The study reported in this Research Communication was conducted to characterise Staphylococcus aureus isolates recovered from mastitic bovine milk from dairy herds in Argentina. A total of 829 mastitic milk samples, both clinical and subclinical, were collected from 21 farms by veterinarians and submitted to the laboratory for testing from which 229 S. aureus isolates were recovered, an isolation rate of 28·1%. These isolates were tested for susceptibility to the antibiotics penicillin, erythromycin and clindamycin. Of the 229 isolates, 53 (23·1%) were resistant to penicillin, 31 (13·5%) to erythromycin and 28 (12·2%) to clindamycin. All isolates were negative for the mecA, mecC and pvl genes by PCR. Southernblot hybridisation revealed that the ermC gene was located on plasmid bands. Eighty isolates were randomly selected from the 229 for further characterisation. Restriction analysis of chromosomal DNA with Cf9I followed by PFGE of the 80 isolates revealed 23 distinct pulsotypes at 80% similarity. Seven major types (A, B, N, P, S, T, U and V) accounted for 68·7% of these isolates and 12 pulsotypes (A, B, F, G, J, K, M, N, P, S, T and U) occurred on more than one farm indicating genetic diversity within the farms. MLST of a representative isolate from dominant types identified the STs 97 705, 746, 2102 and 2187 with ST97 being the most predominant. Antibiotic susceptibility testing showed that 53·7% of the 80 randomly selected isolates were resistant to at least one of the three antibiotics tested. To our knowledge, this study represents the first large scale molecular studies on S. aureus isolates from dairy farms in Argentina.

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in the TARDBP gene (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR/Cas9, we engineered two homozygous knock-in iPSC lines carrying mutations in TARDBP encoding TDP-43A382Tand TDP-43G348C, two common yet understudied ALS TDP-43 variants. MNs differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43A382Tand TDP-43G348CMN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings argue that MN dysfunction precedes the occurrence of TDP-43 pathology and neurodegeneration in ALS, and further implicates synaptic and excitability defects in the pathobiology of this disease.

Amyotrophic lateral sclerosis (ALS) is a disease characterized by upper and lower motor neuron (MN) loss with a signature feature of cytoplasmic aggregates containing TDP-43, which are detected in nearly all patients. Mutations in the gene that encodes TDP-43 (TARBDP) are known to result in both familial and sporadic ALS. In ALS, disruption of neuromuscular junctions (NMJs) constitutes a critical event in disease pathogenesis, leading to denervation atrophy, motor impairments and disability. Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro, linking TDP-43 dysregulation to the loss of NMJ integrity in ALS. Through the lens of the dying-back and dying-forward hypotheses of ALS, this review discusses the roles of TDP-43 related to synaptic function, with a focus on the potential molecular mechanisms occurring within MNs, skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.