Temperature Dependence of Kinetic Friction: A Handle for Plastics Sortation?

Sortation is a crucial step in mechanical recycling of post-consumer plastics (PCR) whereby properties such as density or spectral signature are used to separate plastics. However it is difficult to sort polyolefin flakes at high throughput by these properties. We ask whether the frictional properties of plastics as a function of temperature may be used as an alternate sorting property. However, fundamental studies of friction at temperatures near their melting points are limited. Here we measure the temperature dependence of kinetic friction for three common polyolefins (high and low den- sity polyethylene and polypropylene) as well as polyethylene terephthalate (PET), focusing on the softening/melting regime. The results are augmented by differential scanning calorimetry and temperature dependence measurements of both dynamic modulus and and probe tack. For the polyolefins, we find strong increases in the coefficients of kinetic friction during temperature ramps in the melting/softening regime. For the PET, we report a notable peak in the kinetic friction which we associate with the glass transition and cold-crystallization. We discuss the enhanced friction in the context of rub- ber friction, which exhibits comparable coefficients of kinetic frictions.

Mechanism of co-operation of mutant IL-7Rα and mutant NRAS in acute lymphoblastic leukemia: role of MYC.

Acute lymphoblastic leukemia (ALL) is an aggressive leukemia which can be derived from either T-cell or B-cell precursors. With current treatments, the survival rate is high, but the treatments are highly toxic with severe side effects. Individual mutations in IL7Rssand RAS pathways have been previously shown to be prevalent in ALL and especially in relapsed patients. The relationship of IL-7R77and RAS was investigated by transducing immature mouse thymocytes with the combination of these mutants. The resultant ALL cells were analyzed to identify the regulators and the oncoproteins that are upregulated or downregulated by the combination of IL7Rα with NRAS. Leukemia cells showed a significant increase in IL7Rw-mediated BCL2 expression, and an increase in MYC protein levels, was mainly induced by NRAS signaling. MYC was both necessary and sufficient to replace mutant NRAS and drugs targeting the MYC pathway showed a therapeutic benefit in IL-7R7/NRAS T-ALL. We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.

Virtual student-led neuroscience conferencing: a UK multicentre prospective study investigating delegate outcomes and delivery mode.

BACKGROUND: Clinical neuroscience training programmes are becoming increasingly competitive to enter. UK university neuroscience societies act as a local environment for students to develop their career interests and provide portfolio building opportunities through hosting events such as annual conferences. Recently there has been a transition to more of these events being held online yet the impact of this, if any, remains unclear. This prospective study aimed to identify the impact of student-led neuroscience conferences on delegates and examine attitudes towards an online delivery approach. METHODS: Multi-centre prospective survey study using pre-conference, post-conference, and 6-month post-conference online questionnaires distributed at 6 virtual student-led neuroscience conferences in 2021. The questionnaires had five-domains: demographics, career aspirations, academic skillsets, an educational manipulation check (EMC) and mode of delivery preference. RESULTS: Nine hundred twenty-four surveys were completed across 559 conference attendances. 79.9% of delegates were medical students. Interest in a neuroscience career (p < 0.001), preparedness to undertake research (p < 0.001) and presentation (p < 0.001), as well as EMC scores (p < 0.001) increased immediately post conference. Most participants at 6 months post-attendance had completed an academic project (71.9%) or presentation (50.9%), although 88.8% were lost to follow up. Online format was preferred (65%) with reasons including elimination of travel and access to home facilities whilst lack of face-to-face interaction and engagement were recognised limitations. CONCLUSION: UK student-led online neuroscience conferences play a role in developing knowledge and may facilitate career interest, academic skillset and longer term portfolio building. A hybrid virtual and in-person experience would offer an ideal solution to future conferencing, providing options promoting engagement and interactivity whilst advocating sustainability, accessibility and widening participation.

The cost effectiveness of tranexamic acid for preventing periprosthetic joint infection following total shoulder arthroplasty: a break-even analysis.

BACKGROUND: The use of tranexamic acid (TXA) has become widespread in orthopedics to promote hemostasis and has been successfully used to reduce blood loss and infection risk in joint arthroplasty. However, the cost effectiveness of routine TXA use for the prevention of periprosthetic infections in total shoulder arthroplasty remains unknown. METHODS: The acquisition cost of TXA ($5.22) for our institution, along with values from the literature for the average cost of infection-related care ($55,243) and the baseline infection rates for patients without TXA use (0.70%),were used to perform a break-even analysis. The absolute risk reduction (ARR) of infection necessary to justify the prophylactic use of TXA in shoulder arthroplasty was calculated from the nontreated and break-even infection rates. RESULTS: TXA is considered cost-effective if it prevents one infection out of 10,583 total shoulder arthroplasty's (ARR = 0.009%). It is economically justifiable with an ARR range of 0.001% at a cost of $0.50/g to 0.181% at $100/g. At varying costs of infection-related care ($10,000-$100,000) and varying baseline infection rates (0.50%-8.00%) and routine use of TXA remained cost-effective. CONCLUSION: The use of TXA is an economically viable practice for infection prevention following shoulder arthroplasty if it reduces the infection rate by 0.009%. Future, prospective studies should be conducted to observe whether TXA reduces the infection rate by more than 0.009%, showing cost effectiveness.

Mechanistic and therapeutic implications of EphA-4 receptor tyrosine kinase in the pathogenesis of Alzheimer's disease.

Erythropoietin-producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain. Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA-4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA-4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA-4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA-4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA-4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA-4 that exhibit the potential to modulate EphA-4 and could be used as lead molecules for the targeted therapy of AD.

Discovery of novel polyamide-pyrrolobenzodiazepine hybrids for antibody-drug conjugates.

Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10-11-10-8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads.

Detection of 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae in the United Kingdom, December 2021 to June 2022.

Between December 2021 and June 2022, 10 cases of ceftriaxone-resistant Neisseria gonorrhoeae (ST8123; n = 8) were detected in the United Kingdom, compared with nine cases during the previous 6 years. Most of these cases were associated with travel from the Asia-Pacific region; all were heterosexual people, with most in their 20s. Although all cases were successfully treated, not all partners of cases could be traced, and there is a risk of further transmission of ceftriaxone-resistant gonococcal infection within the UK.

Characteristics of Forces at the Clinician-Patient and Patient-Table Interfaces During Thoracic Spinal Manipulation in Asymptomatic Adults Are Consistent With Deformable Body Models.

Investigating all forces exerted on the patient's body during high-velocity, low-amplitude spinal manipulative therapy (SMT) remains fundamental to elucidate how these may contribute to SMT's effects. Previous conflicting findings preclude our understanding of the relationship between SMT forces acting at the clinician-patient and patient-table interfaces. This study aimed to quantify forces at the clinician-participant and participant-table interfaces during thoracic SMT in asymptnomatic adults. An experienced clinician provided a posterior to anterior SMT centered to T7 transverse processes using predetermined force-time characteristics to 40 asymptomatic volunteers (20 females; average age = 27.2 [4.9] y). Forces at the clinician-participant interface were recorded by triaxial load cells; whereas, forces at the participant-table interface were recorded by the force-sensing table technology. Preload force, total peak force, time to peak, and loading rate at each interface were analyzed descriptively. Total peak vertical forces at the clinician-participant interface averaged 532 (71) N while total peak forces at the participant-table interface averaged 658 (33) N. Forces at the participant-table interface were, on average, 1.27 (0.25) times larger than the ones at the clinician-participant interface. Larger forces at the participant-table interface compared with the ones at the clinician-participant interface during thoracic SMT are consistent with mathematical models developed to investigate thoracic impact simulating a dynamic force-deflection response.

Trends in Incidence of Adolescent Idiopathic Scoliosis: A Modern US Population-based Study.

BACKGROUND: A successful disease screening strategy requires a high incidence of the condition, efficacy of early treatment, and efficient detection. There is limited population-based data describing trends in incidence of adolescent idiopathic scoliosis (AIS) in the United States and potential role of school screening programs on the incidence of AIS. Thus, we sought to evaluate the incidence of AIS over a 20-year period between 1994 and 2013 using a population-based cohort. METHODS: The study population comprised 1782 adolescents (aged 10 to 18 y) with AIS first diagnosed between January 1, 1994 and December 31, 2013. The complete medical records and radiographs were reviewed to confirm diagnosis and coronal Cobb angles at first diagnosis. Age-specific and sex-specific incidence rates were calculated and adjusted to the 2010 United States population. Poisson regression analyses were performed to examine incidence trends by age, sex, and calendar period. RESULTS: The overall age-adjusted and sex-adjusted annual incidence of AIS was 522.5 [95% confidence interval (CI): 498.2, 546.8] per 100,000 person-years. Incidence was about 2-fold higher in females than in males (732.3 vs. 338.8/100,000, P<0.05). The incidence of newly diagnosed AIS cases with radiographs showing a Cobb angle >10 degrees was 181.7 (95% CI: 167.5, 196.0) per 100,000 person-years. The overall incidence of AIS decreased significantly after discontinuation of school screening in 2004 (P<0.001). The incidence of bracing and surgery at initial diagnosis was 16.6 (95% CI: 12.3, 20.9) and 2.0 (95% CI: 0.5, 3.4) per 100,000 person-years, respectively. CONCLUSIONS: Overall population-based incidence of AIS decreased after school screening was discontinued. However, incidence of patients with a Cobb angle >10 degrees, initiation of bracing and surgery did not change significantly over time. This provides further data to help determine the role of scoliosis screening. LEVEL OF EVIDENCE: Level III.

Ethnically diverse urban transmission networks of Neisseria gonorrhoeae without evidence of HIV serosorting.

OBJECTIVE: We aimed to characterise gonorrhoea transmission patterns in a diverse urban population by linking genomic, epidemiological and antimicrobial susceptibility data. METHODS: Neisseria gonorrhoeae isolates from patients attending sexual health clinics at Barts Health NHS Trust, London, UK, during an 11-month period underwent whole-genome sequencing and antimicrobial susceptibility testing. We combined laboratory and patient data to investigate the transmission network structure. RESULTS: One hundred and fifty-eight isolates from 158 patients were available with associated descriptive data. One hundred and twenty-nine (82%) patients identified as male and 25 (16%) as female; four (3%) records lacked gender information. Self-described ethnicities were: 51 (32%) English/Welsh/Scottish; 33 (21%) white, other; 23 (15%) black British/black African/black, other; 12 (8%) Caribbean; 9 (6%) South Asian; 6 (4%) mixed ethnicity; and 10 (6%) other; data were missing for 14 (9%). Self-reported sexual orientations were 82 (52%) men who have sex with men (MSM); 49 (31%) heterosexual; 2 (1%) bisexual; data were missing for 25 individuals. Twenty-two (14%) patients were HIV positive. Whole-genome sequence data were generated for 151 isolates, which linked 75 (50%) patients to at least one other case. Using sequencing data, we found no evidence of transmission networks related to specific ethnic groups (p=0.64) or of HIV serosorting (p=0.35). Of 82 MSM/bisexual patients with sequencing data, 45 (55%) belonged to clusters of ≥2 cases, compared with 16/44 (36%) heterosexuals with sequencing data (p=0.06). CONCLUSION: We demonstrate links between 50% of patients in transmission networks using a relatively small sample in a large cosmopolitan city. We found no evidence of HIV serosorting. Our results do not support assortative selectivity as an explanation for differences in gonorrhoea incidence between ethnic groups.

Urinary tract infection, inflammation, and cognition in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study.

BACKGROUND: Schizophrenia is associated with an increased prevalence of infections throughout the life span. Previous studies have found an association between urinary tract infection (UTI) and acute psychosis. We investigated the prevalence and correlates of UTI in a large cohort of patients with schizophrenia. METHODS: We estimated the prevalence of UTI at the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. We then investigated associations between UTI and inflammatory markers, psychopathology, and cognition, controlling for potential confounding factors. RESULTS: The prevalence of probable UTI at baseline in the CATIE trial was 1.2% (n = 13 of 1,061 participants). Compared with participants with a normal urinalysis (n = 387), after controlling for potential confounders, UTI was a significant predictor of greater impairments (approximately 1 standard deviation difference) in the cognition composite score (beta = -0.153, P = .002), and poorer working memory (beta = -0.190, P < .001). There were no differences in psychopathology scores between participants with probable UTI and those with a normal urinalysis. CONCLUSIONS: Urinary tract infections in patients with schizophrenia may have an impact on cognition. Findings provide additional evidence regarding infectious disease comorbidity, which may be clinically relevant in the treatment of patients with schizophrenia.

Seasonal influence of environmental variables and artificial aeration on Escherichia coli in small urban lakes.

This study investigated patterns of Escherichia coli in urban lakes in Lubbock, Texas. Specific objectives were to (1) document seasonal patterns in abundance of E. coli over a 3-year period, (2) identify environmental factors, including effects of migratory geese and artificial aeration devices that may influence E. coli abundance, and (3) determine if E. coli abundance over time was similar for individual lakes. Water samples were collected monthly for 36 months from six lakes, three of which contained artificial aeration devices (fountains). Regression models were constructed to determine which environmental variables most influence E. coli abundance in summer and winter seasons. Escherichia coli is present in the lakes of Lubbock, Texas year-round and typically exceeds established bacterial thresholds for recreational waters. Models most frequently contained pH and dissolved oxygen as predictor variables and explained from 17.4% to 92.4% of total variation in E. coli. Lakes with fountains had a higher oxygen concentration during summer and contained consistently less E. coli. We conclude that solar irradiation in synergy with pH and dissolved oxygen is the primary control mechanism for E. coli in study lakes, and that fountains help control abundance of fecal bacteria within these systems.

Tumor Necrosis Factor (TNF) Receptor Superfamily Member 1b on CD8+ T Cells and TNF Receptor Superfamily Member 1a on Non-CD8+ T Cells Contribute Significantly to Upper Genital Tract Pathology Following Chlamydial Infection.

BACKGROUND: We demonstrated previously that tumor necrosis factor α (TNF-α)-producing Chlamydia-specific CD8(+) T cells cause oviduct pathological sequelae. METHODS: In the current study, we used wild-type C57BL/6J (WT) mice with a deficiency in genes encoding TNF receptor superfamily member 1a (TNFR1; TNFR1 knockout [KO] mice), TNF receptor superfamily member 1b (TNFR2; TNFR2 KO mice), and both TNFR1 and TNFR2 (TNFR1/2 double KO [DKO] mice) and mix-match adoptive transfers of CD8(+) T cells to study chlamydial pathogenesis. RESULTS: TNFR1 KO, TNFR2 KO, and TNFR1/2 DKO mice displayed comparable clearance of primary or secondary genital Chlamydia muridarum infection but significantly reduced oviduct pathology, compared with WT animals. The Chlamydia-specific total cellular cytokine response in splenic and draining lymph nodes and the antibody response in serum were comparable between the WT and KO animals. However, CD8(+) T cells from TNFR2 KO mice displayed significantly reduced activation (CD11a expression and cytokine production), compared with TNFR1 KO or WT animals. Repletion of TNFR2 KO mice with WT CD8(+) T cells but not with TNFR2 KO CD8(+) T cells and repletion of TNFR1 KO mice with either WT or TNFR1 KO CD8(+) T cells restored oviduct pathology to WT levels in both KO groups. CONCLUSIONS: Collectively, these results demonstrate that TNFR2-bearing CD8(+) T cells and TNFR1-bearing non-CD8(+) T cells contribute significantly to oviduct pathology following genital chlamydial infection.

Artificial selection of microbial communities: what have we learnt and how can we improve?

Microbial communities are capable of performing diverse functions with important bioindustrial and medical applications. One approach to improving community function is to breed new communities by artificially selecting for those displaying high community function ('community selection'). Importantly, community selection can improve the function of interest without needing to understand how the function arises, just like in classical artificial selection of individuals. However, experimental studies of community selection have had varied and largely limited success. Here, we review a conceptual framework to help foster an understanding of community selection and its associated challenges, and provide broad insights for designing effective selection strategies.

An Overview of the Characteristics, Pathogenesis, Epidemiology, and Detection of Human Enterovirus in the Arabian Gulf Region.

Enteroviruses are RNA viruses that initiate infections through the gastrointestinal (GI) tract and are associated with enteric illness in individuals of all ages. Most serious infections of enteroviruses are in infants and young children where it is the common cause of aseptic meningitis and other systemic diseases, leading to a high mortality rate. Enteroviruses belong to the small non-enveloped family of the Picornaviridae family. The virus can spread mainly through fecal-oral and respiratory routes. In the Arabian Gulf countries, the incidence of enteroviral infections is only restricted to a few reports, and thus, knowledge of the epidemiology, characteristics, and pathogenesis of the virus in the gulf countries remains scarce. In this minireview, we sought to provide an overview of the characteristics of enterovirus and its pathogenesis, in addition to gathering the reports of enterovirus infection prevalence in Gulf Cooperation Council (GCC) countries. We also present a summary of the common methods used in its detection.

Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator.

Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ's interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of transcriptional activity. Additionally, the microarray demonstrated an enrichment of FRH binding to FRQ peptides with a net positive charge. We found that positively charged residues occurred in significant "blocks" within the amino acid sequence of FRQ and that ablation of one of these blocks affected both core clock timing and physiological clock output. Finally, we found positive charge clusters were a commonly shared molecular feature in repressive circadian clock proteins. Overall, our study suggests a mechanistic purpose for positive charge blocks and yielded insights into repressive arm protein roles in clock function.

Comparative mitogenomic analysis of Sporisorium reilianum f. sp. zeae suggests recombination events during its evolutionary history.

Introduction: Modern understanding of the concept of genetic diversity must include the study of both nuclear and organellar DNA, which differ greatly in terms of their structure, organization, gene content and distribution. This study comprises an analysis of the genetic diversity of the smut fungus Sporisorium reilianum f. sp. zeae from a mitochondrial perspective. Methods: Whole-genome sequencing data was generated from biological samples of S. reilianum collected from different geographical regions. Multiple sequence alignment and gene synteny analysis were performed to further characterize genetic diversity in the context of mitogenomic polymorphisms. Results: Mitochondria of strains collected in China contained unique sequences. The largest unique sequence stretch encompassed a portion of cox1, a mitochondrial gene encoding one of the subunits that make up complex IV of the mitochondrial electron transport chain. This unique sequence had high percent identity to the mitogenome of the related species Sporisorium scitamineum and Ustilago bromivora. Discussion: The results of this study hint at potential horizontal gene transfer or mitochondrial genome recombination events during the evolutionary history of basidiomycetes. Additionally, the distinct polymorphic region detected in the Chinese mitogenome provides the ideal foundation to develop a diagnostic method to discern between mitotypes and enhance knowledge on the genetic diversity of this organism.

Hospitalisation rates for youth living with perinatally acquired HIV in England.

INTRODUCTION: Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10-35 years) living with PaHIV in England. METHOD: Retrospective observational cohort study over a three-year period 2016-2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. RESULTS: 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16-22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9-11.6). The respective crude incidence rates were 1.5 PY (0.0-8.2) in those aged 10-14 years and 3.5 PY (1.5-7.0) in the 15-19-year-olds. In those aged 20-24 years it was 14.5 PY (10.1-20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9-18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8-8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6-5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. CONCLUSIONS: Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10-19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

Isogenic patient-derived organoids reveal early neurodevelopmental defects in spinal muscular atrophy initiation.

Whether neurodevelopmental defects underlie postnatal neuronal death in neurodegeneration is an intriguing hypothesis only recently explored. Here, we focus on spinal muscular atrophy (SMA), a neuromuscular disorder caused by reduced survival of motor neuron (SMN) protein levels leading to spinal motor neuron (MN) loss and muscle wasting. Using the first isogenic patient-derived induced pluripotent stem cell (iPSC) model and a spinal cord organoid (SCO) system, we show that SMA SCOs exhibit abnormal morphological development, reduced expression of early neural progenitor markers, and accelerated expression of MN progenitor and MN markers. Longitudinal single-cell RNA sequencing reveals marked defects in neural stem cell specification and fewer MNs, favoring mesodermal progenitors and muscle cells, a bias also seen in early SMA mouse embryos. Surprisingly, SMN2-to-SMN1 conversion does not fully reverse these developmental abnormalities. These suggest that early neurodevelopmental defects may underlie later MN degeneration, indicating that postnatal SMN-increasing interventions might not completely amend SMA pathology in all patients.

Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.