Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions.

The unprecedented scale of the COVID-19 pandemic and the rapid evolution of SARS-CoV-2 variants underscore the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential cysteine protease required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir is a novel Mpro inhibitor that has recently completed a phase 2 clinical trial. In this report, we demonstrated that pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro with high selectivity against human proteases. In the enzyme assay, pomotrelvir is also active against Mpro proteins derived from human coronaviruses CoV-229E, CoV-OC43, CoV-HKU1, CoV-NL63, MERS, and SARS-CoV. In cell-based SARS-CoV-2 replicon and SARS-CoV-2 infection assays, pomotrelvir has shown potent inhibitory activity and is broadly active against SARS-CoV-2 clinical isolates including Omicron variants. Many resistance substitutions of the Mpro inhibitor nirmatrelvir confer cross-resistance to pomotrelvir, consistent with the finding from our enzymatic analysis that pomotrelvir and nirmatrelvir compete for the same binding site. In a SARS-CoV-2 infection assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. In conclusion, our results from the in vitro characterization of pomotrelvir antiviral activity support its further clinical development as an alternative COVID-19 therapeutic option.

A marine isotope stage 13 Acheulian sequence from the Amanzi Springs Area 2 Deep Sounding excavation, Eastern Cape, South Africa.

Renewed research at Amanzi Springs has increased resolution on the timing and technology of the Acheulian industry in South Africa. The archeology from the Area 1 spring eye has recently been dated to MIS 11 (∼404-390 ka), and analyses revealed significant technological variability when compared to other southern African Acheulian assemblages. We expand on these results in presenting new luminescence dating and technological analyses of Acheulian stone tools from three artifact-bearing surfaces exposed within the White Sands unit of the Deep Sounding excavation in the Area 2 spring eye. The two lowest surfaces (Surfaces 3 and 2) are sealed within the White Sands and dated between ∼534 to 496 ka and ∼496 to 481 ka (MIS 13), respectively. Surface 1 represents materials deflated onto an erosional surface that cut the upper part of the White Sands (∼481 ka; late MIS 13), which occurred before the deposition of younger Cutting 5 sediments (<408-<290 ka; MIS 11-8). Archaeological comparisons reveal that the older Surface 3 and 2 assemblages are predominated by unifacial and bifacial core reduction and relatively thick, cobble-reduced large cutting tools. In contrast, the younger Surface 1 assemblage is characterized by discoidal core reduction and thinner large cutting tools, mostly made from flake blanks. Typological similarities between the older Area 2 White Sands and younger Area 1 (404-390 ka; MIS 11) assemblages further suggest long-term continuity in site function. We hypothesize Amanzi Springs represent a workshop locality that Acheulian hominins repeatedly visited to access unique floral, faunal, and raw material resources from at least ∼534 to 390 ka.

Human occupation of northern Australia by 65,000 years ago.

The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated in the extinction of Australia's megafauna. Here we report the results of new excavations conducted at Madjedbebe, a rock shelter in northern Australia. Artefacts in primary depositional context are concentrated in three dense bands, with the stratigraphic integrity of the deposit demonstrated by artefact refits and by optical dating and other analyses of the sediments. Human occupation began around 65,000 years ago, with a distinctive stone tool assemblage including grinding stones, ground ochres, reflective additives and ground-edge hatchet heads. This evidence sets a new minimum age for the arrival of humans in Australia, the dispersal of modern humans out of Africa, and the subsequent interactions of modern humans with Neanderthals and Denisovans.

Ulnar Wrist Denervation: Articular Branching Pattern and Selective Blockade of the Dorsal Branch of the Ulnar Nerve.

PURPOSE: Ulnar wrist denervation has been a successful treatment for patients with ulnar-sided wrist pain. The purpose of this study was to characterize the articular branches of the dorsal branch of the ulnar nerve (DBUN) and validate a technique for selective peripheral nerve blockade. METHODS: In cadavers, we performed simulated local anesthetic injections using 0.5 mL of 0.5% methylene into the subcutaneous tissue at a point midway between the palpable borders of the pisiform and ulnar styloid. We then dissected the DBUN, characterized its articular branching pattern, and measured staining intensity of the DBUN and the ulnar nerve relative to a standard. RESULTS: The DBUN branched from the ulnar nerve 7.0 ± 1.2 cm proximal to the ulnar styloid. Among 17 specimens, the DBUN provided an average of 1.2 (range, 0-2) ulnocarpal branches and 1.0 (range, 0-2) carpometacarpal articular branches. A simulated local anesthetic injection successfully stained 100% of the DBUN articular branches at or proximal to their takeoff. There was no staining of the proper ulnar nerves. In all specimens, the DBUN supplied at least one articular branch. CONCLUSIONS: A point midway between the palpable border of the pisiform and ulnar styloid may be an effective location for selectively blocking the DBUN articular afferents. CLINICAL RELEVANCE: In this study, we were able to identify a point halfway between the pisiform and ulnar styloid that has the potential to produce a selective peripheral nerve block of the portion of the DBUN that supplies articular fibers to the ulnocarpal joint and the fifth carpometacarpal joint. This technique may prove useful to surgeons treating ulnar-sided wrist pain.

Hepatitis B virus Core protein nuclear interactome identifies SRSF10 as a host RNA-binding protein restricting HBV RNA production.

Despite the existence of a preventive vaccine, chronic infection with Hepatitis B virus (HBV) affects more than 250 million people and represents a major global cause of hepatocellular carcinoma (HCC) worldwide. Current clinical treatments, in most of cases, do not eliminate viral genome that persists as a DNA episome in the nucleus of hepatocytes and constitutes a stable template for the continuous expression of viral genes. Several studies suggest that, among viral factors, the HBV core protein (HBc), well-known for its structural role in the cytoplasm, could have critical regulatory functions in the nucleus of infected hepatocytes. To elucidate these functions, we performed a proteomic analysis of HBc-interacting host-factors in the nucleus of differentiated HepaRG, a surrogate model of human hepatocytes. The HBc interactome was found to consist primarily of RNA-binding proteins (RBPs), which are involved in various aspects of mRNA metabolism. Among them, we focused our studies on SRSF10, a RBP that was previously shown to regulate alternative splicing (AS) in a phosphorylation-dependent manner and to control stress and DNA damage responses, as well as viral replication. Functional studies combining SRSF10 knockdown and a pharmacological inhibitor of SRSF10 phosphorylation (1C8) showed that SRSF10 behaves as a restriction factor that regulates HBV RNAs levels and that its dephosphorylated form is likely responsible for the anti-viral effect. Surprisingly, neither SRSF10 knock-down nor 1C8 treatment modified the splicing of HBV RNAs but rather modulated the level of nascent HBV RNA. Altogether, our work suggests that in the nucleus of infected cells HBc interacts with multiple RBPs that regulate viral RNA metabolism. Our identification of SRSF10 as a new anti-HBV restriction factor offers new perspectives for the development of new host-targeted antiviral strategies.

Cultural innovation and megafauna interaction in the early settlement of arid Australia.

Elucidating the material culture of early people in arid Australia and the nature of their environmental interactions is essential for understanding the adaptability of populations and the potential causes of megafaunal extinctions 50-40 thousand years ago (ka). Humans colonized the continent by 50 ka, but an apparent lack of cultural innovations compared to people in Europe and Africa has been deemed a barrier to early settlement in the extensive arid zone. Here we present evidence from Warratyi rock shelter in the southern interior that shows that humans occupied arid Australia by around 49 ka, 10 thousand years (kyr) earlier than previously reported. The site preserves the only reliably dated, stratified evidence of extinct Australian megafauna, including the giant marsupial Diprotodon optatum, alongside artefacts more than 46 kyr old. We also report on the earliest-known use of ochre in Australia and Southeast Asia (at or before 49-46 ka), gypsum pigment (40-33 ka), bone tools (40-38 ka), hafted tools (38-35 ka), and backed artefacts (30-24 ka), each up to 10 kyr older than any other known occurrence. Thus, our evidence shows that people not only settled in the arid interior within a few millennia of entering the continent, but also developed key technologies much earlier than previously recorded for Australia and Southeast Asia.

Relief of Sitting Pain by Resecting Posterior Femoral Cutaneous Nerve, and Elucidation of Its Anatomical Branching Pattern.

BACKGROUND: Injury to the posterior femoral cutaneous nerve (PFCN) produces sitting pain in the buttock, posterior thigh, and/or the ischial tuberosity. The anatomy of the PFCN has not been well described, and just one small cohort of patients has been reported to have resection of the PFCN. METHODS: Retrospective review of all patients undergoing resection of the PFCN for sitting pain by the senior author between 2012 and 2019 was performed. Evaluation was done by chart review, intraoperative description of the anatomy of the PFCN, and the outcome of resection of the PFCN with implantation of the proximal nerve into the gluteus muscle. Outcome was determined by direct patient examination, email reports, and telephonic interview. RESULTS: Fifty-two patients were included in this study, of which nine were bilateral operative procedures. Thirty-four patients had sufficient follow-up data at a mean of 23 months (3-85 months, range). MRI evidence of hamstring injury was present in 50% of the patients. The classic PFCN anatomy was present in 44% of limbs with the other 56% having a high division permitting branches to the lateral buttock and posterior thigh to be preserved. In patients with bilateral anatomy observations, symmetry was present in 67%. An excellent result (absence of sitting pain, normal activities of daily living [ADL]) was obtained in 53%, a good result (some residual sitting pain with some reduction in ADL), was obtained in 26% and no improvement was observed in 21% of patients. CONCLUSION: Sitting pain due to injury to the PFCN can be relieved by the resection of the PFCN with implantation of the proximal end into muscle. Presence of an anatomical variation, a high division of the PFCN, can permit preservation of sensation in the lateral buttock and posterior thigh in the patient whose symptoms involve just the perineum and ischial tuberosity.

Fossil and genomic evidence constrains the timing of bison arrival in North America.

The arrival of bison in North America marks one of the most successful large-mammal dispersals from Asia within the last million years, yet the timing and nature of this event remain poorly determined. Here, we used a combined paleontological and paleogenomic approach to provide a robust timeline for the entry and subsequent evolution of bison within North America. We characterized two fossil-rich localities in Canada's Yukon and identified the oldest well-constrained bison fossil in North America, a 130,000-y-old steppe bison, Bison cf. priscus We extracted and sequenced mitochondrial genomes from both this bison and from the remains of a recently discovered, ∼120,000-y-old giant long-horned bison, Bison latifrons, from Snowmass, Colorado. We analyzed these and 44 other bison mitogenomes with ages that span the Late Pleistocene, and identified two waves of bison dispersal into North America from Asia, the earliest of which occurred ∼195-135 thousand y ago and preceded the morphological diversification of North American bison, and the second of which occurred during the Late Pleistocene, ∼45-21 thousand y ago. This chronological arc establishes that bison first entered North America during the sea level lowstand accompanying marine isotope stage 6, rejecting earlier records of bison in North America. After their invasion, bison rapidly colonized North America during the last interglaciation, spreading from Alaska through continental North America; they have been continuously resident since then.

Risk Factors Associated With the Progression From Acute to Chronic Neuropathic Pain After Burn-Related Injuries.

BACKGROUND: Pain, unrelated to the initial thermal trauma itself, can result after burn injury and prolong the recovery/rehabilitation phase of the patient's care. This pain, after discharge from the burn unit, may be acute and self-limiting or chronic and contribute to long-term patient morbidity. The purposes of this study were to compare burn patients who had, after discharge from the burn unit, only acute pain with burn patients who developed chronic, neuropathic pain (CNP) and to determine risks factors for progression from acute to chronic pain in the setting of a burn center. METHODS: A single-center, retrospective chart review of patients admitted to the adult burn center was performed from January 1, 2014, to January 1, 2019. Patients included were older than 15 years, sustained a burn injury, and admitted to the burn unit. Chronic pain was defined as pain lasting greater than 6 months after discharge from the burn unit. Pain descriptors included shooting, stabbing, sharp, burning, tingling, numbness, throbbing, pruritus, intermittent, and/or continuous dysesthetic sensations after the burn. Patients were excluded if they had preexisting neuropathic pain due to an underlying medical illness or previous surgery. RESULTS: During a 5-year period, of the 1880 admissions to the burn unit, 143 burn patients developed post-initial-onset pain as a direct result of their burn. Of the 143 patients with acute pain, pain resolved in 30 patients, whereas pain progressed to CNP in 113 patients (79%). Patient follow-up was a median (interquartile range [IQR]) of 26.5 (10-45) months. Patients whose pain progressed to CNP had significantly greater percent total body surface area burns (median [IQR], 6 [3-25] vs 3 [1-10]; P = 0.032), had more full-thickness burns (66/113 [58%] vs 8/30 [27%] patients, P = 0.004), had surgery (85/113 [75%] vs 16/30 [53%] patients, P = 0.042), had more surgical procedures (median [IQR], 2 [1-6] vs 1 [0-3], P = 0.002), and developed more complications (32/113 [28%] vs 2/30 [7%] patients, P = 0.014) compared with those with acute neuropathic pain, respectively. CONCLUSIONS: Burn patients who progressed from having acute to CNP had significantly greater percent total body surface area burns, had more full-thickness burns, had surgery, had more surgical procedures, and developed more complications compared with burn patients with only acute pain.

New bracketing luminescence ages constrain the Sima de los Huesos hominin fossils (Atapuerca, Spain) to MIS 12.

Recent chronological studies of the Sima de los Huesos (SH) hominin fossil site, Atapuerca, Spain, have established a close minimum age of at least 430 ka for sedimentary material immediately overlying the human remains. However, a firm maximum age limit still needs to be established for the SH fossils in order to better constrain the timing for the onset of Neandertal speciation. In the present study, we address this important chronological gap at SH by providing direct ages for the sediment deposits that host, and immediately underlie, the hominin fossils. Depositional ages were obtained using single-grain thermally-transferred optically stimulated luminescence (TT-OSL), a technique that has yielded reliable 'extended-range' luminescence chronologies at several independently dated Atapuerca sites. Four single-grain TT-OSL depositional ages of 453 ± 56 ka, 437 ± 38 ka, 457 ± 41 ka and 460 ± 39 ka were obtained for the red clay lithostratigraphic units (LU-5 and LU-6) found underlying and encasing the SH hominin bones. A Bayesian age-depth model was constructed using previously published chronologies, as well as the new single-grain TT-OSL ages for LU-5 and LU-6, in order to derive combined age estimates for individual lithostratigraphic units preserved at SH. The combined modeled ranges reveal that the hominin-bearing layer (LU-6) was deposited between 455 ± 17 ka and 440 ± 15 ka (mean lower and upper boundary 68.2% probability range ± 1σ uncertainty, respectively), with a mean age of 448 ± 15 ka. These new bracketing ages suggest that the hominin fossils at SH were most likely deposited within Marine Isotope Stage (MIS) 12, enabling more precise temporal constraint on the early evolution of the Neandertal lineage. The SH fossils represent the oldest reliably dated hominin remains displaying Neandertal features across Eurasia. These Neandertal features are first observed in the facial skeleton, including the mandible and teeth, as well as the temporomandibular joint, and appear consistently across the SH collection. Our chronological findings suggest that the appearance of these Neandertal traits may have been associated with the climatic demise of MIS 12 and the ecological changes that occurred in Iberia during this period. Other Middle Pleistocene hominin fossils from Europe dated to MIS 12-11, or later, show different morphological trends, with some lacking Neandertal specializations. The latest SH dating results enable improved temporal correlations with these contrasting hominin records from Europe, and suggest a complex picture for hominin evolution during the Middle Pleistocene.

Somewhere beyond the sea: Human cranial remains from the Lesser Sunda Islands (Alor Island, Indonesia) provide insights on Late Pleistocene peopling of Island Southeast Asia.

The migration of anatomically modern humans (AMH) from Africa to every inhabitable continent included their dispersal through Island Southeast Asia (ISEA) to Australia. Significantly, this involved overwater dispersal through the Lesser Sunda Islands between Sunda (continental Southeast Asia) and Sahul (Australia and New Guinea). However, the timing and direction of this movement is still debated. Here, we report on human skeletal material recovered from excavations at two rockshelters, known locally as Tron Bon Lei, on Alor Island, Indonesia. The remains, dated to the Late Pleistocene, are the first anatomically modern human remains recovered in Wallacea dated to this period and are associated with cultural material demonstrating intentional burial. The human remains from Tron Bon Lei represent a population osteometrically distinct from Late Pleistocene Sunda and Sahul AMH. Instead, morphometrically, they appear more similar to Holocene populations in the Lesser Sundas. Thus, they may represent the remains of a population originally from Sunda whose Lesser Sunda Island descendants survived into the Holocene.

A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human ß-Tryptase.

ß-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC50 at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.

Nikolaus Rüdinger (1832-1896), His Description of Joint Innervation in 1857, and the History of Surgical Joint Denervation.

BACKGROUND: Selective joint denervation has become a reliable palliative treatment, especially for painful joints in the upper and lower extremity. METHODS: This article highlights the life and work of Nikolaus Rüdinger (1832-1896) who first described joint innervation which became the basis of later techniques of surgical joint denervation. The historical evolution of this method is outlined. RESULTS: Rüdinger made a unique career from apprentice barber to military surgeon and anatomy professor in Munich, Germany. His first description of articular innervation of temporomandibular, shoulder, elbow, wrist, finger, sacroiliac, hip, knee, ankle, foot, and toe joints in 1857 stimulated the subsequent history of surgical joint denervation. Comparing his investigations with modern joint denervation methods, developed by pioneers like Albrecht Wilhelm or A. Lee Dellon, shows his great exactitude and anatomical correspondence despite different current terminology. Clinical series of modern surgical joint denervations reveal success rates of up to 80% with reliable long-term results. CONCLUSION: The history of joint denervation with Rüdinger as its important protagonist offers inspiring insights into the evolution of surgical techniques and exemplifies the value of descriptive functional anatomy, even if surgical application may not have been realized until a century later.

Sciatic and peroneal nerve injuries after endovascular ablation of lower extremity varicosities: case reports and review of the literature.

Varicose veins have traditionally been treated by surgical intervention. When performed in the lower limb, surgical vein stripping can potentially cause injury to the saphenous, sural, tibial, and peroneal nerves due to anatomic proximity. Newer, minimally invasive procedures, such as endovenous laser ablation and endovenous radiofrequency ablation, are more commonly used today. Although the potential for neural injury is greatly reduced, endovenous laser ablation and endovenous radiofrequency ablation have been documented to cause neural damage. Here, we report rare complications of 2 cases of varicosity endovascular ablation. One case involves ablation of the lesser saphenous vein and resulted in injury to the proximal common peroneal and tibial as well as distal sciatic nerves. The second case involves ablation of the vein of Giacomini that resulted in a common peroneal nerve injury. We stress the importance of preoperative anatomic mapping of the highly variable venous and neural systems in the area of ablation to minimize neural complications.

Posttraumatic Midface Pain: Clinical Significance of the Anterior Superior Alveolar Nerve and Canalis Sinuosus.

BACKGROUND: Posttraumatic midface pain secondary to injury of the anterior superior alveolar nerve (ASAN) is characterized as pain localized to the central and lateral incisors, canines, and maxilla. This nerve is susceptible to injury and subsequent formation of neuromas after midface trauma. Surgical intervention requires an accurate and precise understanding of the course of the ASAN. METHODS: Dissections of 12 human cadaver heads were conducted to identify the course of the ASAN through the canalis sinuosus (CS). Fifty 1-mm slice face computed tomographic scans were evaluated to document the dimensions and course of the CS. RESULTS: The ASAN branched laterally from the infraorbital nerve before reaching the infraorbital rim in all cadavers. The bifurcation occurred 18 mm posterior to the infraorbital rim (range, 10-30 mm). At a point 25 mm inferior to the infraorbital rim, the ASAN is found 3.4 mm lateral to the piriform aperture (range, 3-4 mm). Radiographic analysis demonstrated a 12.9-mm horizontal length of the CS across the anterior maxilla (SD, 2.2 mm), a distance of 4.8 mm between the piriform aperture and the CS (SD, 1.2 mm), and 11.7 mm vertical length of the CS along the piriform aperture (SD, 3.0 mm). CONCLUSIONS: The ASAN maintains consistent coordinates at specific points along its course through the midface. An improved understanding of the course of the ASAN will guide future diagnosis of injury to this nerve and surgical intervention for patients with posttraumatic midface pain secondary to ASAN injury.

Luminescence dating and palaeomagnetic age constraint on hominins from Sima de los Huesos, Atapuerca, Spain.

Establishing a reliable chronology on the extensive hominin remains at Sima de los Huesos is critical for an improved understanding of the complex evolutionary histories and phylogenetic relationships of the European Middle Pleistocene hominin record. In this study, we use a combination of 'extended-range' luminescence dating techniques and palaeomagnetism to provide new age constraint on sedimentary infills that are unambiguously associated with the Sima fossil assemblage. Post-infrared-infrared stimulated luminescence (pIR-IR) dating of K-feldspars and thermally transferred optically stimulated luminescence (TT-OSL) dating of individual quartz grains provide weighted mean ages of 433 ± 15 ka (thousands of years) and 416 ± 19 ka, respectively, for allochthonous sedimentary horizons overlying the hominin-bearing clay breccia. The six replicate luminescence ages obtained for this deposit are reproducible and provide a combined minimum age estimate of 427 ± 12 ka for the underlying hominin fossils. Palaeomagnetic directions for the luminescence dated sediment horizon and underlying fossiliferous clays display exclusively normal polarities. These findings are consistent with the luminescence dating results and confirm that the hominin fossil horizon accumulated during the Brunhes Chron, i.e., within the last 780 ka. The new bracketing age constraint for the Sima hominins is in broad agreement with radiometrically dated Homo heidelbergensis fossil sites, such as Mauer and Arago, and suggests that the split of the H. neanderthalensis and H. sapiens lineages took place during the early Middle Pleistocene. More widespread numerical dating of key Early and Middle Pleistocene fossil sites across Europe is needed to test and refine competing models of hominin evolution. The new luminescence chronologies presented in this study demonstrate the versatility of TT-OSL and pIR-IR techniques and the potential role they could play in helping to refine evolutionary histories over Middle Pleistocene timescales.

Archaeological evidence of an ethnographically documented Australian Aboriginal ritual dated to the last ice age.

In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of GunaiKurnai Aboriginal Elders, we undertook archaeological excavations at Cloggs Cave in the foothills of the Australian Alps. In GunaiKurnai Country, caves were not used as residential places during the early colonial period (mid-nineteenth century CE), but as secluded retreats for the performance of rituals by Aboriginal medicine men and women known as 'mulla-mullung', as documented by ethnographers. Here we report the discovery of buried 11,000- and 12,000-year-old miniature fireplaces with protruding trimmed wooden artefacts made of Casuarina wood smeared with animal or human fat, matching the configuration and contents of GunaiKurnai ritual installations described in nineteenth-century ethnography. These findings represent 500 generations of cultural transmission of an ethnographically documented ritual practice that dates back to the end of the last ice age and that contains Australia's oldest known wooden artefacts.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.