTES AS A CONTRIBUTORY FACTOR TO MOTOR NEURON INJURY IN MOTOR NEURON DISEASE. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol. 83(3)
- Age-dependent penetrance and anticipation in ALS+/-FTLD kindreds due to C9ORF72 hexanucleotide intronic repeat expansion mutations (C9HIREM). DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, Vol. 33 (pp 282-282)
- Age-dependent penetrance and anticipation in ALS+/-FTLD kindreds due to C9ORF72 hexanucleotide intronic repeat expansion mutations (C9HIREM). DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, Vol. 33 (pp 36-37)
- TARDBP mutations, amyotrophic lateral sclerosis and alternative splicing. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 37 (pp 20-20)
- Iron metabolism pathways in white matter lesions in the elderly. JOURNAL OF NEURAL TRANSMISSION, Vol. 115(12) (pp 1717-1718)
- HFE gene polymorphisms and risk of brain white matter lesions (WML). NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 34 (pp 32-32)
- Extra-motor manifestations of motor neurone disease and the role of TDP43 in ALS variants. NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol. 33(2) (pp 264-265)
- Further insights into HSP and spastin: Severe complicated phenotypes and evidence of lower motor neurone dysfunction. JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol. 77(1) (pp 137-137)
- Impaired mitochondrial anti-oxidant defence in SOD1-related familial amyotrophic lateral sclerosis (FALS). JOURNAL OF THE NEUROLOGICAL SCIENCES, Vol. 238 (pp S56-S56)
- Perturbation of mitochondrial anti-oxidant defence in a cell-culture model of SOD1-related familial amyotrophic lateral sclerosis. JOURNAL OF NEUROLOGY, Vol. 252 (pp 18-19)
- Hereditary spastic paraparesis with amyotrophy and OXPHOS muscle defect associated with a deletion in the paraplegin (SPG7) gene with apparent autosomal dominant transmission. NEUROLOGY, Vol. 54(7) (pp A425-A425)
- Cu/Zn superoxide dismutase (SOD1) mutations in amyotrophic lateral sclerosis (ALS) CNS tissue: Exclusion of somatic mutations and correlations with molecular pathology. NEUROLOGY, Vol. 48(3) (pp 49005-49005)
- Research group
Tobias Moll (second supervisor)
- Teaching activities
I was instrumental in developing and delivering the MSc in Genomic Medicine at the University of Sheffield. I am co-lead of this programme, as well as module lead for several of the taught modules and the Research Project. I previously led the MSc Translational Neuroscience, which covers basic neurobiology and molecular biology, through to neuroimaging and applied clinical practise.
I am the module leader for the Research Projects on this course. I also contribute to delivery of other PGT courses, including MSc Translational Neuropathology and MSc Clinical Neurology as well as our distance learning course Translational Neuroscience and Neurodegeneration.
In terms of L&T leadership, I am Faculty Director of Postgraduate Teaching, and within the Department of Neuroscience I am Director of Learning and Teaching, as well as Deputy Head for L&T. I chair the Faculty PGT Committee and Neuroscience L&T Committee.
- Professional activities
- Peer review of grant applications for funding bodies including MRC, Wellcome Trust & Motor Neurone Disease Association (MNDA)
- Peer review of submitted articles for high impact journals including Brain, Human Molecular Genetics and Neurology
- Current or past member of MNDA (UK), Agenzia di Ricercaper la Sclerosci Laterale Amiotrophica (Italy) and ALS Canada Grant Review Boards
- Member of the Editorial Board for Journal of Neuropathology and Applied Neurobiology
- Member of Ethics Review Panel for School of Medicine