Tracking Five Millennia of Horse Management with Extensive Ancient Genome Time Series.

Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (≥1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modern legacy of past equestrian civilizations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modern breeding impacted genetic diversity more dramatically than the previous millennia of human management.

Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments.

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the µ-opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a µ-opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.

Population dynamics of Baltic herring since the Viking Age revealed by ancient DNA and genomics.

The world's oceans are currently facing major stressors in the form of overexploitation and anthropogenic climate change. The Baltic Sea was home to the first "industrial" fishery ∼800 y ago targeting the Baltic herring, a species that is still economically and culturally important today. Yet, the early origins of marine industries and the long-term ecological consequences of historical and contemporary fisheries remain debated. Here, we study long-term population dynamics of Baltic herring to evaluate the past impacts of humans on the marine environment. We combine modern whole-genome data with ancient DNA (aDNA) to identify the earliest-known long-distance herring trade in the region, illustrating that extensive fish trade began during the Viking Age. We further resolve population structure within the Baltic and observe demographic independence for four local herring stocks over at least 200 generations. It has been suggested that overfishing at Øresund in the 16th century resulted in a demographic shift from autumn-spawning to spring-spawning herring dominance in the Baltic. We show that while the Øresund fishery had a negative impact on the western Baltic herring stock, the demographic shift to spring-spawning dominance did not occur until the 20th century. Instead, demographic reconstructions reveal population trajectories consistent with expected impacts of environmental change and historical reports on shifting fishing targets over time. This study illustrates the joint impact of climate change and human exploitation on marine species as well as the role historical ecology can play in conservation and management policies.

High performance of the DNA methylation-based WID-qEC test for detecting uterine cancers independent of sampling modalities.

Endometrial cancer (EC) is the most prevalent gynaecological cancer in high-income countries and its incidence is continuing to rise sharply. Simple and objective tools to reliably detect women with EC are urgently needed. We recently developed and validated the DNA methylation (DNAme)-based women's cancer risk identification-quantitative polymerase chain reaction test for endometrial cancer (WID-qEC) test that could address this need. Here, we demonstrate that the stability of the WID-qEC test remains consistent regardless of: (i) the cervicovaginal collection device and sample media used (Cervex brush and PreservCyt or FLOQSwab and eNAT), (ii) the collector of the specimen (gynaecologist- or patient-based), and (iii) the precise sampling site (cervical, cervicovaginal and vaginal). Furthermore, we demonstrate sample stability in eNAT medium for 7 days at room temperature, greatly facilitating the implementation of the test into diagnostic laboratory workflows. When applying FLOQSwabs (Copan) in combination with the eNAT (Copan) sample collection media, the sensitivity and specificity of the WID-qEC test to detect uterine (i.e., endometrial and cervical) cancers in gynaecologist-taken samples was 92.9% (95% confidence interval [CI] = 75.0%-98.8%) and 98.6% (95% CI = 91.7%-99.9%), respectively, whilst the sensitivity and specificity in patient collected self-samples was 75.0% (95% CI = 47.4%-91.7%) and 100.0% (95% CI = 93.9%-100.0%), respectively. Taken together these data confirm the robustness and clinical potential of the WID-qEC test.

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

A recombineering pipeline to clone large and complex genes in Chlamydomonas.

The ability to clone genes has greatly advanced cell and molecular biology research, enabling researchers to generate fluorescent protein fusions for localization and confirm genetic causation by mutant complementation. Most gene cloning is polymerase chain reaction (PCR)�or DNA synthesis-dependent, which can become costly and technically challenging as genes increase in size, particularly if they contain complex regions. This has been a long-standing challenge for the Chlamydomonas reinhardtii research community, as this alga has a high percentage of genes containing complex sequence structures. Here we overcame these challenges by developing a recombineering pipeline for the rapid parallel cloning of genes from a Chlamydomonas bacterial artificial chromosome collection. To generate fluorescent protein fusions for localization, we applied the pipeline at both batch and high-throughput scales to 203 genes related to the Chlamydomonas CO2 concentrating mechanism (CCM), with an overall cloning success rate of 77%. Cloning success was independent of gene size and complexity, with cloned genes as large as 23 kb. Localization of a subset of CCM targets confirmed previous mass spectrometry data, identified new pyrenoid components, and enabled complementation of mutants. We provide vectors and detailed protocols to facilitate easy adoption of this technology, which we envision will open up new possibilities in algal and plant research.

Predicting Rubisco-Linker Condensation from Titration in the Dilute Phase.

The condensation of Rubisco holoenzymes and linker proteins into "pyrenoids," a crucial supercharger of photosynthesis in algae, is qualitatively understood in terms of "sticker-and-spacer" theory. We derive semianalytical partition sums for small Rubisco-linker aggregates, which enable the calculation of both dilute-phase titration curves and dimerization diagrams. By fitting the titration curves to surface plasmon resonance and single-molecule fluorescence microscopy data, we extract the molecular properties needed to predict dimerization diagrams. We use these to estimate typical concentrations for condensation, and successfully compare these to microscopy observations.

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia.

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC = 0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ = 0.48; P < .001) and negatively associated with epigenetic replicative age (ρ = -0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.

The WID-EC test for the detection and risk prediction of endometrial cancer.

The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within 3 years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer.

Holocene deglaciation drove rapid genetic diversification of Atlantic walrus.

Rapid global warming is severely impacting Arctic ecosystems and is predicted to transform the abundance, distribution and genetic diversity of Arctic species, though these linkages are poorly understood. We address this gap in knowledge using palaeogenomics to examine how earlier periods of global warming influenced the genetic diversity of Atlantic walrus (Odobenus rosmarus rosmarus), a species closely associated with sea ice and shallow-water habitats. We analysed 82 ancient and historical Atlantic walrus mitochondrial genomes (mitogenomes), including now-extinct populations in Iceland and the Canadian Maritimes, to reconstruct the Atlantic walrus' response to Arctic deglaciation. Our results demonstrate that the phylogeography and genetic diversity of Atlantic walrus populations was initially shaped by the last glacial maximum (LGM), surviving in distinct glacial refugia, and subsequently expanding rapidly in multiple migration waves during the late Pleistocene and early Holocene. The timing of diversification and establishment of distinct populations corresponds closely with the chronology of the glacial retreat, pointing to a strong link between walrus phylogeography and sea ice. Our results indicate that accelerated ice loss in the modern Arctic may trigger further dispersal events, likely increasing the connectivity of northern stocks while isolating more southerly stocks putatively caught in small pockets of suitable habitat.

The impact of Longitudinal Integrated Foundation Training: preliminary experiences in the United Kingdom.

BACKGROUND: The United Kingdom health system is challenged with retaining doctors entering specialty training directly after their second foundation year. Improving doctors' training experience during the foundation programme may aid such retention. The Longitudinal Integrated Foundation Training (LIFT) pilot scheme aimed to provide a programme that improves the quality of their foundation training experience, advance patient-centred care and provide doctors with more experience in the primary care settings. METHODS: During this pilot study, three methods were employed to evaluate and compare doctors' experiences across their 2-year foundation training programme: Horus ePortfolio assessment of six domains for good medical practice analysed using a T-test, online survey assessments analysed using a 2-tailed chi-square test, and focus group feedback sessions with thematic analysis. RESULTS: Doctors completing LIFT (n = 47) scored a higher but non-significant mean score on all six domains for good medical practice versus doctors completing traditional foundation training (n = 94). By the end of foundation training, 100% of LIFT doctors rated their understanding of how primary and secondary care work together as high versus 78.7% of traditional doctors (p < 0.05). Improvements in wellbeing were observed among LIFT doctors, along with a reduction in the proportion of doctors considering leaving medical training. A significantly greater number of LIFT doctors versus traditional doctors rated their compassion for patients as high (100% versus 86.8%; p < 0.05), intended to become general practitioners (23.1% versus 13.5%; p < 0.05) and rated the extent to which they felt well informed and able to consider a general practice career rather than a hospital career as high (91.7% versus 72.3%, respectively; p < 0.05). Some LIFT doctors felt they had reduced exposure to secondary care, received less on-call experience and considered working a half-day to be problematic; challenges ameliorated by the end of the 2-year foundation programme. CONCLUSION: The LIFT programme enhanced the quality of foundation training and improved doctors' experiences and competencies, generating valuable insights for the future of education and healthcare delivery. Applying the principles of LIFT to foundation training helps doctors to be more compassionate and patient-centred, leading to enhanced individualised patient care.

Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection: A Case Series From a 12-Month Longitudinal Occupational Cohort.

Findings are described in 7 patients with severe acute respiratory syndrome coronavirus 2 reinfection from the National Basketball Association 2020-2021 occupational testing cohort, including clinical details, antibody test results, genomic sequencing, and longitudinal reverse-transcription polymerase chain reaction results. Reinfections were infrequent and varied in clinical presentation, viral dynamics, and immune response.

Scaling-up a pharmacist-led information technology intervention (PINCER) to reduce hazardous prescribing in general practices: Multiple interrupted time series study.

BACKGROUND: We previously reported on a randomised trial demonstrating the effectiveness and cost-effectiveness of a pharmacist-led information technology intervention (PINCER). We sought to investigate whether PINCER was effective in reducing hazardous prescribing when rolled out at scale in UK general practices. METHODS AND FINDINGS: We used a multiple interrupted time series design whereby successive groups of general practices received the PINCER intervention between September 2015 and April 2017. We used 11 prescribing safety indicators to identify potentially hazardous prescribing and collected data over a maximum of 16 quarterly time periods. The primary outcome was a composite of all the indicators; a composite for indicators associated with gastrointestinal (GI) bleeding was also reported, along with 11 individual indicators of hazardous prescribing. Data were analysed using logistic mixed models for the quarterly event numbers with the appropriate denominator, and calendar time included as a covariate. PINCER was implemented in 370 (94.1%) of 393 general practices covering a population of almost 3 million patients in the East Midlands region of England; data were successfully extracted from 343 (92.7%) of these practices. For the primary composite outcome, the PINCER intervention was associated with a decrease in the rate of hazardous prescribing of 16.7% (adjusted odds ratio (aOR) 0.83, 95% confidence interval (CI) 0.80 to 0.86) at 6 months and 15.3% (aOR 0.85, 95% CI 0.80 to 0.90) at 12 months postintervention. The unadjusted rate of hazardous prescribing reduced from 26.4% (22,503 patients in the numerator/853,631 patients in the denominator) to 20.1% (11,901 patients in the numerator/591,364 patients in the denominator) at 6 months and 19.1% (3,868 patients in the numerator/201,992 patients in the denominator). The greatest reduction in hazardous prescribing associated with the intervention was observed for the indicators associated with GI bleeding; for the GI composite indicator, there was a decrease of 23.9% at both 6 months (aOR 0.76, 95% CI 0.73 to 0.80) and 12 months (aOR 0.76, 95% CI 0.70 to 0.82) postintervention. The unadjusted rate of hazardous prescribing reduced from 31.4 (16,185 patients in the numerator/515,879 patients in the denominator) to 21.2% (7,607 patients in the numerator/358,349 patients in the denominator) at 6 months and 19.5% (2,369 patients in the numerator/121,534 patients in the denominator). We adjusted for calendar time and practice, but since this was an observational study, the findings may have been influenced by unknown confounding factors or behavioural changes unrelated to the PINCER intervention. Data were also not collected for all practices at 6 months and 12 months postintervention. CONCLUSIONS: The PINCER intervention, when rolled out at scale in routine clinical practice, was associated with a reduction in hazardous prescribing by 17% and 15% at 6 and 12 months postintervention. The greatest reductions in hazardous prescribing were for indicators associated with risk of GI bleeding. These findings support the wider national rollout of PINCER in England.

Walruses on the Dnieper: new evidence for the intercontinental trade of Greenlandic ivory in the Middle Ages.

Mediaeval walrus hunting in Iceland and Greenland-driven by Western European demand for ivory and walrus hide ropes-has been identified as an important pre-modern example of ecological globalization. By contrast, the main origin of walrus ivory destined for eastern European markets, and then onward trade to Asia, is assumed to have been Arctic Russia. Here, we investigate the geographical origin of nine twelfth-century CE walrus specimens discovered in Kyiv, Ukraine-combining archaeological typology (based on chaîne opératoire assessment), ancient DNA (aDNA) and stable isotope analysis. We show that five of seven specimens tested using aDNA can be genetically assigned to a western Greenland origin. Moreover, six of the Kyiv rostra had been sculpted in a way typical of Greenlandic imports to Western Europe, and seven are tentatively consistent with a Greenland origin based on stable isotope analysis. Our results suggest that demand for the products of Norse Greenland's walrus hunt stretched not only to Western Europe but included Ukraine and, by implication given linked trade routes, also Russia, Byzantium and Asia. These observations illuminate the surprising scale of mediaeval ecological globalization and help explain the pressure this process exerted on distant wildlife populations and those who harvested them.

Ancient DNA evidence for the ecological globalization of cod fishing in medieval and post-medieval Europe.

Understanding the historical emergence and growth of long-range fisheries can provide fundamental insights into the timing of ecological impacts and the development of coastal communities during the last millennium. Whole-genome sequencing approaches can improve such understanding by determining the origin of archaeological fish specimens that may have been obtained from historic trade or distant water. Here, we used genome-wide data to individually infer the biological source of 37 ancient Atlantic cod specimens (ca 1050-1950 CE) from England and Spain. Our findings provide novel genetic evidence that eleventh- to twelfth-century specimens from London were predominantly obtained from nearby populations, while thirteenth- to fourteenth-century specimens were derived from distant sources. Our results further suggest that Icelandic cod was indeed exported to London earlier than previously reported. Our observations confirm the chronology and geography of the trans-Atlantic cod trade from Newfoundland to Spain starting by the early sixteenth century. Our findings demonstrate the utility of whole-genome sequencing and ancient DNA approaches to describe the globalization of marine fisheries and increase our understanding regarding the extent of the North Atlantic fish trade and long-range fisheries in medieval and early modern times.

Glutamatergic systems in neuropathic pain and emerging non-opioid therapies.

Neuropathic pain, a disease of the somatosensory nervous system, afflicts many individuals and adequate management with current pharmacotherapies remains elusive. The glutamatergic system of neurons, receptors and transporters are intimately involved in pain but, to date, there have been few drugs developed that therapeutically modulate this system. Glutamate transporters, or excitatory amino acid transporters (EAATs), remove excess glutamate around pain transmitting neurons to decrease nociception suggesting that the modulation of glutamate transporters may represent a novel approach to the treatment of pain. This review highlights and summarizes (1) the physiology of the glutamatergic system in neuropathic pain, (2) the preclinical evidence for dysregulation of glutamate transport in animal pain models, and (3) emerging novel therapies that modulate glutamate transporters. Successful drug discovery requires continuous focus on basic and translational methods to fully elucidate the etiologies of this disease to enable the development of targeted therapies. Increasing the efficacy of astrocytic EAATs may serve as a new way to successfully treat those suffering from this devastating disease.

Ancient DNA reveals a southern presence of the Northeast Arctic cod during the Holocene.

Climate change has been implicated in an increased number of distributional shifts of marine species during the last century. Nonetheless, it is unclear whether earlier climatic fluctuations had similar impacts. We use ancient DNA to investigate the long-term spawning distribution of the Northeast Arctic cod (skrei) which performs yearly migrations from the Barents Sea towards spawning grounds along the Norwegian coast. The distribution of these spawning grounds has shifted northwards during the last century, which is thought to be associated with food availability and warming temperatures. We genetically identify skrei specimens from Ruskeneset in west Norway, an archaeological site located south of their current spawning range. Remarkably, 14C analyses date these specimens to the late Holocene, when temperatures were warmer than present-day conditions. Our results either suggest that temperature is not the only driver influencing the spawning distribution of Atlantic cod, or could be indicative of uncertainty in palaeoclimate reconstructions in this region. Regardless, our findings highlight the utility of aDNA to reconstruct the historical distribution of economically important fish populations and reveal the complexity of long-term ecological interactions in the marine environment.

Toll-Like Receptors (TLRs) in Health and Disease: An Overview.

Toll-like receptors were discovered as proteins playing a crucial role in the dorsoventral patterning during embryonic development in the Drosophila melanogaster (D. melanogaster) almost 40 years ago. Subsequently, further research also showed a role of the Toll protein or Toll receptor in the recognition of Gram-positive bacterial and fungal pathogens infecting D. melanogaster. In 1997, the human homolog was reported and the receptor was named the Toll-like receptor 4 (TLR4) that recognizes lipopolysaccharide (LPS) of the Gram-negative bacteria as a pathogen-associated molecular pattern (PAMP). Identification of TLR4 in humans filled the long existing gap in the field of infection and immunity, addressing the mystery surrounding the recognition of foreign pathogens/microbes by the immune system. It is now known that mammals (mice and humans) express 13 different TLRs that are expressed on the outer cell membrane or intracellularly, and which recognize different PAMPs or microbe-associated molecular patterns (MAMPs) and death/damage-associated molecular patterns (DAMPs) to initiate the protective immune response. However, their dysregulation generates profound and prolonged pro-inflammatory immune responses responsible for different inflammatory and immune-mediated diseases. This chapter provides an overview of TLRs in the control of the immune response, their association with different diseases, including TLR single nucleotide polymorphisms (SNPs), interactions with microRNAs (miRs), use in drug development and vaccine design, and expansion in neurosciences to include pain, addiction, metabolism, reproduction, and wound healing.

Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.

Chronic neuroinflammation with sustained microglial activation occurs following severe traumatic brain injury (TBI) and is believed to contribute to subsequent neurodegeneration and neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this preclinical study, we examined the effects of delayed depletion of chronically activated microglia on functional recovery and neurodegeneration up to 3 months postinjury. A CSF1R inhibitor, Plexxikon (PLX) 5622, was administered to adult male C57BL/6J mice at 1 month after controlled cortical impact to remove chronically activated microglia, and the inhibitor was withdrawn 1-week later to allow for microglial repopulation. Following TBI, the repopulated microglia displayed a ramified morphology similar to that of Sham uninjured mice, whereas microglia in vehicle-treated TBI mice showed the typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes at 3 months postinjury; these included a smaller cortical lesion, reduced hippocampal neuron cell death, and decreased NOX2- and NLRP3 inflammasome-associated neuroinflammation. Furthermore, delayed depletion of chronically activated microglia after TBI led to widespread changes in the cortical transcriptome and altered gene pathways involved in neuroinflammation, oxidative stress, and neuroplasticity. Using a variety of complementary neurobehavioral tests, PLX5622-treated TBI mice also had improved long-term motor and cognitive function recovery through 3 months postinjury. Together, these studies demonstrate that chronic phase removal of neurotoxic microglia after TBI using CSF1R inhibitors markedly reduce chronic neuroinflammation and associated neurodegeneration, as well as related motor and cognitive deficits.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a debilitating neurological disorder that can seriously impact the patient's quality of life. Microglial-mediated neuroinflammation is induced after severe TBI and contributes to neurological deficits and on-going neurodegenerative processes. Here, we investigated the effect of breaking the neurotoxic neuroinflammatory loop at 1-month after controlled cortical impact in mice by pharmacological removal of chronically activated microglia using a colony stimulating factor 1 receptor (CSF1R) inhibitor, Plexxikon 5622. Overall, we show that short-term elimination of microglia during the chronic phase of TBI followed by repopulation results in long-term improvements in neurological function, suppression of neuroinflammatory and oxidative stress pathways, and a reduction in persistent neurodegenerative processes. These studies are clinically relevant and support new concepts that the therapeutic window for TBI may be far longer than traditionally believed if chronic and evolving microglial-mediated neuroinflammation can be inhibited or regulated in a precise manner.