Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.

Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

The Discrepancy Between Hemoglobin A1c and Glucose Management Indicators in 26 Patients Treated With Continuous Glucose Monitoring in an Internal Medicine Residency Clinic.

We conducted a retrospective observational cohort study between 2020 and 2023 in 26 patients with type 1 and type 2 diabetes mellitus (DM) who were using 3-4 injections per day of insulin and were monitored by continuous glucose monitoring (CGM). The goal of this retrospective observational cohort study is to compare these two metrics in an internal medicine community primary care residency clinic. We used CGM devices, Dexcom G6 and G7, and Freestyle Libre 3. The goal was to compare the patient's hemoglobin A1c (HbA1c) taken during their clinic visit by phlebotomy as a marker for diabetic control with an estimated HbA1c glucose management indicator (GMI) derived from the 30-day CGM readings. HbA1c is derived from the blood, while the GMI value is derived from the interstitial fluid. Both parameters were taken within 30 days of each other. GMI was taken in the last 30 days. We excluded patients with known anemia, chronic kidney disease, polycythemia, cirrhosis of the liver, or metabolic dysfunction associated with steatohepatitis (MASH) because disease states can affect the measured HbA1c. Also, pregnant and African American patients were excluded. We concluded the measured HbA1c was 0.34% (4 mmol/mol) higher than the CGM-derived GMI. The relationship between factors that affect glycemic control was discussed in the article, as well as the future utilization of them in improving diabetic control and management. As the use of CGM continues to grow, addressing differences between laboratory-measured HbA1c and CGM-derived GMI is critical.

XFEM for Composites, Biological, and Bioinspired Materials: A Review.

The eXtended finite element method (XFEM) is a powerful tool for structural mechanics, assisting engineers and designers in understanding how a material architecture responds to stresses and consequently assisting the creation of mechanically improved structures. The XFEM method has unraveled the extraordinary relationships between material topology and fracture behavior in biological and engineered materials, enhancing peculiar fracture toughening mechanisms, such as crack deflection and arrest. Despite its extensive use, a detailed revision of case studies involving XFEM with a focus on the applications rather than the method of numerical modeling is in great need. In this review, XFEM is introduced and briefly compared to other computational fracture models such as the contour integral method, virtual crack closing technique, cohesive zone model, and phase-field model, highlighting the pros and cons of the methods (e.g., numerical convergence, commercial software implementation, pre-set of crack parameters, and calculation speed). The use of XFEM in material design is demonstrated and discussed, focusing on presenting the current research on composites and biological and bioinspired materials, but also briefly introducing its application to other fields. This review concludes with a discussion of the XFEM drawbacks and provides an overview of the future perspectives of this method in applied material science research, such as the merging of XFEM and artificial intelligence techniques.

Reprogramming the pancreatic cancer stroma and immune landscape by a silicasome nanocarrier delivering nintedanib, a protein tyrosine kinase inhibitor.

The prevailing desmoplastic stroma and immunosuppressive microenvironment within pancreatic ductal adenocarcinoma (PDAC) pose substantial challenges to therapeutic intervention. Despite the potential of protein tyrosine kinase (PTK) inhibitors in mitigating the desmoplastic stromal response and enhancing the immune milieu, their efficacy is curtailed by suboptimal pharmacokinetics (PK) and insufficient tumor penetration. To surmount these hurdles, we have pioneered a novel strategy, employing lipid bilayer-coated mesoporous silica nanoparticles (termed "silicasomes") as a carrier for the delivery of Nintedanib. Nintedanib, a triple PTK inhibitor that targets vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, was encapsulated in the pores of silicasomes via a remote loading mechanism for weak bases. This innovative approach not only enhanced pharmacokinetics and intratumor drug concentrations but also orchestrated a transformative shift in the desmoplastic and immune landscape in a robust orthotopic KRAS-mediated pancreatic carcinoma (KPC) model. Our results demonstrate attenuation of vascular density and collagen content through encapsulated Nintedanib treatment, concomitant with significant augmentation of the CD8+/FoxP3+ T-cell ratio. This remodeling was notably correlated with tumor regression in the KPC model. Strikingly, the synergy between encapsulated Nintedanib and anti-PD-1 immunotherapy further potentiated the antitumor effect. Both free and encapsulated Nintedanib induced a transcriptional upregulation of PD-L1 via the extracellular signal-regulated kinase (ERK) pathway. In summary, our pioneering approach involving the silicasome carrier not only improved antitumor angiogenesis but also profoundly reshaped the desmoplastic stromal and immune landscape within PDAC. These insights hold excellent promise for the development of innovative combinatorial strategies in PDAC therapy.

Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Spontaneous sphenoid sinus meningocele with associated amenorrhea and headache: illustrative case.

BACKGROUND: Developmental meningoceles of the sphenoid sinus are uncommon. When encountered, they are often associated with cerebrospinal fluid (CSF) rhinorrhea. OBSERVATIONS: The authors present the case of a 27-year-old female with a large meningocele eroding through the sella turcica and sphenoid sinus into the nasopharynx. The patient presented with intractable headaches and amenorrhea without CSF rhinorrhea. LESSONS: The patient underwent an endoscopic endonasal transsphenoidal reduction of the meningocele with reelevation of the pituitary gland and skull base reconstruction with abdominal fat graft and nasoseptal flap.

A new Caenorhabditis elegans model to study copper toxicity in Wilson disease.

Wilson disease (WD) is caused by mutations in the ATP7B gene that encodes a copper (Cu) transporting ATPase whose trafficking from the Golgi to endo-lysosomal compartments drives sequestration of excess Cu and its further excretion from hepatocytes into the bile. Loss of ATP7B function leads to toxic Cu overload in the liver and subsequently in the brain, causing fatal hepatic and neurological abnormalities. The limitations of existing WD therapies call for the development of new therapeutic approaches, which require an amenable animal model system for screening and validation of drugs and molecular targets. To achieve this objective, we generated a mutant Caenorhabditis elegans strain with a substitution of a conserved histidine (H828Q) in the ATP7B ortholog cua-1 corresponding to the most common ATP7B variant (H1069Q) that causes WD. cua-1 mutant animals exhibited very poor resistance to Cu compared to the wild-type strain. This manifested in a strong delay in larval development, a shorter lifespan, impaired motility, oxidative stress pathway activation, and mitochondrial damage. In addition, morphological analysis revealed several neuronal abnormalities in cua-1 mutant animals exposed to Cu. Further investigation suggested that mutant CUA-1 is retained and degraded in the endoplasmic reticulum, similarly to human ATP7B-H1069Q. As a consequence, the mutant protein does not allow animals to counteract Cu toxicity. Notably, pharmacological correctors of ATP7B-H1069Q reduced Cu toxicity in cua-1 mutants indicating that similar pathogenic molecular pathways might be activated by the H/Q substitution and, therefore, targeted for rescue of ATP7B/CUA-1 function. Taken together, our findings suggest that the newly generated cua-1 mutant strain represents an excellent model for Cu toxicity studies in WD.

The Interplay Between the Immune System, Tumor Suppressor Genes, and Immune Senescence in Mesothelioma Development and Response to Immunotherapy.

Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

Implications of headwater contact zones for the riverine barrier hypothesis: a case study of the Blue-capped Manakin (Lepidothrix coronata).

Rivers frequently delimit the geographic ranges of species in the Amazon Basin. These rivers also define the boundaries between genetic clusters within many species, yet river boundaries have been documented to break down in headwater regions where rivers are narrower. To explore the evolutionary implications of headwater contact zones in Amazonia, we examined genetic variation in the Blue-capped Manakin (Lepidothrix coronata), a species previously shown to contain several genetically and phenotypically distinct populations across the western Amazon Basin. We collected restriction site-associated DNA sequence data (RADcap) for 706 individuals and found that spatial patterns of genetic structure indicate several rivers, particularly the Amazon and Ucayali, are dispersal barriers for L. coronata. We also found evidence that genetic connectivity is elevated across several headwater regions, highlighting the importance of headwater gene flow for models of Amazonian diversification. The headwater region of the Ucayali River provided a notable exception to findings of headwater gene flow by harboring non-admixed populations of L. coronata on opposite sides of a < 1-km-wide river channel with a known dynamic history, suggesting that additional prezygotic barriers may be limiting gene flow in this region.

A proposed paradigm shift in the management of distal radius fractures.

Background and objective: Distal radius fractures represent a remarkable orthopaedic entity. Most distal radius fractures can be treated conservatively with closed reduction and immobilisation with satisfactory results, while open reduction and internal fixation is reserved for displaced fractures. Our objective was to propose a paradigm shift in the management of distal radius fractures. Methods: A literature search of management of distal radius fractures was conducted. PubMed and Cochrane databases were used for the search. English articles with open access or institutional subscription availability were included. Key content and finding: Current literature supports operative management for younger active patients with defined radiographic inclusion parameters, but among the elderly there is little evidence of benefit. Most orthopaedic literature defines "elderly" as patients above 65 years of age. Non-surgical treatment for fractures of the distal radius tends to yield satisfactory functional results, and these favourable outcomes do not necessarily align with normal radiological parameters. For the minority of patients that have symptomatic malunion, corrective osteotomy is a good option to improve the function provided the symptoms can be clearly attributed to the malalignment. Conclusion: The vast majority of distal radius fractures can be managed conservatively. Further studies are recommended to explore the feasibility of advocating for universal conservative treatment for patients with less functional demands while still having the option of staged surgery in the form of corrective osteotomy where there is symptomatic malunion amenable to anatomical correction. Future research should also aim to identify patients who would benefit most from surgical intervention by considering the type of functional recovery needed, rather than relying predominantly on the patient's chronological age as the determining factor in the decision-making process.

Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk.

BACKGROUND: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations. METHODS: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan. RESULTS: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively. CONCLUSIONS: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer. IMPACT: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.

Adapting a Clinical Practice Guideline for Management of Patients with Knee and Hip Osteoarthritis by Hong Kong Physiotherapists.

Knee and hip osteoarthritis are common disabling conditions globally. Although numerous international clinical practice guidelines exist to guide physiotherapy management, not all recommendations issued from these guidelines can be translated to other contexts without considering the cultural acceptability and clinical implementability of targeted countries. Because the ADAPTE framework provides a robust methodology to adapt guidelines to the local context, this study used its methodology to adapt high-quality guideline recommendations to promote optimal physiotherapy care for knee and hip osteoarthritis in Hong Kong. The ADAPTE framework was used and modified to complete the adaptation process. International clinical practice guidelines were identified from eight guideline clearinghouses and six electronic databases. Two independent reviewers critically appraised the eligible guidelines using the AGREE II tool. We extracted and tabulated recommendations from high-quality guidelines. A voting-based consensus among interdisciplinary experts was conducted to decide on suitable recommendations for the Hong Kong context and whether there was a need to modify them. Pertinent recommendations were then translated into the traditional Chinese language. Our team members suggested modifying four tools and adding one to explore the patient's feedback on the recommendations, to the ADAPTE framework. The adaptation was performed on three high-quality guidelines. We adapted 28 and 20 recommendations for treating knee and hip osteoarthritis, respectively. We recommend a multimodal treatment for managing knee and hip osteoarthritis. Land- and aquatic-based exercises, patient education, and self-management were strongly recommended for patients with knee osteoarthritis. Land- and aquatic-based exercises were strongly recommended for patients with hip osteoarthritis. This is the first adaptation study in Hong Kong. It provides guidance to local physiotherapists on managing patients with knee and hip osteoarthritis. Future studies should test the effectiveness of implementing this adapted guideline to improve local physiotherapy care in Hong Kong.

Use of Stromal Intervention and Exogenous Neoantigen Vaccination to Boost Pancreatic Cancer Chemo-Immunotherapy by Nanocarriers.

Despite the formidable treatment challenges of pancreatic ductal adenocarcinoma (PDAC), considerable progress has been made in improving drug delivery via pioneering nanocarriers. These innovations are geared towards overcoming the obstacles presented by dysplastic stroma and fostering anti-PDAC immune reactions. We are currently conducting research aimed at enhancing chemotherapy to stimulate anti-tumor immunity by inducing immunogenic cell death (ICD). This is accomplished using lipid bilayer-coated nanocarriers, which enable the attainment of synergistic results. Noteworthy examples include liposomes and lipid-coated mesoporous silica nanoparticles known as "silicasomes". These nanocarriers facilitate remote chemotherapy loading, as well as the seamless integration of immunomodulators into the lipid bilayer. In this communication, we elucidate innovative ways for further improving chemo-immunotherapy. The first is the development of a liposome platform engineered by the remote loading of irinotecan while incorporating a pro-resolving lipoxin in the lipid bilayer. This carrier interfered in stromal collagen deposition, as well as boosting the irinotecan-induced ICD response. The second approach was to synthesize polymer nanoparticles for the delivery of mutated KRAS peptides in conjunction with a TLR7/8 agonist. The dual delivery vaccine particle boosted the generation of antigen-specific cytotoxic T-cells that are recruited to lymphoid structures at the cancer site, with a view to strengthening the endogenous vaccination response achieved by chemo-immunotherapy.

Estimates of Resting Energy Expenditure and Total Energy Expenditure Using Predictive Equations for Individuals After Bariatric Surgery: a Systematic Review with Meta-analysis.

PURPOSE: Patients after metabolic bariatric surgery (MBS) require attention to maintain energy balance and avoid weight regain. Predictive equations for resting energy expenditure (REE) and total energy expenditure (TEE) are needed since gold standard methods like calorimetry and doubly labeled water are rarely available in routine clinical practice. This study aimed to determine which predictive equation for REE and TEE has the lowest bias in subjects after MBS. METHODS: MEDLINE, Embase, Web of Science, and CENTRAL searches were performed. Meta-analyses were performed with the data calculated by the predictive equations and measured by the gold standard methods for those equations that had at least two studies with these data. The DerSimonian and Laird random-effects model and the I2 statistic were used to quantify heterogeneity in the quantitative analyses. The risk of bias was assessed using the Joanna Briggs Institute critical appraisal checklist. RESULTS: Seven studies were included. The present study found that the Mifflin St. Jeor (1990) equation had the lowest bias (mean difference = - 39.71 kcal [95%CI = - 128.97; 49.55]) for calculating REE in post-BS individuals. The Harris-Benedict (1919) equation also yielded satisfactory results (mean difference = - 54.60 kcal [95%CI = - 87.92; - 21.28]). CONCLUSION: The predictive equation of Mifflin St. Jeor (1990) was the one that showed the lowest bias for calculating the REE of patients following MBS.

Trends of Low Back Pain Research in Older and Working-Age Adults from 1993 to 2023: A Bibliometric Analysis.

Although the number of publications focusing on low back pain in older adults (LBP-O) and working-age adults (LBP-W) has been growing for decades, comparative research trends in these two populations, which may help to guide future investigation, have not been rigorously explored. This analysis aimed to describe publication patterns and trends of research targeting LBP-O and LBP-W over the last three decades. Peer-reviewed LBP-O and LBP-W articles published between 1993 and 2023 were retrieved from the Web of Science, which provided the details of annual publication volume, and prominent journals/countries/institutions. The relationship between the annual publication volumes and years was analyzed by Spearman correlation analysis. The hot topics and emerging trends were analyzed by VOSviewer and CiteSpace, respectively. A total of 4217 LBP-O-related and 50,559 LBP-W-related documents were included. The annual publication volumes of LBP-O and LBP-W articles increased over the years (r=0.995 to 0.998, p<0.001). The United States had the highest number of prominent institutions publishing relevant articles. The most prolific journal for LBP-O (5.4%) and LBP-W-related (6.1%) papers is the journal "Spine". Cognitive behavioral therapy, intervertebral disc (IVD) degeneration, physiotherapy, physical activity, and walking were the recent hot topics and physical activity was an emerging trend in LBP-O, while surgery and IVD degeneration (also a hot topic) were emerging trends in LBP-W. This study highlights the paucity of LBP-O-related research in the past. The United States and the journal Spine stand out in LBP research. The research trend of physical activity in LBP-O is consistent with the recognized importance of physical activity for older adults in general, and for managing LBP-O in particular. Conversely, the emerging trends of surgery and intervertebral disc degeneration in LBP-W research highlight a focus on the biomedical model of LBP despite LBP being a biopsychosocial condition.

New insights into the pathogenesis and transmission of Brucella pinnipedialis: systemic infection in two bottlenose dolphins (Tursiops truncatus).

IMPORTANCE: Brucella spp. are zoonotic pathogens that can affect both terrestrial and marine mammals. Brucella ceti has been identified in various cetacean species, but only one sequence type (ST27) has been reported in humans. However, it is important to conduct surveillance studies to better understand the impact of marine Brucella species on marine mammals, a typically understudied host group. Here, we describe a systemic infection by two related strains of Brucella pinnipedialis (ST25) in a couple of live-stranded bottlenose dolphins, with more severe lesions in the younger animal. Furthermore, B. pinnipedialis was first detected in milk from a female cetacean that stranded with its offspring. Our study reveals novel insights into the epidemiology and pathological consequences of B. pinnipedialis infections in cetaceans, emphasizing the crucial importance of ongoing surveillance and accurate diagnosis to understand the impact of this pathogen on marine mammal populations.

Demographic reconstruction of the Western sheep expansion from whole-genome sequences.

As one of the earliest livestock, sheep (Ovis aries) were domesticated in the Fertile Crescent about 12,000-10,000 years ago and have a nearly worldwide distribution today. Most of our knowledge about the timing of their expansions stems from archaeological data but it is unclear how the genetic diversity of modern sheep fits with these dates. We used whole-genome sequencing data of 63 domestic breeds and their wild relatives, the Asiatic mouflon (O. gmelini, previously known as O. orientalis), to explore the demographic history of sheep. On the global scale, our analysis revealed geographic structuring among breeds with unidirectional recent gene flow from domestics into Asiatic mouflons. We then selected 4 representative breeds from Spain, Morocco, the United Kingdom, and Iran to build a comprehensive demographic model of the Western sheep expansion. We inferred a single domestication event around 11,000 years ago. The subsequent westward expansion is dated to approximately 7,000 years ago, later than the original Neolithic expansion of sheep and slightly predating the Secondary Product Revolution associated with wooly sheep. We see some signals of recent gene flow from an ancestral population into Southern European breeds which could reflect admixture with feral European mouflon. Furthermore, our results indicate that many breeds experienced a reduction of their effective population size during the last centuries, probably associated with modern breed development. Our study provides insights into the complex demographic history of Western Eurasian sheep, highlighting interactions between breeds and their wild counterparts.

Unmasking Type 1 Diabetes in Adults: Insights From Two Cases Revealing Misdiagnosis As Type 2 Diabetes, With Emphasis on Autoimmunity and Continuous Glucose Monitoring.

Type 1 diabetes mellitus (T1DM) is often misdiagnosed as type 2 diabetes mellitus (T2DM) in adults, resulting in inadequate treatment and poor disease management. In this report, we present two patients initially misdiagnosed with T2DM for 14 and four years, respectively, leading to complications like diabetic ketoacidosis (DKA). Reevaluation confirmed adult-onset T1DM through antibody tests. Treatment was adjusted to a basal-bolus insulin regimen with the use of continuous glucose monitoring (CGM). The correct diagnosis and CGM implementation significantly improved diabetes mellitus management. This case report emphasizes the importance of mindful diagnosis in adult patients with diabetes mellitus, considering both type 1 and type 2 differentials.